bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–02–15
79 papers selected by
Cédric Chaveroux, CNRS
  1. Circularization and Ribosome Recycling: From Polysome Topology to Translational Control.
  2. Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.
  3. Synthetic germ granules reveal a direct role of Vasa/DDX4 in RNA localization and translational activation.
  4. Deciphering mRNA Translation During Sperm Capacitation: A New Frontier in Fertility Research.
  5. Hidden in plain sight: illuminating the tRNA landscape by sequencing.
  6. DEAH-Box RNA Helicases in the Spliceosome: Advances in Structure and Function.
  7. Active transport of tRNAs facilitates distributed protein synthesis.
  8. P-bodies act as dynamic control hubs for RNA processing and storage.
  9. m6A RNA modification and myeloid-derived suppressor cells: mechanistic insights and clinical prospects.
  10. tRF-3021a, a tRNA-Ala-TGC derived 3' fragment, promotes glioblastoma cell invasion, suppresses apoptosis, and is required for normal levels of protein synthesis.
  11. Labeling of nascent RNA in the C. elegans intestine.
  12. YTHDF3 at the crossroads of the Epitranscriptome: Structure, networks, and disease roles.
  13. Emerging roles of RNA m6A modification in multiple myeloma pathogenesis and treatment resistance (Review).
  14. Spatial mapping of RNA turnover kinetics and regulatory landscapes of mRNA stability in the mammalian brain.
  15. LncRNA SNHG3: a potential biomarker for human diseases.
  16. Systematic Identification of Germ Granule Proteins Reveals Specialized Roles in RNAi and Small RNA Inheritance.
  17. Antagonism of RNA silencing in the yellow fever mosquito, Aedes aegypti, by the nsP2 protein of the prototype alphavirus.
  18. Ubiquitous low-energy RNA fluctuations and energetic coupling measured by chemical probing.
  19. Modeling binding of the conserved Csr/Rsm protein family across species of the γ-proteobacteria reveals niche-specific adaptation of the post-transcriptional regulon.
  20. LncRNAs in Ovarian Cancer: Emerging Insights and Future Perspectives in Tumor Biology and Clinical Applications.
  21. lncRNA FENDRR as a Prognostic Biomarker and Regulator of Bladder Cancer Progression via the miR-18a-5p/ESR1 Axis.
  22. The Chromaverse Is Colored by Triplexes Formed Through the Interactions of Noncoding RNAs with HNPRNPU, TP53, AGO, REL Proteins, Intrinsically-Disordered Regions, and Flipons.
  23. Epitranscriptomic Regulation of Platinum Resistance via the METTL3-ADAM23 Axis in Ovarian Cancer.
  24. OsFKBP20-1b stabilizes OsUPF1 and OsUPF2 to promote the degradation of aberrant mRNAs during dehydration stress.
  25. Engineered Allosteric RNA Editors Enable Compact, Stimulus-Responsive Post-Transcriptional Circuits.
  26. NCBP1 stress signaling drives alternative S6K1 splicing inhibiting translation.
  27. The WT 1-AS/miR-206 axis regulates the proliferation and migration of breast cancer through the cuproptosis related gene BCL11A.
  28. Mechanisms and disease relevance of mitochondrial translation in humans.
  29. LncRNA CCAT2 role in female-related cancer progression and diagnosis: a comprehensive review.
  30. Research progress on long non‑coding RNAs in lung cancer (Review).
  31. Genome-wide identification and expression analysis of YTH gene family in barley reveals their potential role under abiotic stresses.
  32. A platform for analyzing translational control by RBPs at single-mRNA resolution in cells.
  33. Hidden-break diversity in pancrustacean rRNA profiles.
  34. Programmable artificial RNA condensates in mammalian cells.
  35. Impact of mRNA and protein isoforms in lipoprotein metabolism and how to modulate them.
  36. Long non-coding RNAs as key regulators in sepsis: from immune response to organ dysfunction.
  37. The Multi-Target lncRNA-miRNA-mRNA TRIAD in Pancreatic Cancer Diagnosis and Therapy.
  38. Splicing Factor 3a Subunit 1 Promotes Colorectal Cancer Growth via Anti-Apoptotic Effects of Syntaxin12.
  39. Progress in RNA-Targeted Therapeutics for Human Diseases.
  40. Integrated WGCNA of lncRNA-mRNA Networks Identifies Novel Hub Genes and Potential Therapeutic Agents for Liver Cirrhosis via Molecular Docking Validation.
  41. A gene-specific RNA enrichment protocol for nanopore direct-RNA sequencing.
  42. Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation.
  43. Expression of nano-engineered RNA organelles in bacteria.
  44. Natural language-based representation and modeling of RBP binding.
  45. Review: Specificity determinants of the plant splicing code.
  46. Amplified MS2 labeling reveals heterogeneous dynamics of RNA granules in the live murine brain.
  47. FTO-Mediated m6A Demethylation of SERPINF1 Attenuates Multiple Myeloma Progression via the Wnt/β-Catenin Pathway.
  48. Concurrent Alterations in DNA Methylation and RNA m6A Methylation During Epigenetic and Transcriptomic Reprogramming Induced by Tail Docking Stress in Fat-Tailed Sheep.
  49. Epitranscriptomic profiling of m5C RNA methylation reveals a dynamic response to TSWV infection in tomato.
  50. Exon skipping as a potential diagnostic biomarker in colorectal cancer: an integrated epigenomic-transcriptomic analysis​.
  51. Potato Virus Y NIb Multifunctional Protein Suppresses Antiviral Defense by Interacting with Several Protein Components of the RNA Silencing Pathway.
  52. Nucleotide-Resolution Mapping Reveals Specific Helicase Binding Site on roX2 lncRNA.
  53. Flexibility and modulation of translation initiation in enterovirus genomes.
  54. A conserved Lsm8-exosome module maintains RNA splicing fidelity to control fungal stress adaptation and virulence.
  55. FTO promotes the cervical cancer progression via regulation of FGF2 expression.
  56. Recruitment of bifunctional regulator thermospermine to methylated ribosomes directs xylem fate.
  57. M6A demethylase FTO in leukemia: Function, molecular mechanisms, and therapeutic implications.
  58. Scaffolding of the H4K5ac chromatin remodeling complex by lncRNA MAHAC mediates epithelial-mesenchymal transition.
  59. RBPscan: A quantitative in vivo tool for profiling RNA-binding protein interactions.
  60. A bicistronic viral genome uses a compact type IV IRES near its 3' end to express a transmembrane protein.
  61. Decoding the MYC locus reveals a druggable ultraconserved RNA element.
  62. Targeted RNA Degradation by RIBOTACs: A Novel Therapeutic Avenue for Ophthalmic Diseases.
  63. NSUN6-mediated m5C RNA methylation aggravate osteosarcoma progression through promoting PKP2 mRNA stability and expression.
  64. [Heterogeneity in the regulation of cellular stress responses by FUS gene mutations associated with amyotrophic lateral sclerosis].
  65. The Emerging Roles of GlycoRNAs in the Pathogenesis of Sepsis.
  66. A dose-dependent switch in translation capacity controls the transcription factor response to H 2 O 2 stress.
  67. Ribosomal RNA synthesis by RNA polymerase I is subject to premature termination of transcription.
  68. Protein-inducible ribosomal frameshifting enables programmable translational control for genetic circuit design in Escherichia coli.
  69. Multi-seed searching algorithm for integrated codon optimization of mRNA stability and translational efficiency in vaccine design.
  70. Farnesyl Diphosphate Synthase Promotes Proliferation of Hepatocellular Carcinoma Cells by Interacting With Glucose-6-Phosphate Dehydrogenase.
  71. Translational control of CAK and Cdk T-loop phosphorylation in response to growth in yeast.
  72. Bioinformatic Prediction of Activation States in Molecular Network Pathways of Eukaryotic Initiation Factor 2 (EIF2) Signaling and Coronavirus Pathogenesis.
  73. Remodelling of P-bodies and the cytoskeleton by Orthohantavirus puumalaense (Puumala virus).
  74. Selection-diversification interplay in oligonucleotide chemical evolution.
  75. RNA Quality Control Enables Antibiotic Tolerance.
  76. Integrative multi-omic profiling of the chronically hypoxic heart: focus on m6A and m6Am epitranscriptomic regulation.
  77. Beyond Neurotrophins: A Proposed Neurotrophic-Epigenetic Axis Mediated by Non-Coding RNA Networks for Hericium erinaceus Bioactives-A Hypothesis-Driven Review.
  78. RMzyme: regulations of RNA-modifying enzymes in humans.
  79. Luteolin use in Integrated Stress Response: insight from a case of EIF2AK2-related dystonia.
  1. Int J Mol Sci. 2026 Jan 27. pii: 1251. [Epub ahead of print]27(3):
    Circularization and Ribosome Recycling: From Polysome Topology to Translational Control.
    Zhanna A Afonina, Konstantin S Vassilenko.
      It has been known for decades that eukaryotic cellular mRNAs are frequently translated by multiple ribosomes organized into polysomes of diverse topology, including circular arrangements. The closed-loop model, in which the 5' cap and 3' poly(A) tail are bridged by initiation factors, provided a mechanistic basis for mRNA circularization and suggested that the spatial proximity of termini facilitates ribosome recycling. Various biochemical, structural, and imaging approaches-including electron microscopy, atomic force microscopy, cryo-electron tomography, and single-molecule fluorescence-have since demonstrated that polysomes indeed adopt compact and heterogeneous conformations, with circular assemblies representing a significant fraction. Although direct visualization of ribosome recycling remains technically challenging, ribosome turnover experiments, kinetic analyses and modeling support the concept of closed-loop-assisted reinitiation (CLAR), whereby terminating ribosomes are re-utilized to sustain translation efficiency. Together, the findings suggest that mRNA circularization is a dynamic and regulated state that enhances protein synthesis under specific conditions, while linear or modular polysome architectures may dominate in others. Understanding the balance between these modes of translation remains central to elucidating the interplay between mRNA topology, ribosome dynamics, and translational control.
    Keywords:  eukaryotic translation; mRNA cyclization; polysome; ribosome recycling; translation reinitiation
    DOI:  https://doi.org/10.3390/ijms27031251
  2. RNA. 2026 Feb 08. pii: rna.080883.125. [Epub ahead of print]
    Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.
    Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Translation elongation defects cause ribosome stalling and activate the integrated stress response (ISR). During the ISR, translation initiation suppression and ribosome runoff drive mRNA condensation into stress granules. However, the effects of partial translation elongation inhibition on stress granules are poorly defined. We demonstrate that intermediate levels of tRNA synthetase inhibitors activate the ISR and cause assembly of stress granules in a parabolic dose-response pattern. These stress granules are limited in size and number due to ribosome association with mRNAs. Assembly of stress granules by intermediate levels of the prolyl-tRNA synthetase inhibitor halofuginone requires the canonical stress granule scaffolding proteins G3BP1/2 and GCN2-mediated ISR activation. We performed a candidate-based comparative analysis of the composition of stress granules induced by intermediate levels of halofuginone or canonical stressors arsenite or thapsigargin. The stress granules induced by halofuginone, arsenite, or thapsigargin harbor polyadenylated RNA and the canonical stress granule proteins PABPC1, G3BP1, and UBAP2L. We observe stress- and transcript- specific differences in the localization of candidate RNA molecules to stress granules. These results demonstrate that partial translation elongation inhibition permits stress granule assembly through the balance of ISR activation and mRNA association with ribosomes, with implications for the stress response associated with amino acid or tRNA deficiency, therapeutic tRNA synthetase inhibition, or diseases associated with tRNA synthetase mutations.
    Keywords:  integrated stress response; stress granules; tRNA synthetase; translation; translation elongation
    DOI:  https://doi.org/10.1261/rna.080883.125
  3. bioRxiv. 2026 Feb 03. pii: 2026.02.01.703065. [Epub ahead of print]
    Synthetic germ granules reveal a direct role of Vasa/DDX4 in RNA localization and translational activation.
    Ruoyu Chen, Henoc Zinga, Jay S Goodman, Ruth Lehmann.
      Cytoplasmic RNA granules, including stress granules, P bodies, neuronal RNA granules, and germ granules, are essential for RNA storage and regulation across a wide range of organisms. However, dissecting the contributions of individual factors to granule function is challenging because of the interdependence of components in vivo . This is especially true for DEAD-box helicases, common regulators of mRNA granules, whose specific contributions remain unclear. In this study, we developed a synthetic approach to de novo generate germ granules, enabling us to identify the minimal machinery needed for RNA localization and translational activation. Using a self-assembling PopTag-based scaffold derived from Caulobacter fused to the RNA-binding domain (RBD) of the germplasm organizer Oskar, we found that the recruitment of endogenous germ granule mRNAs ( nanos and pgc ) depended on the DDX4 protein Vasa. By employing orthogonal RNA tethering approaches, we demonstrate that Vasa is both necessary and sufficient for localized mRNA translation. Consistent with these findings, acute depletion of Vasa from endogenous germ granules specifically reduced Nanos translation without affecting mRNA localization, confirming Vasa as a core factor linking RNA recruitment to localized translational activation. These in vivo reconstitution experiments reveal a two-component module in which a scaffold RBD and the Vasa helicase, but not other DEAD-box helicases, enable RNP condensates to accumulate specific RNAs and promote their translation. Overall, our study uncovers previously unrecognized functions of an RNA helicase within ribonucleoprotein condensates and demonstrates the power of synthetic biology to analyze complex biomolecular condensates in living organisms.
    DOI:  https://doi.org/10.64898/2026.02.01.703065
  4. Mol Reprod Dev. 2026 Feb;93(2): e70086
    Deciphering mRNA Translation During Sperm Capacitation: A New Frontier in Fertility Research.
    Saurabh Tiwari, Nehal Thakor, Jacob Thundathil.
      Male infertility accounts for approximately 50% of infertility cases, with nearly 30% remaining unexplained after standard evaluations. This highlights the need for a better understanding of sperm function to advance diagnostic and therapeutic strategies. Sperm were long considered translationally quiescent; however, emerging evidence suggests that sperm translate messenger RNAs (mRNAs) to synthesize proteins crucial for sperm functions. However, mRNA translation during capacitation remains poorly understood, despite its potential importance for fertility diagnostics. RNA-binding proteins (RBPs), small noncoding RNAs (sncRNAs), and epitranscriptomic marks regulate mRNA stability, localization, and translation initiation, modulating gene expression across reproductive tissues. Ejaculated sperm harbor initiation and elongation factors, ribosomal proteins, and other translation components, such as RBPs. Several cytoskeletal proteins and metabolic enzymes exhibit mRNA-binding activity, with the interaction of some RBPs modulated by phosphorylation during capacitation. Sperm RNA is abundant in sncRNAs, whose altered profile has been implicated in various forms of male infertility. Understanding the interplay among RBPs, the epitranscriptome, and sncRNAs could reveal mechanisms underlying sperm function and identify molecular biomarkers for infertility diagnosis. Disruptions in RNA-protein interactions may underlie idiopathic infertility, presenting opportunities for therapeutic intervention. This review highlights emerging research on sperm mRNA translation as a promising avenue for improving fertility diagnosis and treatment.
    Keywords:  RNA‐binding proteins; capacitation; epitranscriptomics; fertility; mRNA translation; posttranslational modifications; spermatozoa
    DOI:  https://doi.org/10.1002/mrd.70086
  5. Genome Biol. 2026 Feb 13.
    Hidden in plain sight: illuminating the tRNA landscape by sequencing.
    Katherine Marlow, Zhangli Su.
      Transfer RNAs (tRNAs) are essential for decoding mRNAs into proteins and are increasingly recognized as dynamic regulators of gene expression. Their function is shaped by intricate layers of post-transcriptional processing, modification, aminoacylation, and fragmentation, all of which have been implicated in human disease. Recent advances in high-throughput sequencing have transformed our ability to profile tRNAs and their associated modifications, uncovering their roles in cancer, neuronal function, immune response, and stress response. In this review, we summarize emerging tRNA sequencing technologies and highlight how these approaches reveal fundamental insights into tRNA regulation and its therapeutic potential.
    Keywords:  Genomics; Nanopore; RNA modification; TRNA; TRNA-derived fragments; Translation
    DOI:  https://doi.org/10.1186/s13059-026-03995-2
  6. FASEB J. 2026 Feb 28. 40(4): e71588
    DEAH-Box RNA Helicases in the Spliceosome: Advances in Structure and Function.
    Zhe Chen.
      Pre-mRNA splicing is orchestrated by the spliceosome through coordinated RNA and protein rearrangements driven by ATP-dependent RNA helicases. DEAH-box helicases serve as principal motors, controlling catalytic activation, exon ligation, and complex disassembly. Early mechanistic understanding was limited by low-resolution cryo-electron microscopy (cryo-EM) structures, leaving RNA substrate interactions largely inferred from biochemical and genetic studies. Recent high-resolution cryo-EM structures (2021-present) have captured all five spliceosomal DEAH-box helicases-DHX16/Prp2, DHX38/Prp16, DHX8/Prp22, DHX15/Prp43, and DHX35-bound to their RNA targets within distinct spliceosomal states. These structures reveal precise recruitment, substrate recognition, and stage-specific actions. In this review, I integrate these insights into a unified framework, highlighting structural, biochemical, and evolutionary perspectives to guide future investigations of helicase regulation and their role in maintaining the fidelity of eukaryotic RNA splicing.
    Keywords:  DEAH‐box RNA helicases; DHX15/Prp43; DHX16/Prp2; DHX35; DHX38/Prp16; DHX8/Prp22; spliceosome
    DOI:  https://doi.org/10.1096/fj.202503744R
  7. bioRxiv. 2026 Jan 27. pii: 2026.01.26.698744. [Epub ahead of print]
    Active transport of tRNAs facilitates distributed protein synthesis.
    Jennifer Morgan Petrosino, Vasiliki Courelli, Keita Uchida, Charles Bond, Barry Cooperman, Alexey I Bogush, Melike Lakadamyali, Benjamin L Prosser.
      Terminally differentiated cells such as cardiomyocytes, skeletal myofibers, and neurons rely on localized protein synthesis to sustain size, remodel and adapt to stress. The subcellular architecture of these cells is also inherently unfavorable for long-range, diffusion-based transport, which may promote their heavy reliance on active transport mechanisms for the localization of RNA and proteins. Transfer RNAs (tRNAs) function as essential regulators of protein synthesis by linking transcription and translation. Since their discovery in the 1950s, tRNA subcellular distribution has been assumed to occur through passive diffusion. Here, we report that there are pools of tRNAs that depend on the microtubule network for distribution in cardiomyocytes, skeletal myofibers and neurons. Employing dual-color live and fixed-cell super-resolution imaging, we demonstrate that active transport of tRNAs involves hitchhiking on the exterior of endolysosomal vesicles (ELV). We establish that leucyl-tRNA synthetase (LeuRS), the tRNA-binding protein that charges leucine to its cognate tRNA and interacts with Rag GTP on the surface of ELVs, is essential for tRNA transport. Disruption of LeuRS-ELV interactions is sufficient to impair long-range, microtubule-dependent tRNA transport, without affecting mRNA or rRNA transport. We also show that preventing tRNA transport is sufficient to impair translation at sites distal from the nucleus as well as globally impair protein synthesis, ultimately reducing cell size. These findings redefine tRNAs as actively trafficked cargo and establish their directed transport as a fundamental layer of translation regulation required for myocyte homeostasis.
