bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–07–05
71 papers selected by
Cédric Chaveroux, CNRS
  1. 16S ribosomal RNA modification drives transcript-specific translation efficiency.
  2. Centrosome linker protein CEP68 modulates cellular stress responses via nuclear condensate formation and HSP27 interaction.
  3. Dynamic redistribution of eIF4F controls cap-dependent translation initiation.
  4. Remodeling of mRNA by eIF4F in human translation initiation.
  5. Acute glucose stimulation drives coordinated translational reprogramming in primary pancreatic islets: from global remodeling to fine-tuned insulin synthesis.
  6. Cannabidiol Activates Integrated Stress Response Signaling and Immune Trafficking Programs in an A375 Melanoma-Jurkat T Cell Coculture Model: A Multi-Omics Analysis.
  7. METTL3 suppresses pyroptosis in obstructive sleep apnea-associated hypertension via YTHDF2-mediated SOX4 mRNA degradation.
  8. The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.
  9. The m6A epitranscriptome in cancer therapy resistance: From cellular plasticity and metabolic rewiring to immune escape and therapeutic targeting.
  10. The Role of Long Noncoding RNAs in Modulation of Stress Granules in Cancer.
  11. Fungistatic effect of sorbic acid on yeast cells via translational repression involving eIF2 α phosphorylation and formation of Ded1- and eIF2B-granules.
  12. The exercise-microbiota-queuine-tRNA axis in Parkinson's disease: evidence, uncertainties, and experimental priorities.
  13. Cryo-EM structure of the naked mole-rat ribosome reveals a stabilized split 28S rRNA.
  14. The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention.
  15. 40S ribosomal subunits move along the 5' UTR through an eIF4A-independent mechanism in higher eukaryotes.
  16. RNA modifications as innovative pharmaceutical targets: emerging drug delivery strategies and precision therapeutics for cancer immunotherapy and metabolic diseases.
  17. Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.
  18. The role of ATF4 in neurons under mitochondrial stress.
  19. Allosteric disordering of eIF2B regulates the integrated stress response.
  20. Phosphorylation Patterns of Preribosomal Proteins Associated with the RNA Exosome.
  21. Silencing of human RNA polymerase I subunit A34 influences multiple cellular processes including rDNA transcription and cell migration.
  22. Post-transcriptional regulation in cancer chemoresistance.
  23. Evaluation of Dorado v5.2.0 de novo basecalling models for the detection of tRNA modifications using RNA004 chemistry.
  24. METTL3/FTO drives ferroptosis in colorectal cancer by targeting m6A modification of MUC1 mRNA and YTHDF2-dependent SLC7A11/GSH pathway.
  25. Non-canonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy.
  26. Norepinephrine Couples Astrocytic Metabolism to mTOR-Driven Protein Synthesis.
  27. Multi-layered RNA decay mechanisms underlie subgenome-biased homoeologous mRNA stability in salt-stressed allopolyploid plants.
  28. Cell-Free In Vitro mRNA Translation In Drosophila Lysates.
  29. Deciphering the Functional Mechanisms of eIF3f in Tumors and Exploring Targeted Therapies.
  30. Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.
  31. Peroxisomal catalase and plasmalogen biosynthesis protect from oxidative stress in Barth syndrome cardiomyopathy.
  32. RNAGEN: A Generative Adversarial Network-Based Model to Generate Synthetic RNA Sequences to Target Proteins.
  33. Gravitational and mechanical forces shape mitochondrial translation.
  34. Evolution of a core ribosomal innovation in octopus.
  35. Bridging two hosts: how intracellular environments shape flaviviral infection.
  36. The Role of RNA Helicase DHX33 in Tumorigenesis.
  37. When mitochondria lose their fold: matrix proteostasis and stress signaling.
  38. A nucleolar stress gene signature enables quantitative scoring across multi-omics contexts.
  39. Human aminoacyl-tRNA synthetases as integrators of translation and cell signalling networks.
  40. Visualizing Diverse RNA Functions in Living Cells With SpinachTM Family of Fluorogenic Aptamers.
  41. Tweezing apart ribosome heterogeneity.
  42. [Clinical significance and molecular mechanisms of m6A modification in oral squamous cell carcinoma].
  43. Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.
  44. [Mechanisms of RNA-binding protein phase separation in steroid-associated necrosis of the femoral head].
  45. METTL3 Promotes Castration-Resistant Prostate Cancer Progression by Enhancing AKR1C3 Expression.
  46. YTHDC2 suppresses oral squamous cell carcinoma progression by inhibiting glutaminolysis via VHL/HIF-1α axis.
  47. Diversion of Arginine's dietary metabolic fate in proteinuric kidney disease.
  48. Mitochondrial quality control in human ageing and longevity.
  49. HRI Kinase Modulation by BTdCPU as a Therapeutic Strategy for Bortezomib Resistance in Prostate Cancer.
  50. Dynamic positioning of Rpc34 winged helix in RNA polymerase III elongation complex for its stability with implications for reinitiation.