    DOI:  https://doi.org/10.64898/2026.01.26.698744
  8. J Biol Chem. 2026 Feb 10. pii: S0021-9258(26)00143-2. [Epub ahead of print] 111273
    P-bodies act as dynamic control hubs for RNA processing and storage.
    Matthew Wenjie Feng, Amir Mossanen-Parsi, Viktoras Stonys, Simon J Hubbard, Mark P Ashe, Chris M Grant.
      Processing bodies (PBs) are cytoplasmic granules that function in the cellular response to stress conditions by regulating mRNA metabolism. Initially, they were thought to represent sites of mRNA turnover, whereas more recent work points to a role in the storage of useful mRNAs. However, their exact intracellular role remains unclear. We used SH-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) to study PB-localisation and global mRNA fate during glucose depletion conditions that induce PB formation in yeast. This enabled us to differentiate newly synthesized and pre-existing RNAs and to separately track mRNA synthesis and degradation. We show that pre-existing mRNAs localise to PBs with differing kinetics with some transcripts localising over the time-course of glucose starvation and some transcripts localising in a more dynamic manner. We identified a small number of transcripts that are enriched only transiently in PBs, consistent with the traditional view of PBs acting as sites for RNA decay. However, most transiently localised transcripts are not destabilized following glucose starvation, with PBs appearing to act as temporary storage sites for transcripts that later undergo alternative fates. For other transcripts, both their pre-existing and newly made transcripts accumulate in PBs over the time-course of glucose depletion and we suggest that these transcripts are important for adaptation once the nutrient stress is relieved. Together, our data indicate a model where transcripts partition into different classes that behave differently following nutrient depletion with PBs acting as triage sites for mRNAs to direct their fate.
    Keywords:  RNA decay; RNA storage; glucose starvation; processing body (P‐body); translation; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2026.111273
  9. Front Immunol. 2026 ;17 1694842
    m6A RNA modification and myeloid-derived suppressor cells: mechanistic insights and clinical prospects.
    Chunhong Li, Xiulin Jiang, Yixiao Yuan, Xi Chen, Shanrui Pu, Kun Lian, Lihua Li, Qiang Wang.
      N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in eukaryotic mRNA, extensively involved in RNA splicing, export, stability, and translation. In recent years, accumulating evidence has demonstrated that m6A modification plays a critical role in regulating the differentiation and function of immune cells. Among these, myeloid-derived suppressor cells (MDSCs), as a key immunosuppressive population within the tumor microenvironment (TME), accelerate tumor progression by inhibiting T cell activity and promoting immune evasion and therapy resistance. Emerging studies indicate that m6A modification modulates the development, accumulation, and immunosuppressive function of MDSCs, thereby contributing to tumor initiation and progression. This review provides a narrative overview of the current evidence regarding the crosstalk between m6A modification and MDSCs, with a focus on the underlying molecular mechanisms and their potential implications for cancer immunotherapy. Furthermore, we discuss future research directions and the challenges associated with clinical translation.
    Keywords:  MDSC; epitranscriptome; immunotherapy; m6A modification; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1694842
  10. bioRxiv. 2026 Jan 28. pii: 2026.01.26.701835. [Epub ahead of print]
    tRF-3021a, a tRNA-Ala-TGC derived 3' fragment, promotes glioblastoma cell invasion, suppresses apoptosis, and is required for normal levels of protein synthesis.
    Esmaeili Fatemeh, Kumarjeet Bannerjee, Ajay Chatrath, Divya Sahu, Yoshiyuki Shibata, Shekhar Saha, Pankaj Kumar, Zhangli Su, Anindya Dutta.
      tRNA-derived fragments (tRFs) are relatively recently discovered class of small RNAs implicated in gene-regulatory processes in diverse biological contexts but there have been very few reports of a clear phenotypic role of these small RNAs in cancer progression. By analyzing small RNA-seq data from The Cancer Genome Atlas (TCGA), we found that high expression of three 3' tRFs (tRF-3a), tRF-3009a, tRF-3021a or tRF-3030a, is significantly associated with poor overall survival in low-grade glioma (LGG). In glioblastoma cells, tRF-3009a, tRF-3021a and tRF-3030a enhance cell invasion and migration but tRF-3021a was uniquely required for cell proliferation and suppression of apoptosis. Interestingly, tRF-3021a knockdown decreases global protein synthesis prior to and independent of apoptosis. These data indicate that tRF-3021a supports glioma cell survival and particularly protein synthesis while promoting cellular invasion and migration. Given its association with poor outcome in LGG patients, tRF-3021a represents a promising biomarker and potential therapeutic target in gliomas and these results provide a foundation for future studies to define its molecular interactors and downstream pathways controlling protein synthesis and apoptosis in cancer cells.
    Implication: tRF-3021a promotes malignant glioma phenotypes, sustains global protein synthesis and prevents spontaneous apoptosis, motivating efforts to evaluate it as a biomarker and therapeutic target.
    DOI:  https://doi.org/10.64898/2026.01.26.701835
  11. PLoS One. 2026 ;21(2): e0341598
    Labeling of nascent RNA in the C. elegans intestine.
    Omid Gholamalamdari, Stephanie C Weber.
      Transcriptional regulation in C. elegans has been difficult to study at the level of nascent RNA because nucleotide analogs do not readily penetrate the cuticle. Here, we establish an ex vivo 5-ethynyl uridine (EU)-click labeling protocol that enables sensitive microscopy detection of newly transcribed RNA in dissected intestines. Using worms expressing fluorescent nucleolar markers, we show that EU incorporation faithfully reports on nascent transcription in both the nucleoplasm (mRNA) and the nucleolus (rRNA) and is abolished by inhibition of RNA polymerases. Spatial analysis further reveals that the majority of nascent rRNA transcripts localize to the fibrillar zone (FZ) of intestinal nucleoli, consistent with the conserved role of this compartment in rRNA synthesis. In addition to imaging applications, this workflow can be adapted for gene expression assays, providing a versatile approach for quantitative analysis of nascent transcription in C. elegans. By enabling direct visualization of nucleolar transcription in intact intestine tissue, this method opens new opportunities to investigate how nucleolar activity is regulated across development, aging, and disease contexts.
    DOI:  https://doi.org/10.1371/journal.pone.0341598
  12. Cell Signal. 2026 Jan;pii: S0898-6568(25)00603-5. [Epub ahead of print]137 112188
    YTHDF3 at the crossroads of the Epitranscriptome: Structure, networks, and disease roles.
    Kai Yu, Jiazhu Sun, Yuchen Shi, Jiawei Zhang, Ben Liu.
      N6-methyladenosine (m6A) is the predominant internal RNA modification that programs RNA splicing, stability, translation, and decay through writer, eraser, and reader proteins. Among readers, YTHDF3 has emerged as a pleiotropic and context-dependent effector. It enhances translation, promotes decay, or stabilizes transcripts-often in concert with YTHDF1/2-and its activities are further tuned by liquid-liquid phase separation and post-translational modifications. Physiologically, YTHDF3 regulates stem-cell fate, neuronal plasticity, and antiviral immunity. In cancer, it exerts dual actions by reinforcing oncogenic and metabolic pathways in many settings, yet restraining tumor growth or immune evasion in others. YTHDF3 also shapes responses to targeted therapy, chemotherapy, and immunotherapy. This review synthesizes the biochemical underpinnings, network positioning, and functional spectrum of YTHDF3, and outlines opportunities for context-specific therapeutic intervention within the epitranscriptomic landscape.
    Keywords:  RNA modifications; YTHDF3; cancer; m(6)A modification
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112188
  13. Int J Oncol. 2026 Apr;pii: 40. [Epub ahead of print]68(4):
    Emerging roles of RNA m6A modification in multiple myeloma pathogenesis and treatment resistance (Review).
    Yasen Maimaitiyiming, Shuoyang Hu, Die Bai, Yingchao Guan, Na Bu, Wenhui Hao, Mayila Maimaiti.
      Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of plasma cells in the bone marrow. Despite advances in therapeutic agents, including proteasome inhibitors, immunomodulatory drugs and immunotherapies, relapse driven by treatment resistance remains a major clinical challenge. This underscores the critical need to elucidate additional molecular mechanisms that drive MM pathogenesis and therapeutic failure. The emerging field of epitranscriptomics, which studies post‑transcriptional RNA modifications, offers a promising perspective. Among these modifications, N6‑methyladenosine (m6A), the most abundant internal mRNA modification, has been implicated in regulating nearly every aspect of RNA metabolism. Growing evidence indicates that dysregulation of the m6A modification machinery plays a pivotal role in MM heterogeneity, disease progression and drug resistance. The present review synthesized current knowledge on how specific m6A regulators contribute to MM oncogenesis by modulating key signaling pathways, interactions with the bone marrow microenvironment and responses to therapy. It also discussed the potential of targeting m6A pathways as a therapeutic strategy to overcome treatment resistance and improve patient outcomes. By highlighting recent advances and future directions, the present review underscored m6A modification as an important frontier in the battle against MM.
    Keywords:  N6‑methyladenosine; biomarkers; multiple myeloma; targeted therapy; treatment resistance
    DOI:  https://doi.org/10.3892/ijo.2026.5853
  14. bioRxiv. 2026 Jan 29. pii: 2026.01.29.702431. [Epub ahead of print]
    Spatial mapping of RNA turnover kinetics and regulatory landscapes of mRNA stability in the mammalian brain.
    Qi Qiu, Hongjie Zhang, Zijie Xia, William Gao, Julie Leu, Dongming Liang, Ying Li, Yijing Su, Emily Feierman, Erin Van Horn, Guo-Li Ming, Erica Korb, Hongjun Song, Zhaolan Zhou, Hao Wu.
      Spatial and activity-dependent gene regulation in the mammalian brain requires coordinated control of RNA synthesis and degradation 1,2 , yet spatially resolved measurement of RNA turnover kinetics in complex tissues remains technically challenging 3 . Here, we present spatial NT-seq , an approach that integrates transgenesis-free metabolic RNA labeling with in situ chemical recoding to spatially co-map RNA abundance and turnover kinetics in the mouse brain. By distinguishing newly synthesized from pre-existing RNAs, this method reveals spatially resolved transcriptional and post-transcriptional responses to electroconvulsive stimulation (ECS), a treatment for refractory depression. We uncover pronounced spatial heterogeneity in RNA turnover, with the dentate gyrus (DG) exhibiting elevated basal RNA turnover and robust ECS-induced responses. These findings reveal a "kinetics scaling" mechanism of coordinated regulation of RNA synthesis and decay, by which DG cells can rapidly remodel their transcript pools in responses to external stimuli or differentiation signals 4,5 . Machine learning applied to in vivo RNA kinetics landscapes further identifies sequence features and post-transcriptional regulators underlying region-and cell-type-specific control of mRNA stability. Together, this integrated experimental and computational framework, in vivo Timescope , enables transcriptome-wide mapping of RNA turnover kinetics and the regulatory architecture of RNA stability across spatial and cellular contexts, providing new insights into the spatiotemporal regulation of RNA dynamics in brain function and disease.
    DOI:  https://doi.org/10.64898/2026.01.29.702431
  15. Front Cell Dev Biol. 2026 ;14 1720402
    LncRNA SNHG3: a potential biomarker for human diseases.
    Fu-Jia Ren, Xiao-Yu Cai, Yao Yao, Guo-Ying Fang.
      With advancements in high-throughput sequencing and molecular biology technologies, the emerging significance of long non-coding RNAs (lncRNAs) in pathological conditions has been progressively unveiled. SNHG3, a member of the small nuclear RNA host gene (SNHG) family, is localized in both the nucleus and cytoplasm, and plays a pivotal role in multiple aspects of RNA metabolism, including transcription, splicing, translation and stability. Accumulating evidence indicates that SNHG3 is implicated in various human diseases, with a predominant focus on its oncogenic functions in different malignancies. Mechanistically, SNHG3 exerts its pathological functions by acting as a miRNA sponge, co-transcription factor or repressor, and stabilizer for oncogenic transcripts. Recent studies have further uncovered the essential role of SNHG3 in neurological disorders, such as brain injury, spinal cord injury, and drug-induced nerve injury. In this review, we comprehensively summarize the involvement of SNHG3 in various human diseases, and highlight its dual potential as a diagnostic and prognostic biomarker. Furthermore, we elucidate the regulatory mechanisms by which SNHG3 influences multiple RNA metabolism processes in related pathological processes, and propose its potential role in alternative splicing and the formation of cytoplasmic or nucleic ribonucleoprotein (RNP) granules.
    Keywords:  RNA metabolism; SNHG3; alternative splicing; biomarker; human diseases
    DOI:  https://doi.org/10.3389/fcell.2026.1720402
  16. bioRxiv. 2026 Jan 28. pii: 2026.01.26.701902. [Epub ahead of print]
    Systematic Identification of Germ Granule Proteins Reveals Specialized Roles in RNAi and Small RNA Inheritance.
    Shihui Chen, Lucas H Prescott, Craig C Mello, Carolyn M Phillips.
      Biomolecular condensates, such as germ granules, organize RNAi pathways critical for fertility and genome regulation. Yet, the protein composition and functional contributions of these condensates remain poorly defined. Here, we applied TurboID proximity labeling to the Caenorhabditis elegans germ granule protein SIMR-1, integrating mass spectrometry with genetic screening, CRISPR-based tagging, and small RNA sequencing. This systematic approach identified several previously uncharacterized germ granule proteins that contribute to fertility, germline immortality, exogenous RNAi, and transgenerational inheritance. Small RNA sequencing of 21 mutants revealed broad and class-specific defects in siRNA and miRNA biogenesis, with distinct factors associated with defects in WAGO-class 22G-RNAs, CSR-class 22G-RNAs, or histone-directed small RNAs. Among these, we identified PINT-1, a highly disordered protein that directly interacts with and is recruited to germ granules by the PIWI Argonaute PRG-1. PINT-1 is required for piRNA-dependent and -independent secondary siRNA biogenesis and germline development. Comparative genomics revealed that PINT-1 has co-evolved with PRG-1 across nematodes, with a conserved structured N-terminus and a rapidly diverging repeat-rich intrinsically disordered region. Together, our findings expand the germ granule proteome and reveal how distinct condensate components contribute to specialized functions within the small RNA pathways, while highlighting an evolutionarily co-adapted PIWI interactor critical for siRNA biogenesis.
    DOI:  https://doi.org/10.64898/2026.01.26.701902
  17. Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2521417123
    Antagonism of RNA silencing in the yellow fever mosquito, Aedes aegypti, by the nsP2 protein of the prototype alphavirus.
    Adarsh K Gupta, Michael R Wiley, Kevin M Myles.
      Alphaviruses establish persistent infections in mosquito vectors despite robust antiviral RNA interference (RNAi) pathways, suggesting that they employ mechanisms to counteract host immunity. We demonstrate that the nsP2 protein of Sindbis virus (SINV), the prototype alphavirus, functions as a viral suppressor of RNA silencing in Aedes aegypti mosquitoes. Using a SINV mutant (2V) that prevents cleavage at the nsP2-nsP3 junction, we show that proper proteolytic processing to release mature nsP2 is essential for efficient viral replication in mosquitoes with intact RNAi pathways. Replication defects in the 2V mutant were rescued in Dicer-2 (Dcr-2) null mutant mosquitoes or by expressing the mature nsP2 protein. Biochemical assays revealed that recombinant nsP2 directly binds double-stranded RNA and inhibits Dicer-mediated processing into small interfering RNAs (siRNAs). Furthermore, mosquitoes infected with the 2V mutant exhibited higher ratios of virus-derived siRNAs per viral RNA compared to wild-type infections, confirming that mature nsP2 suppresses the RNAi response. Our findings provide compelling evidence that nsP2 antagonizes RNA silencing in mosquito vectors, representing a critical adaptation that facilitates alphavirus replication.
    Keywords:  Alphavirus; RNA silencing; RNAi; Sindbis; VSR
    DOI:  https://doi.org/10.1073/pnas.2521417123
  18. bioRxiv. 2026 Jan 30. pii: 2026.01.28.702231. [Epub ahead of print]
    Ubiquitous low-energy RNA fluctuations and energetic coupling measured by chemical probing.
    Edric K Choi, Ritwika Bose, David H Mathews, Anthony M Mustoe, Julius B Lucks.
      RNA function is governed by RNA folding, but strategies for measuring RNA folding thermodynamics are limited, and fundamental questions such as the energy of base pair opening remain debated. Here we introduce Probing-Resolved Inference of Molecular Energetics (PRIME) to extract nucleotide-resolution RNA structural energetics from scalable chemical probing experiments. Applying PRIME to diverse RNAs, we find that RNA base pairs and tertiary interactions dynamically open with free energies of 0.5-3 kcal/mol, revealing that RNA nucleotides ubiquitously sample open conformations at biologically accessible energies. PRIME further resolves energetic coupling across RNAs, providing an energetic understanding of RNA structural dynamics and long-range coordination in RNA folding. PRIME represents a widely accessible strategy for interrogating RNA thermodynamics, enabling mechanistic understanding and engineering of RNA biology.
    DOI:  https://doi.org/10.64898/2026.01.28.702231
  19. bioRxiv. 2026 Feb 06. pii: 2026.02.05.704111. [Epub ahead of print]
    Modeling binding of the conserved Csr/Rsm protein family across species of the γ-proteobacteria reveals niche-specific adaptation of the post-transcriptional regulon.
    Alexandra J Lukasiewicz, Lily G Hoefner, Ani Savk, Lydia M Contreras.
      The γ-proteobacteria are an exceptionally diverse bacterial class whose members thrive in environments from deep-sea vents to human intestinal tracts. Rapid gene expression responses mediated by global post-transcriptional regulatory networks like the Csr/Rsm system are critical for bacterial survival in dynamic niches. CsrA/RsmA functions as a global regulatory RNA-binding protein, directly controlling hundreds to thousands of mRNA targets simultaneously across the transcriptome to coordinate systems-level metabolic and behavioral responses. Despite conservation of the CsrA/RsmA regulatory protein across γ-proteobacteria, the genes it regulates in different species remain poorly characterized. We extended a previously developed biophysical model of CsrA/RsmA-RNA binding from Escherichia coli and Pseudomonas aeruginosa to predict regulons across 16 diverse γ-proteobacterial species. While CsrA/RsmA protein structure and RNA-binding motif recognition are highly conserved, predicted target regulons diverge dramatically across species. Pathway enrichment analysis demonstrated both conserved regulation of core metabolic processes and extensive species-specific regulation of niche-adapted functions including virulence, biocontrol, and environmental stress response. Only two gene groups were shared exclusively among non-pathogens, while pathogens showed no exclusively conserved targets, indicating extensive regulon rewiring. These findings demonstrate that post-transcriptional regulatory networks evolve primarily through mutations in RNA targets that create or eliminate regulatory binding sites, rapidly adapting target repertoires to ecological demands while the regulatory protein mechanism remains conserved.
    Importance: The CsrA/RsmA family represents one of the most influential global regulatory RNA-binding proteins in γ-proteobacteria, directly binding and regulating hundreds of mRNA targets to orchestrate systems-scale control over metabolism, virulence, and environmental adaptation, yet how this conserved mechanism adapts across diverse niches remains unclear. By predicting CsrA/RsmA targets across 16 species, we demonstrate that regulatory evolution occurs primarily through changes in targeted genes rather than the regulatory protein itself. This conserved mechanism with flexible targets may represent an efficient evolutionary strategy for optimizing gene expression for specific lifestyles, highlighting the importance of studying regulation beyond model organisms.
    DOI:  https://doi.org/10.64898/2026.02.05.704111
  20. Cancers (Basel). 2026 Feb 01. pii: 484. [Epub ahead of print]18(3):
    LncRNAs in Ovarian Cancer: Emerging Insights and Future Perspectives in Tumor Biology and Clinical Applications.
    Michaela A Boti, Marios A Diamantopoulos, Sevastiana Charalampidou, Andreas Scorilas.
      Background/Objectives: Ovarian cancer (OC) remains one of the most lethal gynecological malignancies, mainly because it is frequently diagnosed at advanced stages due to nonspecific symptoms and the lack of effective screening strategies. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression, and accumulating evidence implicates them in OC initiation, progression, and treatment response. This review aims to comprehensively summarize the molecular mechanisms of lncRNAs in OC, examine their clinical potential as biomarkers, and discuss emerging technologies that are about to advance lncRNA research and therapeutics in OC. Methods: A comprehensive review of published studies investigating lncRNA expression, function, and clinical relevance in OC was conducted. Mechanistic insights were integrated across multiple regulatory levels, including epigenetic, transcriptional, post-transcriptional, and post-translational control. Advances in transcriptomic technologies and RNA-targeting techniques were also examined. Results: LncRNAs influence OC through diverse mechanisms, including chromatin remodeling, transcriptional regulation, RNA splicing, mRNA stability, protein modulation, competing endogenous RNA networks, and nuclear organization. Their dysregulation is linked to tumor progression, metastasis, chemoresistance, and poor patient outcomes. Numerous lncRNAs exhibit diagnostic and prognostic value, underscoring their clinical potential. Advances in long-read sequencing have improved lncRNA annotation and isoform resolution, while CRISPR-Cas13 offers a potential approach for selective RNA-targeted therapy. Conclusions: LncRNAs are critical molecules in OC development and progression, holding potential in advancing OC diagnosis, prognosis, and treatment. Continued integration of functional studies, advanced sequencing technologies, and RNA-targeting approaches can facilitate the clinical translation of lncRNAs for early OC diagnosis and management.
    Keywords:  CRISPR-Cas13; biomarkers; cancer pathogenesis; gene expression regulation; long non-coding RNAs (lncRNAs); long-read sequencing; ovarian cancer; therapeutic targets; therapeutics; third-generation sequencing
    DOI:  https://doi.org/10.3390/cancers18030484
  21. J Environ Pathol Toxicol Oncol. 2026 ;45(1): 1-12
    lncRNA FENDRR as a Prognostic Biomarker and Regulator of Bladder Cancer Progression via the miR-18a-5p/ESR1 Axis.
    Chao Gao, Xiliang Cao, Long Miao, Wei Chen, Jin Wei, Lu Lou.
      Recent research highlights the pivotal function of long non-coding RNAs (lncRNAs) in bladder cancer (BCa) progression, emphasizing the need to understand their functions. The clinical significance and molecular mechanisms of lncRNA FENDRR in BCa needed to be elucidated. The Gene Expression Omnibus (GEO) database for BCa-related lncRNAs was screened. Tumor and para cancerous tissues from 118 patients with BCa were collected. Real-time quantitative polymerase chain reaction assessed FENDRR, microRNA (miR)-18a-5p, and estrogen receptor 1 (ESR1) levels. Kaplan-Meier curves assessed FENDRR's prognostic significance. Cell Counting Kit-8, Transwell, and flow cytometry evaluated cell proliferation, migration, invasion, and apoptosis. Dual-Luciferase Reporter and RNA Immunoprecipitation assays revealed miR-18a-5p targeting of FENDRR and ESR1. FENDRR exhibited differential expression in BCa GEO databases. Notably, FENDRR and ESR1 were downregulated, while miR-18a-5p was upregulated in BCa tissues and cell lines. Low FENDRR expression correlated with poor clinical prognosis. Upregulating FENDRR hindered cell proliferation, migration, and invasion while promoting apoptosis; however, miR-18a-5p reversed this suppression. Mechanistically, miR-18a-5p directly targets both FENDRR and ESR1. Our study reveals that low FENDRR expression is a poor prognostic indicator in BCa. FENDRR inhibits miR-18a-5p to upregulate ESR1 and hinder cancer progression, suggesting potential therapeutic targets.
    DOI:  https://doi.org/10.1615/JEnvironPatholToxicolOncol.2025056717
  22. Int J Mol Sci. 2026 Feb 02. pii: 1482. [Epub ahead of print]27(3):
    The Chromaverse Is Colored by Triplexes Formed Through the Interactions of Noncoding RNAs with HNPRNPU, TP53, AGO, REL Proteins, Intrinsically-Disordered Regions, and Flipons.
    Alan Herbert.
      Triplexes (TRX) are a class of flipons that can form due to the interaction of RNA with B-DNA. While many proteins have been proposed to bind triplexes, structural models of these interactions do not exist. Here, I present AlphaFold V3 (AF3) models that reveal interactions between the high-mobility group protein B1 (HMGB1), HNRNPU (SAF-A), TP53, ARGONAUTE (AGO), and REL domain proteins. The TRXs result from the sequence-specific docking of RNAs to DNA via Hoogsteen base pairing. The RNA and DNA strands in apolar TRX are oriented in the opposite 5' to 3' direction, while copolar TRX have RNA and DNA strands pointing in the same 5' to 3' direction. TRXs can incorporate different RNA classes, including long noncoding RNAs (lncRNAs), short RNAs, such as miRNAs, piRNAs, and tRNAs, nascent RNA fragments, and non-canonical base triplets. Many pathways regulated by TRX formation have evolved to constrain retroelements (EREs), which are both an existential threat to the host and a source of genotypic variation. TRXs help set the boundaries of active chromatin, repressing the expression of most EREs, while depending on other flipons to modulate cellular programs. The TRXs help nucleate folding of intrinsically disordered proteins.
    Keywords:  AGO; DNA; NFKB; PIWI; RAD51; SATB1; flipons; histone; intrinsically disordered regions; methylation; p53; triplexes
    DOI:  https://doi.org/10.3390/ijms27031482
  23. Cells. 2026 Feb 04. pii: 294. [Epub ahead of print]15(3):
    Epitranscriptomic Regulation of Platinum Resistance via the METTL3-ADAM23 Axis in Ovarian Cancer.
    Ujin Kim, Junzui Li, Daniela Matei, Hao Huang.
      N6-methyladenosine (m6A) has emerged as a pivotal regulator of post-transcriptional gene control, yet its contribution to chemotherapy resistance remains insufficiently defined. Here, we describe a previously unrecognized METTL3-ADAM23 epitranscriptomic regulatory relationship associated with platinum (Pt) resistance in ovarian cancer (OC). We show that cisplatin treatment increases global m6A levels and METTL3 expression, linking Pt exposure to activation of the m6A machinery. Functional perturbation studies demonstrate that METTL3 overexpression enhances cisplatin resistance, whereas METTL3 knockdown or pharmacologic inhibition with the selective METTL3 inhibitor STM2457 sensitizes OC cells to Pt treatment in vitro and improves Pt response in vivo. Transcriptomic profiling identifies ADAM23, a cell-adhesion-related tumor suppressor, as a METTL3-dependent, m6A-associated transcript, with altered mRNA expression observed across multiple experimental systems and several high-confidence predicted m6A sites within its transcript. Cisplatin-associated METTL3 upregulation correlates with reduced ADAM23 expression, suggesting a potential regulatory relationship that may contribute to chemoresistance. Together, these findings support a model in which METTL3-associated increases in m6A methylation are linked to Pt resistance, in part through modulation of ADAM23 expression, and highlight METTL3 as a potential therapeutic target in OC.
    Keywords:  ADAM23; METTL3; RNA methylation; epitranscriptomic; ovarian cancer; platinum resistance
    DOI:  https://doi.org/10.3390/cells15030294
  24. J Integr Plant Biol. 2026 Feb 09.
    OsFKBP20-1b stabilizes OsUPF1 and OsUPF2 to promote the degradation of aberrant mRNAs during dehydration stress.
    Haemyeong Jung, Hyun Ji Park, Seung Hee Jo, Ki-Hong Jung, Choonkyun Jung, Hye Sun Cho.
      The selective degradation of aberrant mRNAs plays a vital role in ensuring cellular survival under stress conditions. Here, we investigated the role of OsFKBP20-1b, a splicing factor, in dehydration stress response in rice (Oryza sativa). We show that OsFKBP20-1b associates with the core nonsense-mediated mRNA decay (NMD) components, UP-FRAMESHIFT1 (OsUPF1) and OsUPF2, enhances their stability, thereby supporting the efficient degradation of aberrant transcripts during dehydration stress. These associations were demonstrated using bimolecular fluorescence complementation (BiFC), co-immunoprecipitation (Co-IP), and in vitro binding assays. Integrative analyses combining ribosome profiling and transcriptome sequencing further revealed that OsFKBP20-1b influences both alternative splicing (AS) patterns and translational dynamics of stress-responsive transcripts. Notably, loss of OsFKBP20-1b compromises OsUPF1- and OsUPF2-mediated decay of aberrant mRNAs under dehydration conditions. Consistent with these molecular defects, osfkbp20-1b mutant plants exhibited heightened sensitivity to dehydration stress. Together, our findings identify OsFKBP20-1b as a key regulator linking pre-mRNA splicing with cytoplasmic RNA surveillance during dehydration stress, thereby providing mechanistic insight into post-transcriptional control of stress adaptation in rice. These results advance our understanding of RNA quality control pathways in plants and suggest potential molecular targets for improving drought-resilience in crops.
    Keywords:  OsFKBP20‐1b; RNA surveillance; alternative splicing (AS); drought stress; nonsense‐mediated decay (NMD)
    DOI:  https://doi.org/10.1111/jipb.70178
  25. bioRxiv. 2026 Jan 29. pii: 2026.01.29.702378. [Epub ahead of print]
    Engineered Allosteric RNA Editors Enable Compact, Stimulus-Responsive Post-Transcriptional Circuits.
    Alexander M Marzilli, John T Ngo.
      Translational regulation offers a powerful biological control axis with the potential to enable programmable control over synthetic mRNAs. Here, we introduce inducible Deaminases Acting on RNA (iDARs): deaminase domains (DDs) with conditional RNA-editing activities. Using a domain-insertion strategy, we designed autoinhibited enzymes that can be converted into active RNA editors in response to triggers based on small molecules (chemiDARs), intracellular antigens (antiDARs), protease cleavage (lysiDAR), and optical excitation (optiDAR). Coupling these domains with novel stop codon containing RNA substrates enabled conditional protein translation or transcript degradation. Mutational tuning of inositol hexaphosphate (IP 6 )-binding pockets produced tightly regulated deaminases with minimal basal activity, facilitating dose-dependent readthrough translation in response to low-nanomolar drug concentration, with dynamic ranges exceeding 100-fold. By encoding iDARs alongside their substrates, we developed "self-editing" polycistronic transcripts capable of directing translation of encoded proteins in a trigger-dependent manner following delivery to cells as in vitro transcribed mRNAs. Overall, iDARs provide a generalizable framework for generating controllable deaminases, enabling the design of post-transcriptional circuits that link biochemical sensing to readouts based on de novo translation or mRNA decay.
    DOI:  https://doi.org/10.64898/2026.01.29.702378
  26. Nat Chem Biol. 2026 Feb 10.
    NCBP1 stress signaling drives alternative S6K1 splicing inhibiting translation.
    Dalu Chang, Mahdi Assari, Chananya Suwathep, Khomkrit Sappakhaw, Chayasith Uttamapinant, Marcus J C Long, Yimon Aye.
      Subcellular stress profoundly influences protein synthesis. However, both the nature of spatiotemporally restricted chemical cues and local protein responders to these cues remain elusive. Unlocking these mechanisms requires the ability to functionally map in living systems locale-specific stress responder proteins and interrogate how chemical modification of each responder impacts proteome synthesis. We resolved this problem by integrating precision localized electrophile generation and genetic code expansion tools. Upon examination of four distinct subcellular locales, only nuclear-targeted electrophile stress stalled translation. We discovered that NCBP1-a nuclear-resident protein with multifaceted roles in eukaryotic mRNA biogenesis-propagated this nuclear stress signal through a single cysteine (C436) from among its 19 conserved cysteines. This NCBP1(C436)-specific modification elicited alternative splicing of more than 250 genes. Mechanistically, global protein synthesis stall was choreographed by impaired association between electrophile-modified NCBP1(C436) and SF3A1, an essential component of spliceosome, triggering the production of alternatively spliced S6 kinase, whose expression was sufficient to dominantly inhibit protein translation.
    DOI:  https://doi.org/10.1038/s41589-025-02135-4
  27. Transl Cancer Res. 2026 Jan 31. 15(1): 18
    The WT 1-AS/miR-206 axis regulates the proliferation and migration of breast cancer through the cuproptosis related gene BCL11A.
    Jiasi Li, Huiliang Yang, Renwu Liu.
       Background: Breast cancer (BC) remains one of the most harmful malignancies in women, characterized by high heterogeneity, frequent recurrence, and metastasis. The competitive endogenous RNA (ceRNA) mechanism is crucial in tumor biology. While cuproptosis, a novel copper-induced cell death, shows therapeutic promise in BC, its ceRNA-associated regulatory network is largely unknown. This study aimed to identify and characterize a specific ceRNA axis involved in BC progression and to investigate its functional relationship with cuproptosis.
    Methods: To explore this, we identified a potential ceRNA axis, WT1-AS/miR-206/BCL11A in BC. Its role was investigated using copper ion and reactive oxygen species (ROS) assays to evaluate cuproptosis, functional enrichment and phenotypic analyses to assess cell proliferation and migration, and luciferase reporter assays to validate molecular interactions. Rescue experiments were further conducted to delineate functional dependencies.
    Results: We demonstrated that the WT1-AS/miR-206/BCL11A axis promotes BC malignancy. Suppressing BCL11A significantly increased intracellular copper levels and ROS, thereby enhancing cuproptosis. This axis was essential for driving BC cell proliferation and migration. Mechanistically, luciferase assays confirmed that the long non-coding RNA WT1-AS acts as a molecular sponge for miR-206, which in turn targets and upregulates BCL11A expression. Rescue experiments indicated that the oncogenic effects of WT1-AS are partially mediated through BCL11A.
    Conclusions: Our study elucidates a novel ceRNA network, the WT1-AS/miR-206/BCL11A axis, which regulates BC progression and modulates cuproptosis. These findings provide fresh insights into BC biology and highlight potential diagnostic and therapeutic targets centered on cuproptosis regulation.
    Keywords:  Cuproptosis; breast cancer (BC); competitive endogenous RNA (ceRNA)
    DOI:  https://doi.org/10.21037/tcr-2025-1448
  28. Nat Rev Mol Cell Biol. 2026 Feb 13.
    Mechanisms and disease relevance of mitochondrial translation in humans.
    Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.
      Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41580-026-00948-2
  29. Clin Exp Med. 2026 Feb 08. 26(1): 130
    LncRNA CCAT2 role in female-related cancer progression and diagnosis: a comprehensive review.
    Ahmad Ghorbani Vanan, Farnaz Hassanzadeh, Farid Ghorbaninezhad, Fatemeh Taheri, Omid Bahrami, Parimehr Heidari, Zahra Baharvand, Simin Raissi, Pooya Eini, Safa Tahmasebi, Elham Safarzadeh.
      Female-related cancers, including breast, ovarian, endometrial, and cervical malignancies, are among the most prevalent and clinically significant health challenges worldwide. Their development involves a complex interplay of genetic mutations, environmental factors, lifestyle influences, and therapeutic interventions. Long non-coding RNAs (lncRNAs) have emerged as critical regulators in these cancers, modulating epigenetic mechanisms, transcriptional programs, and post-transcriptional processes. Aberrant lncRNA expression promotes tumor initiation, drives progression and metastasis, and facilitates epithelial-mesenchymal transition (EMT) and angiogenesis. Among these, colon cancer-associated transcript 2 (CCAT2) has been identified as an oncogenic lncRNA across multiple tumor types. CCAT2 primarily activates the Wnt/β-catenin signaling pathway, enhancing β-catenin transcriptional activity and upregulating downstream targets such as MYC and cyclin D1, which are essential for cancer cell proliferation and survival. Despite growing evidence of its oncogenic role, the specific contribution of CCAT2 to female-related cancers remains incompletely understood. This study systematically reviews recent findings on CCAT2's role in the development and progression of breast, ovarian, endometrial, and cervical cancers, elucidates the underlying molecular mechanisms, and evaluates its potential as a diagnostic and prognostic biomarker. Furthermore, the translational potential of CCAT2 as a therapeutic target is discussed, highlighting opportunities for improving clinical outcomes in these malignancies.
    Keywords:  Breast cancer; CCAT2; Cervical cancer; Endometrial cancer diagnosis; LncRNAs; Ovarian cancer
    DOI:  https://doi.org/10.1007/s10238-026-02040-7
  30. Mol Med Rep. 2026 Apr;pii: 117. [Epub ahead of print]33(4):
    Research progress on long non‑coding RNAs in lung cancer (Review).
    Renjie Pan, Chaohui Wang, Yan Tang, Fengzhou Zhong, Yan Zhuang, Qiuxia Zhao.
      Lung cancer remains a significant global health challenge, largely due to difficulties in early detection and the lack of effective therapeutic strategies for more advanced‑stage disease. Elucidating the molecular mechanisms underlying lung carcinogenesis and identifying reliable biomarkers is of urgent importance. Long non‑coding RNAs (lncRNAs), a class of transcripts of >200 nucleotides without protein‑coding potential, have recently emerged as key regulators of tumor cell invasion, metastasis, proliferation, apoptosis and angiogenesis. Accumulating evidence suggests that lncRNAs hold notable promise as diagnostic and prognostic biomarkers in lung cancer. However, a comprehensive overview that integrates their mechanistic roles, clinical potential and the technological advances in their detection, while critically addressing the associated challenges, is lacking, to the best of the authors' knowledge. In the present review, a summary of recent advances in the mechanistic roles of lncRNAs during lung cancer progression and their involvement in therapy response and chemoresistance was provided, along with an up‑to‑date discussion of emerging detection technologies and their implications for clinical translation. The advantages, limitations and challenges of using lncRNAs as diagnostic or prognostic biomarkers in lung cancer are discussed. By synthesizing these aspects, the present review aimed to highlight the novel insights into lncRNAs and outline future research directions, thereby addressing a critical gap in the current literature.
    Keywords:  biomarker; chemoresistance; exosomal long non‑coding RNAs; long non‑coding RNAs; lung cancer; prognosis; treatment
    DOI:  https://doi.org/10.3892/mmr.2026.13827
  31. Genetica. 2026 Feb 12. 154(1): 11
    Genome-wide identification and expression analysis of YTH gene family in barley reveals their potential role under abiotic stresses.
    Muhammad Mudasir, Muhammad Shahzad, Ayesha Bibi, Shareef Gul, Liu Qiuyi, Sarmad Frogh Arshad, Hameed Gul, Ali Shahzad.
      N6-methyladenosine (m6A) is a prevalent modification of eukaryotic mRNAs that plays a crucial role in gene regulation and genome integrity. YT521-B homology (YTH) domain-containing RNA-binding proteins act as essential m6A readers, influencing the fate of m6A-modified RNAs through their involvement in RNA splicing, processing, stability, and translation. In plants, YTH genes regulate plant growth and development by modulating these post-transcriptional processes. Despite the significance of barley (Hordeum vulgare L) as a staple crop, the YTH genes in this species remain largely unexplored. We conducted a detailed analysis of the barley genome and identified 14 YTH genes. Phylogenetic classification categorized these genes into 5 distinct groups. These genes are distributed across seven chromosomes, and their predicted protein products are primarily localized within the nucleus. We observed conserved exon structures and domains among the various groups of HvYTHs. Analysis of the promoter region identified several regulatory elements associated with developmental processes, stress responses, and hormone regulation. Protein-protein interaction predictions suggested associations with m6A methyltransferase components and stress-responsive factors. Additionally, miRNA target analysis identified potential post-transcriptional regulators of HvYTH genes. Expression profiling using RNA-seq data revealed both tissue-specific and stress-responsive patterns. Several HvYTH genes showing differential expression under cold, heat, and heavy metal stress. qRT-PCR validation confirmed the upregulation of HvYTH8 across all stress conditions, while HvYTH5, HvYTH10, and HvYTH12 members exhibited stress-specific upregulation or downregulation. These results underscore the functional divergence of HvYTH genes in mediating abiotic stress tolerance, providing potential targets for improving barley resilience.
    Keywords:  Abiotic stresses; Barley; Expression analysis; Gene family; YTH domain; m6A methylation
    DOI:  https://doi.org/10.1007/s10709-026-00260-z
  32. Biophys Physicobiol. 2025 ;22(4): e220025
    A platform for analyzing translational control by RBPs at single-mRNA resolution in cells.
    Hotaka Kobayashi, Robert H Singer.
      Translation-the process by which mRNAs are decoded into nascent peptides-is fundamental to life. This process is regulated by various RNA-binding proteins (RBPs), which interact with their target mRNAs. While traditional biochemical approaches have provided valuable insights into translational control, they rely on ensemble measurements of bulk mRNAs in test tubes. Consequently, the behavior of individual mRNAs and their spatiotemporal dynamics in cells during translational control remain largely unexplored. Offering a way to address such limitations, we developed a method for imaging translational control by Argonaute (AGO) proteins, a class of RBPs, at single-mRNA resolution in cells. This method, which employs three-color fluorescence microscopy to detect mRNAs, nascent peptides, and AGO, can also serve as a versatile platform for analyzing translational control by other RBPs. In this protocol, we provide a step-by-step guide for implementing this method to facilitate spatiotemporal studies of translational control at the single-cell and single-mRNA levels.
    Keywords:  Argonaute; RNA-binding protein; mRNA; single-molecule imaging; translation
    DOI:  https://doi.org/10.2142/biophysico.bppb-v22.0025
  33. PeerJ. 2026 ;14 e20693
    Hidden-break diversity in pancrustacean rRNA profiles.
    Aitana Casanova Gómez, Francesc Mesquita-Joanes, Ferran Palero.
       Background: In the 28S rRNA molecule of many invertebrates, a hidden break splits this large subunit into two noncovalently associated fragments (28Sa and 28Sb), masking 28S in electrophoretic profiles and biasing the standard measurements of RNA quality in extracted tissue samples. Pancrustacean diversity in RNA hidden breaks remains incompletely surveyed, particularly for Oligostraca.
    Methods: We sampled 12 species spanning Branchiopoda, Malacostraca, and Oligostraca around Valencia (Spain). RNA was stabilized with DNA/RNA Shield, extracted with Quick-RNA MagBead, and profiled on an Agilent 5200 Fragment Analyzer. Peaks were assigned to 18S and 28S fragments using BLAST-inferred gene lengths from reference genomes and annotated rDNA. We analyzed 28S secondary-structure domains (D-regions) using RNAfold and focusing on D3 and D7a.
    Results: Oligostracans and most branchiopods analyzed showed the canonical single-peak profile consistent with 18S, 28Sa, and 28Sb of similar size. Malacostracans exhibited greater profile diversity, including multiple distinct peaks attributable to expansions that alter the relative sizes of 28Sa and b, including expansions near D7a. Comparative analyses indicate conserved D3/D7a architecture across Oligostraca/Branchiopoda and higher variability with frequent expansions in Malacostraca.
    Conclusions: Our data extend RNA profile diversity to Oligostraca, refine fragment-size estimates with higher-resolution capillary electrophoresis, and link malacostracan profile heterogeneity to D7a and other expansions. We recommend rRNA-aware quality control for arthropod samples and targeted sequencing of poorly sampled lineages (e.g., Mystacocarida, Cephalocarida, Remipedia) to resolve mechanisms and the phylogenetic distribution of the hidden break.
    Keywords:  28S rRNA; Branchiopoda; D7a; Fragment analyzer; Hidden break; Malacostraca; Oligostraca; Pancrustacea; rRNA secondary structure
    DOI:  https://doi.org/10.7717/peerj.20693
  34. bioRxiv. 2026 Jan 30. pii: 2026.01.28.702393. [Epub ahead of print]
    Programmable artificial RNA condensates in mammalian cells.
    Shiyi Li, Yuna Kim, Kevin Wang, Eric John Payson, Anli A Tang, Maria Villalba Nieto, Dino Osmanovic, Madison Yang, Diego Dilao, Alexandra Bermudez, Wen Xiao, Melody M H Li, Neil Y C Lin, Kathrin Plath, Douglas L Black, Elisa Franco.
      Artificial biomolecular condensates have emerged as powerful tools to control cellular behaviors. Here we introduce a method to build artificial condensates within living mammalian cells through the design of modular RNA motifs formed by a single, short strand of RNA. These condensates emerge spontaneously, creating RNA-rich compartments that remain separated from their surrounding environment. The RNA sequences include stem-loop domains that fold as the RNA is transcribed, and then condense in the nucleus and cytoplasm through loop-loop interactions. These sequences can be optimized and diversified, enabling the generation of distinct, non-mixing condensate populations and the programmable control of their subcellular localization. The RNA motifs can also be modified to recruit small molecules, proteins, and RNA molecules in a sequence-specific manner to the RNA-rich phase. By introducing additional RNAs that link two distinct types of condensates, we can create droplets with multiple subcompartments, whose organization can be controlled by tuning the stoichiometry of different RNA sequences. These artificial condensates provide a versatile platform for studying and manipulating molecular functions inside living cells.
    DOI:  https://doi.org/10.64898/2026.01.28.702393
  35. Curr Opin Lipidol. 2026 Feb 09.
    Impact of mRNA and protein isoforms in lipoprotein metabolism and how to modulate them.
    Kelly M Martinovich, Jessica M Cale, May T Aung-Htut.
       PURPOSE OF REVIEW: More than 95% of human genes undergo alternative pre-mRNA processing based on cell type, developmental stages, and environmental stimuli, among other factors. Not all alternatively spliced mRNAs are translated to proteins, and some of the noncoding mRNA isoforms play vital roles in cellular homeostasis. This review summarizes protein coding and noncoding RNA isoforms reported for key genes involved in lipoprotein metabolism, and emerging technologies that can be exploited to specifically induce a desired isoform.
    RECENT FINDINGS: As sequencing technologies become more accessible, more variations in gene transcripts are being detected. Publicly available databases collate these as they arise, but not all of them are captured. Additionally, the function, if any, of many of these alternatively spliced transcripts is currently unknown. Novel strategies to investigate specific transcripts are also continuously evolving.
    SUMMARY: Most human genes are alternatively spliced, generating various mRNAs and protein isoforms. Any cis or trans factors that alter the balance of these isoforms can have deleterious effects. The fundamental knowledge on the role of each isoform in maintaining cellular health is currently lacking. Emerging technologies which allow modulation of natural mRNA splicing can be used to further our understanding of natural isoform expression and function.
    Keywords:  alternative splicing; lipoprotein metabolism.; mRNA isoforms; protein isoforms
    DOI:  https://doi.org/10.1097/MOL.0000000000001026
  36. Eur J Med Res. 2026 Feb 09.
    Long non-coding RNAs as key regulators in sepsis: from immune response to organ dysfunction.
    Jian Xue, Yumei Zhang, Guiyang Yu, Zhengjun Liu.
      Sepsis remains a leading cause of morbidity and mortality in intensive care units worldwide, driven by a dysregulated host response to infection that culminates in multi-organ dysfunction. Current diagnostic biomarkers and therapeutic strategies lack the needed sensitivity, specificity and efficacy, underscoring an urgent need for novel molecular insights. Long non-coding RNAs (lncRNAs), a diverse class of transcripts exceeding 200 nucleotides without protein-coding capacity, have emerged as pivotal regulators of sepsis pathophysiology. They orchestrate immune responses, inflammatory cascades, cellular apoptosis, metabolic reprogramming and the lethal cross-talk among diverse cell death pathways. Through intricate interactions with DNA, RNA and proteins, lncRNAs also drive organ-specific injury via distinct cell-type specific mechanisms. Specific lncRNAs, including NEAT1, MALAT1 and GAS5, are deeply implicated in disease onset, progression and prognosis, highlighting their potential as both biomarkers and therapeutic targets. In this review, we synthesize current evidence on the roles of lncRNAs in immune modulation, organ dysfunction and metabolic regulation during sepsis. We also evaluate their promise in diagnosis, prognosis and therapy, and discuss major translational barriers, such as physicochemical instability, poor permeability and disease heterogeneity, that must be overcome for clinical application. A deeper understanding of these molecules may unlock novel strategies for the early diagnosis, prognosis, and treatment of sepsis.
    Keywords:  Biomarkers; Immune regulation; Long non-coding RNAs; Multiple organ dysfunction; Sepsis
    DOI:  https://doi.org/10.1186/s40001-026-04018-3
  37. Int J Mol Sci. 2026 Jan 30. pii: 1400. [Epub ahead of print]27(3):
    The Multi-Target lncRNA-miRNA-mRNA TRIAD in Pancreatic Cancer Diagnosis and Therapy.
    Hyeon-Su Jeong, Yun Ju Lee, Du Hyeong Lee, Hyun-Young Roh, Ga-Ram Jeong, Heui-Soo Kim.
      Pancreatic cancer (PC) is one of the most lethal malignancies worldwide, characterized by late diagnosis, aggressive progression, and limited responsiveness to current therapeutic strategies. Although extensive genomic analyses have identified key driver protein-coding genes (PCGs), therapeutic approaches targeting individual genes have shown limited clinical benefit. This limitation highlights the molecular complexity of PC, where tumor progression is governed by regulatory networks that extend beyond genetic alterations. Non-coding RNAs (ncRNAs), which constitute nearly 98% of the human genome, have emerged as regulators of gene expression in cancer. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate oncogenic processes, including aberrant signaling activation, tumor microenvironment remodeling, epithelial-mesenchymal transition, immune evasion, and resistance. Beyond their independent functions, lncRNAs, miRNAs, and mRNAs form an integrated regulatory network known as the lncRNA-miRNA-mRNA TRIAD, enabling control of gene expression. Such network-based regulation provides a framework for multi-target therapeutic strategies. Moreover, the rapid responsiveness and disease-specific expression patterns of ncRNAs suggest strong potential as diagnostic and prognostic biomarkers in PC, where early detection remains challenging. This review summarizes the regulatory roles of PCGs, miRNAs, and lncRNAs in PC and highlights the lncRNA-miRNA-mRNA TRIAD as a framework for understanding gene regulatory networks.
    Keywords:  TRIAD; biomarker; ceRNA; lncRNA; miRNA; muti-target; non-coding RNA; pancreatic cancer; protein-coding gene; treatment
    DOI:  https://doi.org/10.3390/ijms27031400
  38. Int J Mol Sci. 2026 Jan 24. pii: 1195. [Epub ahead of print]27(3):
    Splicing Factor 3a Subunit 1 Promotes Colorectal Cancer Growth via Anti-Apoptotic Effects of Syntaxin12.
    Takahiro Sasaki, Hiroaki Konishi, Tatsuya Dokoshi, Aki Sakatani, Hiroki Tanaka, Koji Yamamoto, Keitaro Takahashi, Katsuyoshi Ando, Nobuhiro Ueno, Shin Kashima, Kentaro Moriichi, Hiroki Tanabe, Toshikatsu Okumura, Mikihiro Fujiya.
      RNA dysregulation mediated by aberrant RNA-binding proteins (RBPs) is closely associated with tumorigenesis. However, the tumorigenic mechanisms of each RBP remained unclear. In this study, we demonstrate that downregulation of Splicing factor 3A1 (SF3A1) markedly suppressed the proliferation of colorectal cancer (CRC) cells, with minimal cytotoxicity observed in non-cancerous epithelial cells. The tumor-promoting function of SF3A1 was further validated in an HCT116 xenograft mouse model. Multiple apoptosis assays-including TdT-mediated dUTP nick end labeling (TUNEL) staining, poly-ADP-ribose polymerase (PARP) immunoblotting, and caspase-3/7 activity measurements-showed that SF3A1 inhibited apoptotic signaling in CRC cells. Transcriptome analysis, combined with RNA-immunoprecipitation (RIP), identified Syntaxin 12 (STX12) as a downstream effector of SF3A1. Knockdown of STX12 induced apoptosis in CRC cells but had no effect on the viability of non-cancerous HCEC-1CT epithelial cells. Furthermore, STX12 mRNA levels were significantly reduced following SF3A1 knockdown, indicating that SF3A1-mediated stabilization of STX12 contributes to apoptosis resistance in CRC cells. Collectively, our findings establish that SF3A1 promotes CRC progression by stabilizing STX12 mRNA and selectively inhibiting apoptosis in malignant cells, thereby identifying the SF3A1-STX12 regulatory axis as a novel and selective therapeutic target for CRC.
    Keywords:  RNA binding protein; Syntaxin 12; apoptosis; colorectal cancer; splicing factor 3A1
    DOI:  https://doi.org/10.3390/ijms27031195
  39. MedComm (2020). 2026 Feb;7(2): e70607
    Progress in RNA-Targeted Therapeutics for Human Diseases.
    Wangzheqi Zhang, Aimin Jiang, Bin-Kui Jia, Yuming Jin, Yinghu Chen, Zhaoyu Li, Yan Liao, Haoling Zhang, Zhiheng Lin, Xiao Fang, Linhui Wang.
      RNA-targeted therapy is reshaping molecular medicine by shifting the traditional "protein-centric" view toward an "RNA-regulatory network" paradigm. Beyond carrying genetic information, RNA plays essential roles in posttranscriptional regulation, signaling pathways, and epigenetic modulation. Advances in high-throughput sequencing, structural biology, and delivery technologies have accelerated the development of diverse RNA therapeutics, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNA (miRNA) modulators, messenger RNA (mRNA) therapeutics, aptamers, short hairpin RNA, and CRISPR/Cas-guided single-guide RNAs. However, a concise comparison of these major RNA modalities and the translational barriers that limit their broader clinical application is still lacking. This review outlines the mechanisms and representative applications of these RNA-based strategies in gene silencing, editing, protein replacement, immune activation, and targeted drug delivery. Special emphasis is placed on ASOs and siRNAs for neurological, metabolic, and infectious diseases, as well as mRNA therapeutics that are transforming vaccine development. Common challenges-such as in vivo stability, delivery efficiency, and immune activation-are also discussed. Finally, we highlight how chemical modification, nanotechnology, and artificial intelligence-assisted design are enhancing the specificity, stability, and safety of RNA therapeutics, providing a framework for advancing next-generation precision RNA medicine.
    Keywords:  CRISPR/Cas9; RNA‐targeted therapy; antisense oligonucleotides; messenger RNA; small interfering RNA
    DOI:  https://doi.org/10.1002/mco2.70607
  40. Int J Mol Sci. 2026 Jan 27. pii: 1260. [Epub ahead of print]27(3):
    Integrated WGCNA of lncRNA-mRNA Networks Identifies Novel Hub Genes and Potential Therapeutic Agents for Liver Cirrhosis via Molecular Docking Validation.
    Tong Wu, Jiayu Jin, Yuhan Yang, Jing Sui, Yajie Zhou, Hongmei Yuan.
      Liver cirrhosis (LC) is a complex pathological condition characterized by extensive transcriptomic reprogramming, yet the regulatory role of non-coding RNAs in disease progression remains poorly understood. This study aimed to systematically investigate long non-coding RNA (lncRNA)-messenger RNA (mRNA) interaction networks in LC through weighted gene co-expression network analysis (WGCNA). Gene expression profiles from datasets GSE197406, GSE107170, and GSE17548 were retrieved from the Gene Expression Omnibus (GEO) database, and differentially expressed lncRNAs and mRNAs were identified. Co-expression modules were constructed using WGCNA. Furthermore, functional enrichment analyses were conducted and drug repurposing opportunities were evaluated. Additionally, lncRNA-mRNA co-expression networks and lncRNA-mRNA-pathway networks were constructed to identify key regulatory relationships. Molecular docking simulations were subsequently performed to validate potential drug-target interactions. The results revealed several co-expression modules significantly associated with LC, particularly the turquoise module (r = 0.81). Genes within this module were enriched in several biological pathways, including the PI3K-Akt signaling pathway, NF-κB signaling pathway, and chemokine signaling pathway. The hub lncRNA in the turquoise module, NONHSAT134945.2, was found to be co-expressed with mRNAs involved in inflammasome-mediated pyroptosis and hepatocyte activation, such as CSF1R, HCK, and CASP1. Based on this hub gene signature, AB-1010, GW768505A, and Dasatinib were identified as potential therapeutic candidates. Molecular docking analysis confirmed that these compounds exhibit high binding affinity to CSF1R and HCK, with all interatomic distances maintained below 3.5 Å. These findings provide new insights into the molecular mechanisms underlying LC and suggest that the NONHSAT134945.2-CSF1R/HCK axis may serve as a valuable target for future translational research and therapeutic development.
    Keywords:  drug target; liver cirrhosis; long non-coding RNAs; molecular docking; weighted gene co-expression network analysis
    DOI:  https://doi.org/10.3390/ijms27031260
  41. PLoS One. 2026 ;21(2): e0339960
    A gene-specific RNA enrichment protocol for nanopore direct-RNA sequencing.
    Maja Bele Dyrendalsli, Cecilie Løkke, Christer Einvik.
      Oxford Nanopore direct-RNA sequencing, a third-generation sequencing technology, allows for the analysis of native RNA molecules in their natural cellular state. However, cellular RNA is predominantly composed of ribosomal RNA and transcripts from ubiquitously expressed housekeeping genes, which limits the coverage of transcripts from lowly expressed genes. To address this limitation, targeted sequencing can be employed to enrich read coverage by focusing specifically on genes of interest. Here, we present a step-by-step protocol for gene-specific RNA enrichment followed by Oxford Nanopore direct-RNA sequencing. The enrichment protocol utilizes biotinylated DNA capture probes complementary to the target gene. Following in-solution hybridization of probes to total RNA, a series of stringent washes is applied before elution of the enriched RNA sample. The protocol describes all steps from isolation of cellular total RNA to bioinformatic analyses of raw sequencing data. As a proof of concept, capture probes were designed to specifically enrich all RNA species encoded by the MYCN oncogene. The enrichment protocol successfully isolated RNAs from the MYCN gene, achieving a purification factor of 4.8 × 103. Direct-RNA sequencing of the enriched RNA sample revealed that 65% of the primary mapped reads aligned to MYCN transcripts. We also include a more thorough analysis of the most abundant non-target mapped reads and unmapped reads. This protocol proves to be highly effective in removing unwanted RNA species, delivering robust enrichment for the target gene, and significantly enhancing the efficiency of long-read direct-RNA sequencing.
    DOI:  https://doi.org/10.1371/journal.pone.0339960
  42. Science. 2026 Feb 12. 391(6786): eaea1272
    Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation.
    Mohamed A El-Brolosy, Atharv Oak, An T Hoang, Yassine Damergi, André Fischer, Reuben A Saunders, Jingchuan Luo, Amer Balabaki, Jeremy Guez, Troy W Whitfield, Seth R Goldman, Arash Latifkar, Yuancheng Ryan Lu, Didier Y R Stainier, Konrad J Karczewski, Olivia Corradin, Jonathan S Weissman.
      Transcriptional adaptation (TA) is a genetic robustness mechanism through which mutant messenger RNA (mRNA) decay induces sequence-dependent up-regulation of so-called adapting genes. How cytoplasmically generated mRNA fragments affect nuclear transcription remains poorly understood. Using genome-wide CRISPR screens, we uncover ILF3 as an RNA binding protein connecting cytoplasmic mRNA decay and transcription during TA and show that it is required for a range of TA substrates. ILF3 is enriched at adapting genes' RNAs, and its artificial recruitment through dCas13 promotes gene expression. Using tiling oligonucleotide screens, we identify trigger RNA fragments that activate adapting genes when introduced into cells. Further functional dissection reveals a critical role for homology between trigger and target sequences. These findings enhance our molecular understanding of TA and inform the design of programmable oligonucleotides for gene expression augmentation.
    DOI:  https://doi.org/10.1126/science.aea1272
  43. Nat Commun. 2026 Feb 14.
    Expression of nano-engineered RNA organelles in bacteria.
    Brian Ng, Catherine Fan, Milan Dordevic, Adam Knirsch, Layla Malouf, Giacomo Fabrini, Sabrina Pia Nuccio, Roger Rubio-Sánchez, Graham Christie, Masahiro Takinoue, Pietro Cicuta, Lorenzo Di Michele.
      Designing synthetic biomolecular condensates, or membraneless organelles, offers insights into the functions of their natural counterparts and is equally valuable for cellular and metabolic engineering. Choosing E. coli for its biotechnological relevance, we deploy RNA nanotechnology to design and express non-natural membraneless organelles in vivo. The designer condensates assemble co-transcriptionally from branched RNA motifs interacting via base-pairing. Exploiting binding selectivity, we express orthogonal, non-mixing condensates, and by embedding a protein-binding aptamer, we achieve selective protein recruitment. Condensates can be made to dissolve and reassemble upon thermal cycling, thereby reversibly releasing and re-capturing protein clients. The synthetic organelles are expressed robustly across the cell population and remain stable despite enzymatic RNA processing. Compared with existing solutions based on peptide building blocks or repetitive RNA sequences, these nanostructured RNA motifs enable algorithmic control over interactions, affinity for clients, and condensate microstructure, opening further directions in synthetic biology and biotechnology.
    DOI:  https://doi.org/10.1038/s41467-026-69336-w
  44. bioRxiv. 2026 Feb 08. pii: 2026.02.05.704032. [Epub ahead of print]
    Natural language-based representation and modeling of RBP binding.
    Shaimae Elhajjajy, Zhiping Weng.
      RNA-binding proteins (RBPs) are critical regulators of the human transcriptome, but the binding patterns of most RBPs are insufficiently characterized. While sequence context facilitates RBP binding specificity, its precise contribution remains unclear. Existing computational methods to decipher RBP binding patterns are limited by their architecture-dependence, challenging interpretability, and, importantly, lack of focus on context. We present a novel comprehensive approach to address the aforementioned knowledge gaps. We first introduce a natural language-based representation to model RNA sequences using lexical, syntactic, and semantic forms, then devise a sequence decomposition method based on these structures to deconstruct RNA sequences into regions, each containing a target k-mer and its flanking contexts. We leverage this linguistic conceptualization to predict RBP binding under a Multiple Instance Learning (MIL) framework, which we solve using a novel method of significant region extraction termed "iterative relabeling". We demonstrate that our bottom-up approach discovers key regions contributing to RBP binding in an architecture-dependent, accurate, and interpretable manner.
    DOI:  https://doi.org/10.64898/2026.02.05.704032
  45. J Exp Bot. 2026 Feb 09. pii: erag063. [Epub ahead of print]
    Review: Specificity determinants of the plant splicing code.
    Rica Burgardt, Hannah Walter, Andreas Wachter.
      Alternative splicing (AS) of precursor mRNAs (pre-mRNAs) constitutes a major means to increase transcriptome complexity in higher eukaryotes and critically contributes to the re-programming of gene expression in response to internal and environmental signals. Technological advances have enabled us to determine transcriptome-wide AS patterns at unprecedented accuracy, depth, and throughput. Furthermore, powerful tools for examining the regulatory mechanisms underlying AS decisions have been successfully established for plants, including methods for profiling the in vivo interaction landscape of splicing regulatory proteins with their target pre-mRNAs. Combining these novel approaches with functional studies of individual AS events identified many critical components of the plant splicing code, consisting of cis-regulatory elements on the pre-mRNA and trans-acting factors, such as splicing regulatory proteins. Their concerted action affects splice site selection by the spliceosome, thereby generating highly dynamic and complex AS outputs. Here, we will review our current knowledge of AS regulation by RNA sequence and structural motifs in cis and networks of trans-acting splicing regulators. We will also discuss how, despite overall low complexity of the target motifs for binding of splicing regulators and their often-redundant functions, high levels of precision and specificity in AS can be achieved.
    Keywords:   cis-regulatory; trans-acting; Arabidopsis; RNA structure; SR protein; alternative splicing; hnRNP; photomorphogenesis; splicing
    DOI:  https://doi.org/10.1093/jxb/erag063
  46. bioRxiv. 2026 Feb 05. pii: 2026.02.03.703574. [Epub ahead of print]
    Amplified MS2 labeling reveals heterogeneous dynamics of RNA granules in the live murine brain.
    Hyungsik Lim, Grace P Cooper.
      Dynamics of messenger ribonucleic acids (mRNAs) and the complexes with associated proteins (RNPs), also known as RNA granules, provide post-transcriptional control of gene expression. This regulation is crucial for cell-type diversity and activity-dependent plasticity of the mammalian central nervous system (CNS). However, elucidating the physiological significance of RNA granules has been hampered by the lack of technologies for probing them in live mouse brain. Here, we describe a novel method to visualize RNA granules in native CNS tissues in vivo. To amplify the fluorescence signal from single mRNAs incorporating MS2 stem loops, MS2 capsid protein (MCP) was conjugated with 4 tandem superfolder green fluorescent proteins (sfGFPs). Using MCP-4×sfGFP, a significant population of RNPs could be detected in specific cells of the CNS, enabling new findings, e.g., remarkable heterogeneity of Actb mRNA dynamics across neurons and glial cells. The highly sensitive in vivo RNA imaging could be useful for illuminating the regulation of the dynamics of RNA granules in naive and diseased animals.
    Significance: RNA granules, complexes of RNAs and binding proteins, play a vital role in regulating gene expression and mRNA dynamics. Despite the importance, monitoring their behavior in functional neural tissue has proven technically challenging, in part due to optical turbidity and weak fluorescent tags. In this study, we present a new approach to better observe RNA granules in specific cells of murine brain through the use of amplified fluorescent signals and advanced imaging techniques. Our method provides a powerful means to analyze the properties of RNA granules within neurons and glial cells in vivo, offering valuable insights into healthy and neurodegenerative brains.
    DOI:  https://doi.org/10.64898/2026.02.03.703574
  47. J Microbiol Biotechnol. 2026 Feb 11. 36 e2510039
    FTO-Mediated m6A Demethylation of SERPINF1 Attenuates Multiple Myeloma Progression via the Wnt/β-Catenin Pathway.
    Xiushuai Dong, Xi Chen, Yaoyao Tian, Lianjie Wang, Wei Wang.
      Multiple myeloma (MM) is an intractable hematologic malignancy characterized by clonal growth of malignant plasma cells in the bone marrow. Recent studies have highlighted the role of N6-methyladenosine (m6A) RNA modifications in MM progression; however, the function of the m6A demethylase fat mass and obesity-associated protein (FTO) remains unclear. This study aims to explore the mechanisms by which FTO-mediated m6A demethylation of Serpin Family F Member 1 (SERPINF1) impacts MM progression. SERPINF1 and FTO expressions were assessed via real-time quantitative polymerase chain reaction (RT-qPCR). The impact of such expressions on MM was evaluated using CCK-8, EdU, transwell, and tumor xenograft model assays. Key molecules involved in the Wnt/β-catenin pathway were assessed via Western blotting. The relationship between SERPINF1 and FTO was determined through correlation analysis, methylated RNA immunoprecipitation, luciferase, RT-qPCR, Western blotting, RNA immunoprecipitation, and actinomycin D treatment assays. Finally, the effect of their interaction on MM was assessed through rescue experiments. SERPINF1 expression was reduced in MM samples. SERPINF1 overexpression suppressed the malignant traits of MM cells and reduced the levels of β-catenin, c-Myc, and cyclin D1. In vivo experiments revealed that SERPINF1 overexpression suppressed tumor growth in xenograft models. Mechanistically, FTO expression was upregulated in MM and SERPINF1 expression was negatively regulated by demethylating its m6A sites via IGF2BP1. Rescue experiments demonstrated that SERPINF1 overexpression reversed FTO-induced oncogenic phenotypes. These findings suggest that FTO-mediated m6A demethylation suppressed SERPINF1 expression in MM, whereas SERPINF1 overexpression inhibited tumor progression via the Wnt/β-catenin pathway.
    Keywords:  FTO; Multiple myeloma; SERPINF1; Wnt/β-catenin; m6A demethylation
    DOI:  https://doi.org/10.4014/jmb.2510.10039
  48. Animals (Basel). 2026 Feb 04. pii: 481. [Epub ahead of print]16(3):
    Concurrent Alterations in DNA Methylation and RNA m6A Methylation During Epigenetic and Transcriptomic Reprogramming Induced by Tail Docking Stress in Fat-Tailed Sheep.
    Jian Zhang, Yannan Ma, Shuzhen Song.
      Tail docking, serving as an important management intervention in animal husbandry, plays a significant role in regulating tail fat deposition and improving production performance and health status in fat-tailed sheep. This study systematically revealed the reprogramming effects of tail docking on the epigenetic landscape and transcriptome of fat-tailed sheep by integrating whole-genome bisulfite sequencing (WGBS) and RNA m6A methylated immunoprecipitation sequencing (MeRIP-seq). At the DNA level, the tail-docked group exhibited a pronounced trend of hypomethylation across multiple functional genomic regions, including promoters, exons, and introns. Differentially methylated regions (DMRs) were significantly enriched in pathways related to tissue development and stress response, such as the Hippo signaling pathway and adherens junctions. Pyrosequencing validation of the promoter region of the key gene DGAT1 further confirmed the reliability of the WGBS data. At the RNA level, RNA m6A modifications showed an overall up-regulated pattern: the tail-docked group displayed higher numbers of m6A peaks, greater total peak length, and increased genomic coverage compared to the control group, along with better overall prediction of modification sites. Genes associated with differential m6A peaks were closely related to processes such as stem cell pluripotency and cytoskeleton regulation. qPCR validation of several methylation-related enzyme genes (e.g., METTL3, FTO, YTHDF1) yielded results consistent with the sequencing trends. Through integrated analysis of DNA methylation and RNA methylation, we identified 143 genes with concurrent changes in methylation and mRNA expression, among which 41 genes were regulated by both DNA and RNA methylation. These genes were primarily enriched in the adherens junction pathway. Notably, two core genes CITED4 and ZNF644 showed significant changes across all three levels: DNA methylation, RNA methylation, and mRNA expression. This study systematically elucidates the epigenetic mechanism by which tail docking stress induces coordinated DNA hypo-methylation and RNA m6A hyper-methylation to regulate transcriptomic reprogramming in response to environmental intervention. The findings provide novel insights into the molecular basis of trait formation in livestock.
    Keywords:  DNA methylation; RNA m6A methylation; epigenetic regulation; fat-tailed sheep; tail docking
    DOI:  https://doi.org/10.3390/ani16030481
  49. Front Plant Sci. 2025 ;16 1722290
    Epitranscriptomic profiling of m5C RNA methylation reveals a dynamic response to TSWV infection in tomato.
    Xinyi Zhao, Yanwei Gong, Yubing Jiao, Wanhong Zhang, Dong An, Yingwen Wang, Binna Lv, Ying Li, Lili Shen, Jinguang Yang.
      Cytosine-5 methylation (m5C) is a crucial epitranscriptomic mark in eukaryotes that modulates RNA stability and gene expression. While the roles of m5C are partially understood in model plants, its function in horticultural crops under biotic stress remains largely unexplored. To address this gap, we investigated the role of m5C modification in tomato response to tomato spotted wilt virus (TSWV) infection. We constructed the first comprehensive m5C epitranscriptomic map in Solanum lycopersicum. To investigate its role in plant immunity, we further profiled the dynamic changes of the m5C methylome upon TSWV infection, followed by integrative multi-omics analysis. Functional validation was performed through virus-induced gene silencing (VIGS) of the key RNA methyltransferase gene SlTRM4B. The m5C epitranscriptomic map revealed conserved modification patterns with enrichment at transcription start and stop sites. Upon TSWV infection, a global increase in m5C modification levels was observed across the transcriptome, which was correlated with the significant upregulation of RNA methyltransferase (RCMT) family genes, particularly SlTRM4B. Integrative multi-omics analysis revealed that genes exhibiting both hypermethylation and increased expression were significantly enriched in the plant-pathogen interaction pathway. VIGS of SlTRM4B demonstrated that this methyltransferase is essential for maintaining the stability of its target transcripts under TSWV infection, leading to enhanced disease susceptibility. Collectively, our findings demonstrate that SlTRM4B-mediated m5C RNA methylation fine-tunes post-transcriptional regulation to reprogram the transcriptome for disease resistance in tomato. This work provides novel insights into the epitranscriptomic mechanisms governing plant responses to viral pathogens.
    Keywords:  RNA stability; Solanum lycopersicum; TSWV; m5C; m5C-RIP-seq
    DOI:  https://doi.org/10.3389/fpls.2025.1722290
  50. Hum Genomics. 2026 Feb 13.
    Exon skipping as a potential diagnostic biomarker in colorectal cancer: an integrated epigenomic-transcriptomic analysis​.
    Lili Zhang, Jian Cui, Jinxin Shi, Jiahui Cai, Tianhan Sun, Gaoyuan Sun, Yifei Li, Hexin Li, Siyuan Xu, Xiaokun Tang, Ziwei Chen, Hongyuan Cui, Fei Xiao, Gang Zhao.
       BACKGROUND: Colorectal cancer (CRC) is the third most common cancer globally. Alternative splicing contributes significantly to CRC tumorigenesis through aberrant transcript generation. However, the regulatory influence of RNA modifications on splicing remains poorly understood, largely due to technical difficulty. Nanopore direct RNA sequencing addresses this by enabling simultaneous detection of RNA modifications and Alternative splicing events (ASEs).
    METHODS: We conducted Nanopore direct RNA sequencing on paired tumor and normal tissues from surgical resections at Beijing Hospital. Differential putative RNA modification sites and ASEs linked to CRC were systematically identified. To validate the key findings, we utilized a large patient cohort from The Cancer Genome Atlas (TCGA) and predicted 3D protein structures with AlphaFold3. The predicted structures were then compared using TM-align. Regulatory relationships between RNA modifications and splicing were explored through predictive modeling of potential cis-regulatory pairs. The splicing events were also validated.
    RESULTS: The MYH11-201 transcript of the MYH11 gene contains an additional exon (ENSE00001632812) compared to the MYH11-203 isoform. Both bioinformatic analysis and experimental validation confirmed frequent loss of this exon in tumor tissues. This finding was further validated in the TCGA cohort, demonstrating a significant preference for exon skipping in tumor tissues. These results suggest that the skipping of ENSE00001632812 is a promising candidate biomarker associated with CRC pathogenesis. Notably, this exon's PF00063 domain interacts with multiple tumor suppressor genes and oncogenes domains, suggesting its functional importance. The structures revealed pronounced rotational divergence within a putative C-terminal transmembrane domain-like region. Furthermore, we utilized Nanopore sequencing to explore the potential interplay between alternative splicing and RNA modifications. We implemented an integrated analytical workflow (available at https://github.com/lelelililele/Nanopore-ASEs-and-RNA-modification) combining modification calling and splicing analysis tools to investigate RNA modification-related enzymes and splicing-related proteins in CRC.
    CONCLUSIONS: This pilot study utilizes Nanopore direct RNA sequencing to characterize exon skipping events and RNA modifications in CRC. We identified the skipping of MYH11 exon ENSE00001632812 as a potential candidate for future diagnostic investigation. By integrating modification and splicing data, we highlighted putative regulatory pairs that warrant further functional exploration. While our findings offer new insights into CRC molecular mechanisms, extensive validation in independent large-scale cohorts and functional assays is essential to confirm the diagnostic utility and mechanistic roles of these targets.
    Keywords:  Alternative splicing events; Colorectal cancer; Exon skipping; Nanopore sequencing; RNA modifications
    DOI:  https://doi.org/10.1186/s40246-026-00931-0
  51. Int J Mol Sci. 2026 Jan 25. pii: 1208. [Epub ahead of print]27(3):
    Potato Virus Y NIb Multifunctional Protein Suppresses Antiviral Defense by Interacting with Several Protein Components of the RNA Silencing Pathway.
    Prakash M Niraula, Saniyaa Howell, Chase A Stratton, Michael T Moore, Matthew B Dopler, Muhammad I Abeer, Michael A Gitcho, Vincent N Fondong.
      Potyvirus genomes are expressed as a single large open reading frame, which is translated into a polyprotein that is post-translationally cleaved by three virus-encoded proteases into 10 functional proteins. Several of these potyviral proteins, including nuclear inclusion protein b (NIb), are multifunctional. Here, using the classic GFP silencing in Nicotiana benthamiana gfp-transgenic plants, we show that potato virus Y (PVY) NIb, in addition to its canonical role as the viral RNA-dependent RNA polymerase (RdRP), functions as a suppressor of RNA silencing. Mutational analyses reveal a previously unreported NIb nuclear localization signal (NLS) consisting of a triple-lysine motif. NIb suppression of RNA silencing activity was lost when the NLS was mutated, suggesting that nuclear localization is required for NIb suppression of RNA silencing activity. Analysis of sequenced GFP siRNAs revealed three reproducible hotspot regions at ≈175 nt, ≈320-330 nt, and a broader 3'-proximal region spanning ≈560-700 nt that contains multiple local maxima. These data show differences in the positional distribution of siRNAs between samples expressing NIb and those expressing NIbDel3×2, the NIb null mutant that does not suppress RNA silencing. However, the positional distribution of GFP-derived small RNAs across the transgene differed modestly between NIb and NIbDel3×2, while both treatments showed the same three reproducible hotspot regions. Furthermore, NIb was found to interact with four key RNA silencing pathway proteins-AGO4, HSP70, HSP90, and SGS3. Except for HSP90, each of these proteins showed degradation products that were absent in NIb mutants that did not suppress RNA silencing. These findings support a role for NIb in countering host defense during virus infection.
    Keywords:  AGO4; HSP70; HSP90; RdRP; SGS3; nuclear inclusion protein b (NIb); siRNA; suppressor of RNA silencing
    DOI:  https://doi.org/10.3390/ijms27031208
  52. J Mol Biol. 2026 Feb 11. pii: S0022-2836(26)00074-4. [Epub ahead of print] 169701
    Nucleotide-Resolution Mapping Reveals Specific Helicase Binding Site on roX2 lncRNA.
    Susmit Narayan Chaudhury, Nathan Edward Jespersen, Karissa Y Sanbonmatsu.
      Long noncoding RNAs (lncRNAs) often serve as dynamic scaffolds for chromatin-related complexes, but the structural details that control their interaction with proteins remain poorly understood. The core of the X-chromosome hyperactivation process is the RNA helicase MLE (Male-Less), which helps incorporate roX RNAs into the Male-Specific Lethal (MSL) complex and causes a 2-fold increase in X-linked gene expression in males. In this study, we map MLE-roX2 interactions at the nucleotide level to show how (1) the helicase (MLE) binds the 5' RNA helices and (2) ATP hydrolysis drives region-specific RNA remodeling. Using a combination of biochemical techniques, including SHAPE chemical probing, hydroxyl radical footprinting, Electrophoretic Mobility Shift Assay (EMSA), and fluorescence polarization, we demonstrate that MLE binds two of the 5'-helices of roX2 RNA without ATP, while ATP specifically induces localized unfolding in one of the helices at the 3'-domain. This rearrangement specifically exposes the AU-rich roX-box motif, which in turn remodels the roX2 RNA. We show that MLE specifically interacts with particular nucleotides in R2H1-R2H3, followed by ATP-dependent local structural rearrangement at the 3' end of the roX2 RNA. Our findings provide the first direct evidence of domain-specific, roX2-MLE interaction and ATP-driven lncRNA rearrangement, advancing our understanding of helicase-guided lncRNA structural changes and establishing a framework linking lncRNA rearrangements to the regulation of chromatin-associated complexes.
    Keywords:  Chemical Probing; RNA-Protein interaction; X-Chromosome Inactivation; lncRNA structure
    DOI:  https://doi.org/10.1016/j.jmb.2026.169701
  53. PLoS Pathog. 2026 Feb;22(2): e1013967
    Flexibility and modulation of translation initiation in enterovirus genomes.
    Rhian L O'Connor, Georgia M Cook, Jacqueline Hankinson, Ksenia Fominykh, Samantha H Cheng, Daniel A Nash, Aurélie Cenier, Komal M Nayak, Stephen C Graham, Janet E Deane, Matthias Zilbauer, Andrew E Firth, Valeria Lulla.
      Enteroviruses comprise a large group of mammalian pathogens that often utilize two open reading frames (ORFs) to encode their proteins: the upstream protein (UP) and the main polyprotein. In some enteroviruses, in addition to the canonical upstream AUG (uAUG), there is another AUG that may represent an alternative upstream initiation site. An analysis of enterovirus sequences containing additional upstream AUGs identified several clusters, including strains of pathogenic Enterovirus alphacoxsackie and E. coxsackiepol. Using ribosome profiling on coxsackievirus CVA13 (E. coxsackiepol), we demonstrate that both upstream AUG codons can be used for translation initiation in infected cells. Moreover, we confirm translation from both upstream AUGs using a reporter system. Mutating the additional upstream AUG in the context of CVA13 did not result in phenotypic changes in immortalized cell lines. However, the wild-type virus outcompeted this mutant in human intestinal organoids and differentiated neuronal systems, representing an advantage in physiologically relevant infection sites. Mutation of the stop codon of the shorter upstream ORF led to dysregulated translation of the other ORFs in the reporter system, suggesting a potential role for the additional uORF in modulating the expression level of the other ORFs. Additionally, we demonstrate regulation of uORF translation in response to stress. These findings reveal the remarkable plasticity of enterovirus IRES-mediated initiation and the competitive advantage of double-upstream-AUG-containing viruses in terminally differentiated intestinal organoids and neuronal systems.
    DOI:  https://doi.org/10.1371/journal.ppat.1013967
  54. Stress Biol. 2026 Feb 10. 6(1): 14
    A conserved Lsm8-exosome module maintains RNA splicing fidelity to control fungal stress adaptation and virulence.
    Yiyi Ren, Haolan Cheng, Xingmin Han, Meiling Guo, Chenghui Xu, Jiayue Yan, Zhiwei Ge, Zhonghua Ma, Yun Chen.
      Fusarium graminearum, the causal agent of Fusarium head blight (FHB), poses a major threat to global food security by contaminating cereals with the mycotoxin deoxynivalenol (DON). Although transcriptional and protein-level regulation of its stress response and virulence has been extensively studied, the functional significance of mRNA processing in these critical processes remains largely unexplored. Here, we identify Lsm8, a highly conserved core subunit of the nuclear Lsm2-8 complex, as a pivotal regulator linking RNA splicing fidelity to fungal growth, stress adaptation, and virulence. Deletion of LSM8 disrupted Lsm2-8 assembly and nuclear localization, resulting in widespread intron retention in genes essential for stress signaling (HOG1, ATF1), development (GPA1, STE12), and trichothecene biosynthesis. Consequently, osmoadaptation was impaired, sexual reproduction was abolished, and both DON production and virulence were drastically reduced. We further demonstrate that intron-retained transcripts are predominantly degraded by the RNA exosome, revealing a conserved Lsm8-exosome module that maintains splicing fidelity and RNA surveillance. Given the deep evolutionary conservation of Lsm8 across eukaryotes, these findings uncover a fundamental post-transcriptional regulatory layer governing fungal stress response, virulence, and mycotoxin biosynthesis, and highlight RNA-processing factors as universal determinants of virulence and promising antifungal targets across eukaryotic pathogens.
    Keywords:   Fusarium graminearum ; Fungal virulence; Intron retention; Lsm2-8 complex; Mycotoxin biosynthesis; Post-transcriptional regulation; RNA exosome; RNA splicing fidelity; Stress response
    DOI:  https://doi.org/10.1007/s44154-026-00285-6
  55. Ann Med Surg (Lond). 2026 Feb;88(2): 1359-1368
    FTO promotes the cervical cancer progression via regulation of FGF2 expression.
    Jie Chen, Yun Gu, Ying Zheng, Min Gu, Chenyi Yang, Chunping Ye.
       Background: Cervical cancer remains one of the most common gynecological malignancies worldwide, with epigenetic RNA modifications playing a critical role in its development. This study aims to investigate the role of fat mass and obesity-associated protein (FTO) in cervical cancer progression and its impact on N6-methyladenosine (m6A) RNA methylation, focusing on Fibroblast Growth Factor 2 (FGF2) as a key downstream mediator.
    Methods: We analyzed FTO expression in adjacent normal and cervical cancer tissues by using immunohistochemistry (IHC), Western blot, and q-PCR. We also examined FTO expression and m6A modification levels in cervical cancer cell lines versus control cell lines. To investigate the impact of FTO overexpression and knockdown on cell proliferation and apoptosis, a series of functional assays, including CCK-8, flow cytometry, and immunofluorescence staining, were carried out. Furthermore, we investigated the regulation of FGF2 by FTO using the GEPIA database, qRT-PCR, and Western blot.
    Results: There was a notable elevation of FTO expression in cervical cancer tissues as opposed to the adjacent normal tissues. Increased levels of FTO protein and mRNA were detected in tumor tissues, along with reduced m6A modification levels of FTO mRNA. Cervical cancer cells showed higher FTO expression and decreased m6A modification compared to control cell lines. Enhanced FTO expression in HeLa cells resulted in lower global m6A levels, increased cell proliferation, and reduced apoptosis. Conversely, FTO knockdown led to reduced cell proliferation, reduced FGF2 mRNA and protein levels, diminished lactate production, and impaired cell proliferation, and increased apoptosis.
    Conclusion: FTO significantly influences cervical cancer progression, at least in part, through m6A modification of FGF2, thereby affecting downstream signaling. Targeting FTO and its downstream effectors holds potential as a therapeutic strategy for cervical cancer treatment.
    Keywords:  FGF2; FTO; apoptosis; cell proliferation; cervical cancer; m6A RNA methylation
    DOI:  https://doi.org/10.1097/MS9.0000000000004625
  56. Science. 2026 Feb 12. 391(6786): 694-699
    Recruitment of bifunctional regulator thermospermine to methylated ribosomes directs xylem fate.
    Donghwi Ko, Raili Ruonala, Alexandre Faille, Eva Hellmann, Hanna Help, Huili Liu, Ronni Nielsen, Anders Haakonsson, Nuria De Diego, Anja Paatero, Mariia V Shcherbii, Karolina Stefanowicz, Sanja Ćavar Zeljković, Tine Drud Lundager Rasmussen, Ondrej Novak, Zsuzsanna Bodi, Gugan Eswaran, Brecht Wybouw, Matthieu Bourdon, Cristina Urbez, Xiaonan Liu, Kari Salokas, Tiina Öhman, Tanya Waldie, Petri Törönen, Sedeer El-Showk, Martin Balcerowicz, Fabrice Besnard, Xiaomin Liu, Patrick Perkins, Serina Mazzoni-Putman, Julia P Vainonen, Maija Sierla, Mikko J Frilander, Susanne Mandrup, Teva Vernoux, Karin Ljung, Alejandro Ferrando, Miguel A Blazquez, Liisa Holm, Rupert Fray, Markku Varjosalo, Ottoline Leyser, Ville O Paavilainen, Ari Pekka Mähönen, Anna Stepanova, Jose Alonso, Steffen Heber, Robert Malinowski, Finn Kirpekar, Alan J Warren, Ykä Helariutta.
      Polyamines are often associated with ribosomes and are thought to stabilize their integrity. In Arabidopsis, the polyamine thermospermine (tSpm) affects xylem cell fate. tSpm induces translation of SUPPRESSOR-OF-ACAULIS51 (SAC51) and SAC51-LIKEs (SACLs), which inhibit heterodimerization of the xylem development proteins LONESOME-HIGHWAY (LHW) and TARGET-OF-MONOPTEROS5. Here, we report a methyltransferase, OVERACHIEVER, that methylates the peptidyl transferase center of the 25S ribosomal RNA (rRNA). Residue m3U2952 promotes functional tSpm binding to a specific site connecting the P-site transfer RNA (tRNA) with rRNA residues in the peptidyl transferase center. This interaction enhances the translation of SACLs but inhibits that of LHW. Our study uncovers the dependency between a conserved rRNA base methylation and a polyamine in orchestrating cell fate decisions, highlighting a role for the ribosome chemical landscape in translational regulation.
    DOI:  https://doi.org/10.1126/science.adx2867
  57. Pathol Res Pract. 2026 Feb 04. pii: S0344-0338(26)00047-6. [Epub ahead of print]280 156396
    M6A demethylase FTO in leukemia: Function, molecular mechanisms, and therapeutic implications.
    Yinli Zhang, Shenxian Qian.
      Fat mass and obesity-associated protein (FTO) is a Fe(II)/2-oxoglutarate-dependent RNA demethylase that removes the N6-methyladenosine (m6A) mark and rewires post-transcriptional gene control. In leukemia, FTO is often overexpressed and promotes leukemogenesis by increasing the stability and translation of mRNAs that govern differentiation, metabolism, and survival. In acute myeloid leukemia (AML), FTO-dependent m6A erasure is associated with impaired differentiation (e.g., ASB2/RARA), reinforcement of MYC/CEBPA programs, and glycolytic and stress-adaptation pathways that support therapy resistance and relapse. In acute lymphoblastic leukemia (ALL), FTO contributes to disease maintenance through metabolic rewiring (e.g., ELK3-driven glycolysis), repression of tumor-suppressive transcripts (e.g., IRF8), and stabilization of ribosome-biogenesis mRNAs that sustain proliferative fitness, with additional influence from microenvironmental cues such as exosome-mediated transfer. Preclinical studies show that genetic depletion, small-molecule inhibition, or targeted degradation of FTO increases m6A on key targets, suppresses leukemic growth, and can sensitize cells to standard therapies, supporting FTO as a druggable epitranscriptomic vulnerability. This review summarizes FTO structure and function, highlights subtype-specific mechanisms in AML and ALL, and discusses emerging therapeutic strategies and translational challenges.
    Keywords:  AML; FTO; M6A demethylase
    DOI:  https://doi.org/10.1016/j.prp.2026.156396
  58. Nucleic Acids Res. 2026 Feb 05. pii: gkag101. [Epub ahead of print]54(4):
    Scaffolding of the H4K5ac chromatin remodeling complex by lncRNA MAHAC mediates epithelial-mesenchymal transition.
    Kai-Wen Hsu, Jeng-Shou Chang, Joseph Chieh-Yu Lai, Li-Hao Yang, Pei-Hua Peng, Tzu-Chin Lin, Kou-Juey Wu.
      Anchoring of a chromatin remodeler complex by long non-coding RNAs (lncRNAs) is a frequently utilized mechanism for lncRNAs to regulate gene expression. Hypoxia is a microenvironmental condition that plays a crucial role in promoting tumor progression. We previously identified a hypoxia-inducible lncRNA, RP11-390F4.3, that regulates epithelial-mesenchymal transition (EMT) without a delineated mechanism. Here, we show that the lncRNA RP11-390F4.3 (renamed MAHAC: MAintenance of Histone ACetylation) specifically induces histone H4 lysine 5 acetylation (H4K5ac) mark and promotes the deposition of H4K5ac mark on the promoters of EMT transcription factors. MAHAC scaffolds the ILF3/NF90-ILF2-CBP complex, which is co-localized with the members of the complex inside the nucleus under hypoxia. The minimal MAHAC region (nt 686-741) required for scaffolding the complex was mapped, and it induces allosteric activation of H4K5ac in in vitro histone acetyltransferase assay. This minimal MAHAC region is essential for hypoxia-induced EMT, migration, invasion, and H4K5ac activation. These findings demonstrate that hypoxia-induced MAHAC represents an unexplored allosteric regulator of H4K5ac that activates EMT and induces tumor progression.
    DOI:  https://doi.org/10.1093/nar/gkag101
  59. Mol Cell. 2026 Feb 06. pii: S1097-2765(26)00023-7. [Epub ahead of print]
    RBPscan: A quantitative in vivo tool for profiling RNA-binding protein interactions.
    Dmitry A Kretov, Owen Sanborn, Thora McIsaac, Elaine Park, Imrat Imrat, Samuel Wu, Marianne Régis, Louis-Mathieu Harvey, Daniel Cifuentes.
      RNA-binding proteins (RBPs) are essential regulators of gene expression at the post-transcriptional level, yet obtaining quantitative insights into RBP-RNA interactions in vivo remains challenging. Here, we developed RBP specificity and contextual analysis via nucleotide editing (RBPscan), which integrates RNA editing with massively parallel reporter assays to profile RBP binding in vivo. In RBPscan, fusion of an RBP to the adenosine deaminase acting on RNA (ADAR) catalytic domain induces RNA editing of a recorder mRNA carrying the tested RBP-binding site, serving as a readout of the RBP-RNA interaction. We demonstrate the utility of RBPscan in zebrafish embryos, human cells, and yeast, showing that it quantifies binding strength, resolves dissociation constants, identifies binding motifs for various RBPs, and links binding affinities to their impact on mRNA stability. RBPscan also provides positional mapping of Pumilio-binding sites in the long non-coding RNA NORAD. With its simplicity, scalability, and cross-system compatibility, RBPscan is a versatile tool for investigating protein-RNA interactions and complements established methods for studying post-transcriptional regulatory networks.
    Keywords:  ADAR; RBP-binding specificity; RBPs; RNA editing; RNA motif discovery; RNA-binding proteins; adenosine deaminase acting on RNA; dose-response analysis; massively parallel reporter assays; microRNAs; protein-RNA interactions
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.003
  60. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00060-4. [Epub ahead of print]45(2): 116982
    A bicistronic viral genome uses a compact type IV IRES near its 3' end to express a transmembrane protein.
    Madeline E Sherlock, Katherine E Segar, Jeffrey S Kieft.
      Hepatitis C virus (HCV) and many other RNA viruses contain a type IV internal ribosome entry site (IRES) in their 5' untranslated region (UTR). These IRES RNAs interact directly with the ribosome, enabling cap-independent translation initiation. Using bioinformatic homology searches, we identify a putative type IV IRES within the annotated 3' UTR of megrivirus E (MeV-E). In addition to its unusual genomic location, the MeV-E 3' IRES has a reduced size compared with HCV and many type IV IRESs. We determine the 3D structure of the MeV-E 3' IRES in complex with the ribosome using cryoelectron microscopy (cryo-EM) and show that the MeV-E 3' IRES initiates translation, but at lower levels than the larger IRES in the MeV-E 5' UTR. This small type IV IRES enables translation of a second open reading frame in the MeV-E genome, which likely encodes a transmembrane protein conserved in other megriviruses.
    Keywords:  CP: microbiology; CP: molecular biology; RNA structure; cryo-EM; internal ribosome entry site; translation regulation; viral RNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.116982
  61. bioRxiv. 2026 Jan 30. pii: 2026.01.29.702547. [Epub ahead of print]
    Decoding the MYC locus reveals a druggable ultraconserved RNA element.
    Peiguo Shi, Feiyue Yang, Fnu Tala, Wesley Huang, Alexis O Aparicio, Colin H Kalicki, Aditi Trehan, Michael R Murphy, Esther R Rotlevi, Linqing Xing, Muredach P Reilly, Jianwen Que, Xuebing Wu.
      The human genome is dominated by noncoding sequences, most of which are poorly conserved across species. How genetic information is distributed between coding and noncoding regions remains a fundamental unresolved question. Using CRISPR saturation mutagenesis at base-pair resolution, we mapped the functional fitness landscape of the 10-kb human MYC locus with a near-PAMless, high-fidelity SpRY-Cas9. This unbiased interrogation revealed that the majority (67%) of functionally essential base-pairs in this locus are noncoding. Paradoxically, the phenotypic impact of noncoding sequences correlates inversely with evolutionary conservation, driven in part by rapidly diverging cis-regulatory DNA elements that remain functionally constrained in humans. Within this landscape, we identified an ultraconserved RNA element in the 3' untranslated region (UTR) that is indispensable for MYC-dependent cancer cells. Remarkably, steric-blocking antisense oligos targeting this RNA element selectively eliminate MYC-addicted cancer cells by suppressing MYC function without reducing MYC abundance. Mechanistically, this 3' UTR element promotes perinuclear localization of MYC mRNA and efficient nuclear import of the short-lived MYC protein, enabling its function as a nuclear transcription factor. Together, these findings highlight noncoding sequences as major carriers of functional genetic information, provide a comprehensive fitness map of the MYC locus, and uncover a therapeutically actionable RNA element that disables MYC-driven cancer.
    DOI:  https://doi.org/10.64898/2026.01.29.702547
  62. Int J Mol Sci. 2026 Feb 03. pii: 1493. [Epub ahead of print]27(3):
    Targeted RNA Degradation by RIBOTACs: A Novel Therapeutic Avenue for Ophthalmic Diseases.
    Dario Rusciano, Caterina Gagliano, Alessandro Avitabile, José Fernando Maya-Vetencourt.
      Ophthalmic diseases, including inherited retinal dystrophies, age-related macular degeneration (AMD), and glaucomatous neuropathies, are often driven by the expression of pathogenic proteins or dysfunctional non-coding RNAs that are currently considered 'undruggable' with conventional small-molecule therapeutics. The emerging strategy of Ribonuclease-Targeting Chimeras (RIBOTACs) offers a revolutionary approach to address this therapeutic gap. RIBOTACs are heterobifunctional small molecules designed to bind a specific target RNA with one moiety and recruit a latent endogenous ribonuclease, such as RNase L, with the other, thereby catalyzing the RNA's degradation. This targeted degradation can potentially halt the production of mutant proteins, eliminate toxic gain-of-function RNAs, or modulate key regulatory pathways involved in angiogenesis, inflammation, and apoptosis-core processes in many blinding diseases. This review explores the immense potential of applying RIBOTAC technology to ophthalmology, discussing prospective targets such as mutant alleles in retinitis pigmentosa, VEGF transcripts in neovascular AMD, and inflammatory mediators in uveitis. We will also address the unique challenges and opportunities for RIBOTAC development in the eye, including delivery strategies to overcome ocular barriers, the need for high specificity to avoid off-target RNA degradation, and the optimization of pharmacokinetic properties for intraocular administration. With continued innovation, RIBOTACs are poised to evolve into a robust therapeutic platform, expanding the druggable genome and enabling precise, durable treatments for a range of currently intractable ophthalmic conditions.
    Keywords:  RIBOTACS; RNA degradation; RNA-based strategy; blindness; ocular diseases; ribonuclease
    DOI:  https://doi.org/10.3390/ijms27031493
  63. Bone. 2026 Feb 11. pii: S8756-3282(26)00058-X. [Epub ahead of print] 117832
    NSUN6-mediated m5C RNA methylation aggravate osteosarcoma progression through promoting PKP2 mRNA stability and expression.
    Chunyan Zhao, Yun Tang, Yongpeng He, Fagen Zhang, Wenqian Li, Xiaochun Chen, Zhengyang Yu, Kaiwen Fu.
       BACKGROUND: Osteosarcoma (OS) is a highly aggressive malignant bone tumor with poor prognosis. Both Plakophilin 2 (PKP2) and NOP2/Sun RNA methyltransferase 6 (NSUN6) were reported to be upregulated in OS, and NSUN6 is one of the important RNA methyltransferases catalyzing 5-methylcytosine (m5C) formation and participates in many critical bioprocesses in various tumors. However, the roles and underlying molecular mechanisms of NSUN6-mediated m5C modification in OS remain unclear.
    METHODS: Differentially expressed genes in OS and the expression of PKP2 were analyzed using the GSE126209 dataset of the GEO database. The mRNA and protein levels of PKP2 as well as NSUN6 in OS tissues and cells were then measured by RT-qPCR and western blot. Then, the relationship between the expression of PKP2 and the survival rate of OS patients was presented by the Kaplan-Meier (KM) survival curve. Subsequently, OS cell proliferation, migration, and apoptosis were assessed by colony formation, Transwell, and flow cytometry. Meanwhile, the mitochondrial membrane potential, the levels of MDA, ROS, and Fe2+ was determined by the corresponding kits. Besides, the binding of PKP2 and NSUN6 was verified by RIP assay. Dot blot and Me-RIP assay were used to evaluate the 5-methylcytosine (m5C) modification level of PKP2. Finally, a xenograft model was constructed to investigate the role of NSUN6/PKP2 axis in vivo.
    RESULTS: PKP2 was highly expressed in OS tissues and cells. PKP2 knockdown could effectively inhibit the proliferation and migration of OS cells, and promote their apoptosis, oxidative stress and ferroptosis. NSUN6 stabilized PKP2 expression through m5C methylation modification. Moreover, overexpression of PKP2 completely reversed the effects of NSUN6 knockdown on OS cells and xenograft tumors in mice.
    CONCLUSION: NSUN6 regulated the m5C methylation modification of PKP2 to stabilize its expression, thereby driving the malignant progression of OS cells, providing a promising targeted therapeutic strategy for OS.
    Keywords:  Ferroptosis; NOP2/Sun RNA methyltransferase 6; Osteosarcoma; Oxidative stress; Plakophilin 2; m5C methylation modification
    DOI:  https://doi.org/10.1016/j.bone.2026.117832
  64. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025 Oct 28. pii: 1672-7347(2025)10-1755-16. [Epub ahead of print]50(10): 1755-1770
    [Heterogeneity in the regulation of cellular stress responses by FUS gene mutations associated with amyotrophic lateral sclerosis].
    Chenchen Yu, Weiqian Zeng, Piyanat Meekrathok, Yue Bu, Junling Wang, Jian Qiu.
       OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective death of motor neurons, exhibiting marked clinical heterogeneity and lacking effective treatment. The etiology and pathogenic mechanisms remain incompletely understood. The FUS (fused in sarcoma) gene is one of the key causative genes in ALS. Pathogenic mutations in the encoded protein are predominantly clustered in the C-terminal nuclear localization signal (NLS) region, and distinct NLS mutation sites show considerable differences in pathogenic potency, clinical phenotypes, and molecular mechanisms. This study focuses on 2 representative pathogenic NLS mutations of FUS (FUSR514S and FUSP525L) to investigate their differential regulation of cellular stress responses and explore the underlying mechanisms.
    METHODS: Multiple sequence alignment of FUS protein homologs from 12 species was performed using an online tool from the National Center for Biotechnology Information (NCBI) to determine the evolutionary conservation of residues R514 and P525. The three-dimensional (3D) structure of the nuclear transport receptor-FUS complex [Protein Data Bank (PDB) ID: 5YVG] was analyzed and visualized using PyMOL. Structure of FUS mutants were generated using the mutation wizard tool in PyMOL by selecting the target conformational isomer and executing the mutation workflow. Tet-on inducible expression cell models for FUS wild-type (WT) and mutant FUS (FUSR514SS and FUSP525L) were established in human embryonic kidney 293T (HEK293T) cells. Protein expression levels and subcellular localization of FUS were assessed by Western blotting and immunofluorescence assay, respectively. FUS aggregation states were compared between WT and mutant FUS using a digitonin-based permeabilization and extraction assay, followed by sodium dodecylsulfate-polyacrylamide gel electrophoresis-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis. Blue native PAGE (BN-PAGE) was used to evaluate the stability of FUS-containing complexes. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured by flow cytometry. Stress granule (SG) formation was induced using sodium arsenite, and the effects of WT and mutant FUS on SG dynamics were analyzed by immunofluorescence assay. Protein expression changes of mitochondrial function-related proteins [translocase of outer membrane 20 kD subunit (Tom20) and voltage-dependent anion channel 1 (VDAC1)] and key molecules of the integrated stress response (ISR) pathway [phosphorylated-eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4)] were examined by Western blotting.
    RESULTS: Sequence alignment revealed that R514 and P525 are highly conserved across FUS homologs from 12 species. Structural analysis indicated that the FUSR514S and FUSP525L mutations disrupt hydrogen bonding or hydrophobic interactions between FUS and importin-β2, weakening the stability of these interactions. Western blotting confirmed the successful establishment of inducible WT and mutant FUS expression cell models, and exogenous FUS expression slightly suppressed endogenous FUS protein levels. Immunofluorescence assay demonstrated that WT FUS is predominantly localized in the nucleus, whereas both FUSR514S and FUSP525L mutants mislocalize to the cytoplasm with a punctate, granular distribution. Compared with WT FUS, neither mutant significantly affected mitochondrial membrane potential, ROS levels, or the homeostasis of mitochondrial function-related proteins (all P>0.05). Upon sodium arsenite exposure, mutant FUS formed SGs more rapidly, generated SGs with larger diameters, and displayed distinct intracellular distribution and aggregation patterns relative to WT (P>0.05). After drug withdrawal, WT and mutant FUS showed no significant difference in their effects on SG disassembly (P<0.05). Under basal conditions, FUSR514S exhibited significantly higher eIF2α phosphorylation levels than WT, and ATF4 protein levels also showed an increasing trend (P<0.05). No statistically significant difference was observed between FUSP525L and WT FUS in these measures (P>0.05). Sodium arsenite treatment increased eIF2α phosphorylation across all groups, eliminating inter-mutant differences.
    CONCLUSIONS: Distinct pathogenic NLS mutations of FUS differentially regulate cellular stress responses through different mechanisms, contributing to ALS initiation and progression. Among these, FUSP525L promotes the formation of larger stress granules, whereas FUSR514S more readily activates the cellular ISR.
    Keywords:  amyotrophic lateral sclerosis; fused in sarcoma gene; integrated stress response; stress granules; stress response
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2025.250211
  65. Cells. 2026 Feb 01. pii: 275. [Epub ahead of print]15(3):
    The Emerging Roles of GlycoRNAs in the Pathogenesis of Sepsis.
    Xiang Li, Saichaitanya Nallajennugari, Joshua Fu, Anfal Faisal, Mingui Fu.
      Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation, organ dysfunction, and potentially death. Despite significant advances in understanding the pathophysiology of sepsis, effective therapeutic options remain limited, and mortality rates remain unacceptably high. Therefore, a deeper understanding of sepsis pathogenesis and the identification of novel therapeutic targets are urgently needed to improve patient outcomes. Recent studies have revealed that RNAs can undergo glycosylation, generating a previously unrecognized class of molecules known as glycosylated RNAs (glycoRNAs), which are localized on the outer surface of cells. GlycoRNAs are highly expressed in immune cells, and accumulating evidence indicates that they play important roles in regulating immune responses, including immune cell adhesion and infiltration, immune cell activation, and immune evasion. In addition, glycoRNAs are abundantly expressed on the epithelial cell surfaces of the respiratory, digestive, urinary, and reproductive systems, suggesting that glycoRNAs may function as a component of epithelial barriers that protect against pathogenic invasion. Collectively, these findings suggest that glycoRNAs may play a critical role in the pathogenesis of sepsis. This review summarizes the expression and functions of glycoRNAs in immune and barrier systems and highlights their potential roles during distinct immunological phases of sepsis.
    Keywords:  glycoRNAs; immune cells; inflammation; pathogenesis; sepsis
    DOI:  https://doi.org/10.3390/cells15030275
  66. bioRxiv. 2026 Jan 31. pii: 2026.01.28.701883. [Epub ahead of print]
    A dose-dependent switch in translation capacity controls the transcription factor response to H 2 O 2 stress.
    Chance Parkinson, Woody March-Steinman, Elizabeth Jose, Lisa Shanks, Andrew L Paek.
      Hydrogen Peroxide (H 2 O 2 ) stress activates transcription factors (TFs) in a dose-dependent manner, with distinct TFs activated in response to low versus high H 2 O 2 . Here, we show that high H₂O₂ imposes a translational constraint that prevents accumulation of TFs requiring de novo protein synthesis. Under low H 2 O 2 conditions, TFs including p53, NRF2, and ATF4, accumulate and drive stress-responsive gene expression. In contrast, high H 2 O 2 induces coordinated inhibition of translation initiation and elongation through activation of the integrated stress response (ISR), suppression of mTORC1 signaling, and activation of eEF2K, thereby blocking accumulation of these TFs. Inhibition of translation and repression of p53, NRF2, and ATF4 coincides with nuclear shuttling of pre-existing TFs, including FOXO1, NFAT1, and NF-κB. We propose that shuttling TFs provide a backup mechanism to respond to severe oxidative stress while translation is inhibited. Together, these findings identify translational control as a central switch governing transcription factor response to H 2 O 2 stress.
    DOI:  https://doi.org/10.64898/2026.01.28.701883
  67. Elife. 2026 Feb 12. pii: RP106503. [Epub ahead of print]14
    Ribosomal RNA synthesis by RNA polymerase I is subject to premature termination of transcription.
    Chaïma Azouzi, Katrin Schwank, Sophie Queille, Marta Kwapisz, Marion Aguirrebengoa, Anthony Henras, Simon Lebaron, Herbert Tschochner, Annick Lesne, Frederic Beckouët, Olivier Gadal, Christophe Dez.
      The RNA polymerase I (Pol I) enzyme that synthesizes large rRNA precursors exhibits a high rate of pauses during elongation, indicative of a discontinuous process. We show here that premature termination of transcription (PTT) by Pol I in yeast Saccharomyces cerevisiae is a critical regulatory step limiting rRNA production in vivo. The Pol I mutant, SuperPol (RPA135-F301S), produces 1.5-fold more rRNA than the wild type (WT). Combined CRAC and rRNA analysis link increased rRNA production in SuperPol to reduced PTT, resulting in shifting polymerase distribution toward the 3' end of rDNA genes. In vitro, SuperPol shows reduced nascent transcript cleavage, associated with more efficient transcript elongation after pauses, to the detriment of transcriptional fidelity. Notably, SuperPol is resistant to BMH-21, a drug impairing Pol I elongation and inducing proteasome-mediated degradation of Pol I subunits. Compared to WT, SuperPol maintains subunit stability and sustains high transcription levels upon BMH-21 treatment. These comparative results show that PTT is alleviated in SuperPol while it is stimulated by BMH-21 in WT Pol I.
    Keywords:  BMH-21; RNA polymerase I; S. cerevisiae; genetics; genomics; premature termination of transcription; rDNA transcription
    DOI:  https://doi.org/10.7554/eLife.106503
  68. J Biol Eng. 2026 Feb 07.
    Protein-inducible ribosomal frameshifting enables programmable translational control for genetic circuit design in Escherichia coli.
    Seongho Hong, Yelin Lim, Hansol Kang, Jongmin Kim.
       BACKGROUND: Programmed ribosomal frameshifting (PRF) is a translational mechanism that enables the ribosome to shift reading frames and access alternative coding sequences. PRF occurs naturally in a wide range of organisms, including viruses, bacteria, and eukaryotes, where it supports compact encoding and stoichiometric control of protein expression. Despite the great potential of PRF in synthetic circuit designs, a broader adoption of PRF in circuit designs has been hampered by rather strict sequence constraints and structural requirements.
    RESULTS: This work introduces a synthetic translational regulatory platform, protein-inducible ribosomal frameshifting (PIRF), by integrating aptamer-protein interactions with a - 1 PRF motif to enable regulated translation in Escherichia coli. PIRF modules respond to intracellular RNA-binding proteins such as PP7 and MS2, triggering frameshifting in a condition-dependent manner. PIRF could be used to program logic gate operations through frame-dependent translation and enable multilayered regulation in synthetic circuits. Further, the flexible PIRF designs enable reading frame-dependent control of fusion protein expression, protein aggregation, and periplasmic localization via strategic positioning of peptide tags and protein coding sequences. While PIRF enabled regulated frameshifting and could be flexibly reconfigured for a variety of circuits and applications, a measurable level of basal frameshifting was often observed, which may require additional strategies for further optimization in the future. Together, PIRF supports applications in programmable and logical control of downstream protein expression, including condition-dependent aggregation and regulated subcellular localization.
    CONCLUSIONS: PIRF provides a compact and genetically encoded strategy for programmable protein-level regulation, expanding the synthetic biology toolkit for translational control, biosensing and biotherapeutics.
    Keywords:  Logic gates; Protein aggregation; RNA aptamer-protein interactions; Ribosomal frameshifting; Synthetic biology
    DOI:  https://doi.org/10.1186/s13036-026-00629-w
  69. Brief Bioinform. 2026 Jan 07. pii: bbag047. [Epub ahead of print]27(1):
    Multi-seed searching algorithm for integrated codon optimization of mRNA stability and translational efficiency in vaccine design.
    Yuhan Bo, Bingxin Liu, Shengyu Huang, Yanwei Liu, Libin Deng, Dake Zhang, Jing Zhang.
      Messenger RNA (mRNA) vaccines have revolutionized vaccinology with their rapid development cycles and adaptability, yet their broad application is constrained by unresolved challenges in balancing mRNA structural stability and translational efficiency. Here, we introduce a groundbreaking multi-seed searching algorithm for mRNA codon optimization, an innovative framework that synergistically co-optimizes minimum free energy and codon adaptation index through adaptive integration of simulated annealing and genetic algorithms. This novel approach enhances global search capability to escape local optima, a critical limitation of existing tools. Evaluations across long therapeutic mRNA sequences and short peptides (neoantigens from bladder cancer and melanoma) reveal our algorithm outperforms state-of-the-art LinearDesign, delivering superior balanced improvements in both stability and translational efficiency validating its unique ability to navigate the inherent trade-offs between these two key metrics. Built on this algorithm, the Optiseed platform introduces transformative features including customizable scoring functions, flexible parameters for tailored optimization, and support for integrating untranslated regions (UTRs), poly(A) tails, and other elements to enable end-to-end vaccine construct design. This innovation addresses the rigidity of conventional tools, empowering precise, context-specific optimization. Optiseed represents a robust, scalable solution for mRNA vaccine codon optimization. Its superior performance across diverse sequences underscores its potential to accelerate mRNA-based therapeutic development, particularly in personalized cancer immunotherapy, while offering a framework adaptable for other applications such as infectious disease vaccine design.
    Keywords:  CAI; MFE; MSSA; codon optimization; mRNA vaccine
    DOI:  https://doi.org/10.1093/bib/bbag047
  70. Cancer Med. 2026 Feb;15(2): e71620
    Farnesyl Diphosphate Synthase Promotes Proliferation of Hepatocellular Carcinoma Cells by Interacting With Glucose-6-Phosphate Dehydrogenase.
    Jingfeng Liu, Yisheng Zhu, Jiyang Lv, Xiaohao Hu, Yan Zhong.
       BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy characterized by metabolic reprogramming that supports tumour growth and survival. This study identifies farnesyl diphosphate synthase (FDPs), a key enzyme in the mevalonate pathway, as a critical regulator of HCC proliferation and apoptosis.
    METHODS: We applied bioinformatics analysis through TCGA and GSE database to identify the expression of FDPs within HCC patients. Then, mechanistic studies were conducted including Western blots, apoptosis assay, RT-qPCR, rescue assay, RNA-sequencing, in vivo study to prove the role of FDPs in regulating HCC progression.
    RESULTS: FDPs was found to be significantly upregulated in HCC tissues, and its down-regulation promotes tumour cell apoptosis while inhibiting tumour cell proliferation in vitro and in vivo. Mechanistically, we identified FDPs regulate glucose-6-phosphate dehydrogenase (G6PD) by RNA sequencing, bioinformatics prediction, and rescue experiments, indicating its involvement in glycolysis regulation in tumour cells. The identification of this FDPs-G6PD axis suggests a novel metabolic pathway contributing to HCC development.
    CONCLUSION: In summary, this study highlights FDPs play an essential oncogenic role in HCC, linking it to metabolic reprogramming and tumour survival. These findings establish FDPs as a promising therapeutic target, offering a foundation for further exploration of its regulatory mechanisms and potential clinical applications.
    Keywords:  cell apoptosis; cell proliferation; cholesterol metabolism; glycolysis; hepatocellular carcinoma
    DOI:  https://doi.org/10.1002/cam4.71620
  71. bioRxiv. 2026 Jan 30. pii: 2026.01.28.702203. [Epub ahead of print]
    Translational control of CAK and Cdk T-loop phosphorylation in response to growth in yeast.
    Heidi M Blank, Eun-Gyu No, Ainsley E Nelson, Abigail Payne, Sofia Lykidis, Michael Polymenis.
      Cyclin-dependent kinases (Cdks) require activating T-loop phosphorylation, a modification that is considered constitutive. Here, we examined the regulation of the Cdk-activating kinase, Cak1, in budding yeast. We measured Cak1 levels and the activating T169 phosphorylation of Cdc28 (the budding yeast Cdk) across various nutrient environments. We found that the abundance of Cak1 and the T169 phosphorylation is significantly reduced in cells that are proliferating very slowly or have entered quiescence. A small upstream open reading frame (uORF) in the CAK1 transcript represses Cak1 synthesis, especially in poor growth conditions. Eliminating the uORF increased Cak1 levels but did not alter proliferation kinetics under most laboratory contexts. Instead, it reduced the viability of quiescent cells and the fitness of slowly proliferating chemostat cultures. In cells lacking several type 2C protein phosphatases, which remove the T169 phosphorylation, there was a pronounced acceleration of initiation of cell division in the absence of the uORF in CAK1 . Our results suggest an unexpected layer of control, impinging on the activating phosphorylation of the Cdk. The uORF-mediated repression of Cak1 synthesis directly couples protein synthesis to the activity of the core cell cycle machinery.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.01.28.702203
  72. Int J Mol Sci. 2026 Feb 04. pii: 1525. [Epub ahead of print]27(3):
    Bioinformatic Prediction of Activation States in Molecular Network Pathways of Eukaryotic Initiation Factor 2 (EIF2) Signaling and Coronavirus Pathogenesis.
    Shihori Tanabe, Sabina Quader, Ryuichi Ono, Hiroyoshi Y Tanaka, Horacio Cabral.
      Eukaryotic initiation factor 2 (EIF2) signaling plays a crucial role in regulating mRNA translation and initiating eukaryotic protein synthesis. Computational molecular network pathway analysis of the canonical pathways of the coronaviral infection revealed that EIF2 signaling is inactivated when the coronavirus pathogenesis pathway is activated and vice versa. Our computational analyses indicated that the coronavirus pathogenesis pathway and EIF2 signaling had inverse activation states. Computational investigation of upstream or downstream microRNA (miRNA) revealed that EIF2 signaling directly interacted with miRNAs, including let-7, miR-1292-3p (miRNAs with the seed CGCGCCC), miR-15, miR-34, miR-378, miR-493, miR-497, miR-7, miR-8, and MIRLET7. A total of 36 nodes, including 8 molecules (ATF4, BCL2, CCND1, DDIT3, EIF2A, EIF2AK3, EIF4E, and ERK1/2), 1 complex (the ribosomal 40s subunit), and 1 function (apoptosis) in the coronavirus pathogenesis pathway, overlapped with EIF2 signaling. Alterations in EIF2 signaling may play a role in the pathogenesis of coronavirus.
    Keywords:  EIF2 signaling; coronavirus; microRNA; molecular pathway; network activation
    DOI:  https://doi.org/10.3390/ijms27031525
  73. J Gen Virol. 2026 Feb;107(2):
    Remodelling of P-bodies and the cytoskeleton by Orthohantavirus puumalaense (Puumala virus).
    Hannah Sabeth Schwarzer-Sperber, Annette Petrich, Matthias Schade, Niklaas Nilson, Linah Chibrac-Ahad, Maik J Lehmann, Katharina Paulick, Sabrina Weiss, Tina Dluzak, Daniel Bourquain, Peter T Witkowski, Detlev H Krüger, Andreas Herrmann, Roland Schwarzer.
      Orthohantaviruses are emerging zoonotic pathogens that can cause life-threatening diseases in humans. Their tripartite, negative-sense RNA genome is encapsidated by the viral nucleoprotein, but the subcellular localization and dynamics of these viral RNAs and proteins remain poorly characterized. Here, we present a comprehensive microscopy-based analysis of Puumala virus, the most prevalent orthohantavirus in northern and western Europe. Using fluorescence in situ hybridization (FISH) and Multiple Sequential FISH, we mapped the distribution of viral mRNAs, viral genomic RNAs (vRNAs), nucleoproteins and associated host cell factors, quantifying their intracellular abundance, co-localization and subcellular positioning. We observed distinct clustering of vRNAs with varying degrees of nucleoprotein association, a progressive increase in nucleoprotein expression levels during infection and a concomitant rise in the abundance of P-bodies. Moreover, we report a marked spatial reorganization of actin, microtubules and P-bodies, indicating substantial structural remodelling of host cells during orthohantavirus infections. Using a novel end-specific FISH assay, we observed a preferential 5'-end degradation of vRNAs in P-bodies, shedding new light on orthohantavirus RNA turnover within host RNA-processing compartments. Finally, co-localization analyses revealed the formation of potential 'viral factories' composed of nucleoprotein, vRNAs and viral mRNAs, indicating an intricate assembly hierarchy. Collectively, these findings improve our understanding of orthohantavirus replication and highlight the dynamic interplay between virus and host cell components.
    Keywords:  P-bodies; actin; cytoskeleton; fluorescence in situ hybridization (FISH); microscopy; orthohantaviruses
    DOI:  https://doi.org/10.1099/jgv.0.002220
  74. Biophys Physicobiol. 2025 ;22(4): e220028
    Selection-diversification interplay in oligonucleotide chemical evolution.
    Jiro Kakizaki, Ryo Mizuuchi.
      The emergence of catalytic RNAs (ribozymes) may have set the stage for an "RNA world" preceding protein evolution. The probability of ribozyme emergence and maintenance would have depended on available oligonucleotide compositions. Excessively high or low sequence diversity could hinder ribozyme formation, whereas balanced diversity is likely more favorable. Multiple steps of chemical evolution-from nucleotide supply and oligomerization to subsequent copying and assembly through nonenzymatic reactions-likely shaped oligonucleotide diversity. In this review, we discuss how oligonucleotide chemical evolution may have involved both selective enrichment and diversification of sequence compositions, with their interplay generating oligonucleotide pools of varying diversity across environments and evolutionary timescales. Current experiments on nonenzymatic RNA-based reactions remain limited to short timescales, but strategies combining DNA and protein enzymes could provide efficient models to investigate the compositional dynamics of oligonucleotides.
    Keywords:  RNA world; chemical evolution; origins of life; ribozyme; sequence diversity
    DOI:  https://doi.org/10.2142/biophysico.bppb-v22.0028
  75. bioRxiv. 2026 Feb 03. pii: 2026.02.02.703294. [Epub ahead of print]
    RNA Quality Control Enables Antibiotic Tolerance.
    Andrew T Nishimoto, Juan C Ortiz-Marquez, Michelle R Scribner, Yanying Yu, Qidong Jia, Haley Echlin, Amy R Iverson, Abigail E McKnight, Nadia Olivero, Aaron Poole, Enolia Marr, Jordan Coggins, Adam Rosenthal, Chrispin Chaguza, Randolph K Larsen, Mark E Hatley, Ralph R Isberg, Vaughn S Cooper, Tim van Opijnen, Jason W Rosch.
      The mechanisms underlying adaptation to antibiotic pressure within complex host environments remain incompletely understood. By experimentally evolving Streptococcus pneumoniae subjected to various antibiotics and immune states, we demonstrate populations adopting distinct adaptive strategies depending on specific selective context. General antibiotic stress drives convergent mutations in rny , encoding the RNA degradosome scaffold RNase Y, that exhibit broad-spectrum antibiotic tolerance and accelerated recovery. Single-cell transcriptomics revealed antibiotic-induced death is driven by transcriptional collapse, a catastrophic loss of RNA quantity and integrity. In contrast, rny mutants avert this via a bet-hedging strategy: a resilient minority maintains a baseline transcriptional profile, while a quiescent majority undergoes selective RNA degradation to preserve transcript fidelity. Upon stress removal, these populations execute a prioritized transcriptional ribosomal reboot, facilitating accelerated recovery. These findings identify RNA turnover as a tunable master regulator to survive combined pressures of antibiotics and immunity.
    DOI:  https://doi.org/10.64898/2026.02.02.703294
  76. Front Cell Dev Biol. 2026 ;14 1756287
    Integrative multi-omic profiling of the chronically hypoxic heart: focus on m6A and m6Am epitranscriptomic regulation.
    Marketa Hlavackova, Daniel Benak, Dita Sotakova-Kasparova, Kristyna Holzerova, Anton Skriba, Anna Simonova, Hana Cahova, Tatyana Kobets, Tereza Jancova, Frantisek Kolar.
      Reduced oxygen availability is an environmental factor characteristic of high-altitude conditions that plays a critical role in shaping cellular homeostasis and epigenomic regulation. Adaptation to various models of chronic hypoxia represents a well-recognized physiological process that enhances cardiac tolerance to ischemic stress; however, the molecular mechanisms coordinating metabolic, proteomic, and post-transcriptional remodeling in this adaptive response to low-oxygen conditions remain insufficiently understood. Here, we combined quantitative metabolomic, lipidomic, and proteomic profiling with targeted protein analyses to characterize the molecular landscape of rat hearts adapted to continuous normobaric hypoxia (CNH, 10% O2 for 3 weeks). Multi-omics integration revealed tightly coupled remodeling across metabolic and structural domains, consistent with enhanced energetic efficiency and oxidative stress resistance. Pathway enrichment identified coordinated activation of energy reprogramming (AMPK, glycolysis, and PPAR signaling), reinforcement of antioxidant defense (glutathione metabolism), membrane remodeling (glycerophospholipid and peroxisomal pathways), and protein quality control (autophagy-lysosome and proteasome systems). Beyond these canonical adaptive responses, CNH markedly affected the epitranscriptomic machinery: both m6A demethylases ALKBH5 and FTO - enzymes previously linked to cardioprotective effects - were upregulated, accompanied by increased abundance of multiple m6A readers (YTHDF1-3, YTHDC1), whereas methyltransferases METTL3 and PCIF1 remained stable. At the level of RNA modifications, global m6A levels in total RNA were unchanged, whereas m6Am levels were significantly increased under hypoxia. These results demonstrate that chronic hypoxia reprograms the heart not only at the metabolic and proteomic levels but also through epitranscriptomic regulation, suggesting that RNA methylation dynamics may contribute to the cardioprotective phenotype. Collectively, our findings provide a system-level framework linking metabolic flexibility, redox balance, and post-transcriptional control during hypoxic adaptation.
    Keywords:  epitranscriptomics; heart; hypoxia; m6A; m6Am
    DOI:  https://doi.org/10.3389/fcell.2026.1756287
  77. Int J Mol Sci. 2026 Jan 27. pii: 1269. [Epub ahead of print]27(3):
    Beyond Neurotrophins: A Proposed Neurotrophic-Epigenetic Axis Mediated by Non-Coding RNA Networks for Hericium erinaceus Bioactives-A Hypothesis-Driven Review.
    Giovanni Luca Cipriano, Ivana Raffaele, Alessia Floramo, Veronica Argento, Deborah Stefania Donato, Chiara Malatino, Serena Silvestro, Giovanni Schepici, Maria Francesca Astorino, Marco Calabrò, Ivan Anchesi.
      Hericium erinaceus (H. erinaceus), a medicinal mushroom, is a source of bioactive compounds with demonstrated neuroprotective potential. This activity is primarily attributed to two distinct classes of compounds: erinacines from the mycelium, which potently induce the synthesis of neurotrophins, protein growth factors essential for neuronal survival and health, and hericenones from the fruiting body, which subsequently appear to enhance or potentiate neurotrophin-activated signaling pathways. Preclinical evidence substantiates their ability to enhance neurotrophin levels, particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), and activate their cognate Trk receptors. Activation of these pathways, including PI3K/AKT/mTOR and MAPK/ERK, converges on transcription factors such as CREB, promoting neuronal survival, neurite outgrowth, and synaptic plasticity. However, the precise molecular mechanisms linking these small molecules to the complex orchestration of neurotrophic gene expression remain incompletely defined. This review synthesizes current knowledge of the neurotrophic pharmacology of H. erinaceus bioactives and proposes a novel framework suggesting that non-coding RNAs (ncRNAs) play a key regulatory role. We hypothesize that hericenones and erinacines modulate key transcriptional hubs, such as CREB, Nrf2, and NF-κB, which in turn regulate the expression of specific ncRNAs (e.g., miR-132, miR-146a) known to control neurogenesis, synaptogenesis, oxidative stress, and neuroinflammation. This ncRNA-mediated mechanism may represent an un-explored axis that explains the pleiotropic neuroprotective effects of these compounds. We critically appraise the existing preclinical evidence, identify significant methodological limitations and translational gaps, and propose a structured research roadmap to test these ncRNA-centric hypotheses, aiming to accelerate the rational development of H. erinaceus-derived compounds for neurodegenerative diseases.
    Keywords:  Hericium erinaceus; neurodegeneration; neuroprotection; neurorehabilitation; neurotrophins; non-coding RNA
    DOI:  https://doi.org/10.3390/ijms27031269
  78. Signal Transduct Target Ther. 2026 Feb 12. 11(1): 52
    RMzyme: regulations of RNA-modifying enzymes in humans.
    Ruihan Luo, Haixia Xu, Qingbo Zhou, Shanli Ding, Min Qiang, Jianguo Wen, Pora Kim, Xiaojuan Yang, Yunshi Cai, Kunlin Xie, Jiang Zhu, Yungang Xu, Tian Lan, Xiaobo Zhou, Hong Wu.
      RNA modifications represent a dynamic layer of gene expression regulation, RNA stability, and translation with profound implications for cellular function and disease. However, the critical regulation and functions of RNA-modifying proteins (RMPs) remain poorly understood. Here, we present a large-scale characterization of RMPs through 378 multiomics datasets encompassing genomics, bulk and single-cell transcriptomics, epitranscriptomics, proteomics, and posttranslational modifications (PTMs) across 63 human tissues. Our analysis of experimental perturbations of RMPs revealed dynamic differential modification peaks and expressed genes. We applied nonnegative matrix factorization to annotate RMP-mediated cell types in single-cell transcriptomes. Functional annotations in acute myeloid leukemia (AML) revealed RMPs such as ALKBH5 as critical mediators of m6A dynamics, influencing pathways involved in translation initiation, immune regulation, and tumorigenesis. We revealed cell type-specific modification patterns, including those in ALKBH5-enriched AML stem cells with special ligand‒receptor interactions and genetic variations modulated by m6A. We integrated proteogenomic data to uncover PTM-associated regulatory, mutation, and protein‒protein interaction networks linked to RMPs. We developed RMzyme, a platform that consolidates our findings and provides insights into RMPs and their downstream effects. This resource is expected to facilitate biomedical research into the molecular mechanisms of human diseases through the lens of RNA modifications and multiomics data integration.
    DOI:  https://doi.org/10.1038/s41392-025-02568-2
  79. Eur J Paediatr Neurol. 2026 Feb 05. pii: S1090-3798(26)00004-8. [Epub ahead of print]60 109-113
    Luteolin use in Integrated Stress Response: insight from a case of EIF2AK2-related dystonia.
    Antonio Spagarino, Luca Urru, Miryam Rosa Stella Foti, Marianna Farnè, Elisa Pisaneschi, Stefania Bigoni, Cristina Forest, Agnese Suppiej.
      This study presents the first reported case of a 3-year-old child with EIF2AK2-related dystonia treated with adjunctive luteolin supplementation. EIF2AK2-related dystonia, characterized by exacerbations during infections, is associated with disruptions in the integrated stress response (ISR). The ISR, a cellular signaling pathway activated in response to stress, culminates in the phosphorylation of eIF2α, which modulates protein synthesis and can induce cell death. Pathogenic variants in EIF2AK2 disrupt this pathway, contributing to the development of dystonia. Luteolin, a flavonoid possessing anti-inflammatory and neuroprotective properties, was hypothesized to modulate the ISR, thereby attenuating infection-induced dystonic exacerbations. The patient, exhibiting early-onset dystonia with clinical worsening during febrile episodes, harbored a de novo pathogenic variant in EIF2AK2. Following initial clinical improvement with trihexyphenidyl, adjunctive luteolin therapy was initiated, resulting in further clinical enhancements. Quantitative assessment using dystonia rating scales (UDRS, MSS, DSS) demonstrated sustained improvement, characterized by a reduction in the severity and frequency of infection-triggered relapses. The proposed mechanism of action involves luteolin disrupting the PACT-PKR interaction, a critical step in ISR activation, thus preventing excessive eIF2α phosphorylation and subsequent cellular dysfunction. This mechanism, supported by in vitro studies utilizing relevant disease models, suggests luteolin's potential to stabilize cellular homeostasis under stress. This case report indicates that luteolin may serve as a promising adjunctive therapeutic strategy for patients with infection-sensitive dystonic phenotypes, such as EIF2AK2-related dystonia. Further randomized controlled trials are warranted to validate these findings and establish the optimal dosing regimen and long-term safety profile of luteolin in vivo.
    Keywords:  Dystonia; EIF2AK2; Integrated stress response; Luteolin
    DOI:  https://doi.org/10.1016/j.ejpn.2026.02.001
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