  51. Integrated Glycoproteomics Identifies Dynamic IgA1 N-Glycosylation and FUT8 as a Functional Mediator in Multiple Myeloma.
  52. Proteomic Impact of Peripheral Expression of Mutant Huntingtin in C. elegans.
  53. p53-associated regulation of COX17 enhances elesclomol-induced copper-associated cytotoxicity and suppresses gastric cancer growth.
  54. Nutrient sensing and transceptor-mediated metabolic control in yeast.
  55. Structural basis of the regulation by CDK11 kinase of early spliceosome activation and evidence for its proofreading by DHX15 helicase.
  56. MBNL1-mediated alternative splicing in cancer: underlying mechanism, isoform regulation, and translational perspectives.
  57. Dynamic resource allocation in eukaryotic Resource Balance Analysis.
  58. Mechanisms influencing transient cytoplasmic protein targeting to intracellular lipid droplets.
  59. Arsenic Promotes Nonalcoholic Steatohepatitis via MCFD2-Induced PERK/eIF2α-Mediated Integrated Stress Response.
  60. GRP78 in human diseases: From molecular chaperone to therapeutic target.
  61. ATPR promotes differentiation in gastric cancer cells by endocan.
  62. SbHsp70 overexpression enhances drought and salinity tolerance in wheat through improved cellular stability and stress-associated structural adaptations.
  63. Defective queuosine and i6A/ms2i6A modification of tRNATyr cause frameshifting and protein aggregation.
  64. FgMob1 is involved in mitotic exit and regulates the development, abiotic stress response, and pathogenicity of Fusarium graminearum.
  65. Chronic stress promotes colorectal cancer progression by inducing M2 macrophage polarization and activating the CCL2-CCR2 axis.
  66. Protein homeostasis disruption in cisplatin-induced skeletal muscle atrophy: toxicological insights from experimental studies.
  67. Beyond The Nucleus: Translating Engineered Protein Localization To Chromatin Modifying Enzymes.
  68. [Development of Protein and RNA Degraders for Drug Discovery].
  69. Interaction of ARA54 with androgen receptor in mediating testosterone-dependent regulation of caput epididymal GPX5 expression in mice.
  70. Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function.
  71. Angiogenin mediates cell-cell fusion as a mitochondrial RNA processing enzyme.
  1. bioRxiv. 2026 Apr 20. pii: 2026.04.20.719615. [Epub ahead of print]
    16S ribosomal RNA modification drives transcript-specific translation efficiency.
    Zachory M Park, Christina R Savage, Amanda R Decker-Farrell, Chin-Hsien Tai, Tapan K Maity, Weiming Yang, Lisa M Jenkins, Kumaran S Ramamurthi.
      Bacterial ribosomal RNAs (rRNAs) are decorated with conserved nucleotide modifications, but the functionality of these modifications is often underexplored. MraW (RsmH) is a 16S rRNA methyltransferase that fine-tunes ribosomal function. We identified a loss-of-function allele in mraW that corrected a late-stage sporulation defect in Bacillus subtilis by bypassing a key sporulation checkpoint via altered translational regulation. Purified ribosomes isolated from Δ mraW cells displayed a ∼2-fold decrease in translation efficiency; in vivo , Δ mraW cells produced decreased levels of the sporulation checkpoint protein CmpA. This regulation was mediated by sequences from the 5' untranslated region and the coding sequence of cmpA , which form a step-loop structure that occlude early codons of the mRNA. Proteomic analysis revealed that MraW directly or indirectly regulates the production of multiple proteins, some of which form similar structural elements as the cmpA transcript. We propose that MraW modification of 16S rRNA enhances translation efficiency in general, and that specific transcripts, whose gene products are likely required in limiting quantities, have evolved structural features that act as a regulatory mechanism to govern protein levels. This type of regulation may be most apparent in bacteria which exhibit uncoupled transcription and translation.
    HIGHLIGHTS: A conserved 16S rRNA modification enhances translation of structured mRNAsEarly mRNA stem-loops impose translational control dependent on ribosome modificationmRNA structure and rRNA modifications likely co-evolved to fine-tune protein dosage.
    DOI:  https://doi.org/10.64898/2026.04.20.719615
  2. iScience. 2026 Jul 17. 29(7): 116491
    Centrosome linker protein CEP68 modulates cellular stress responses via nuclear condensate formation and HSP27 interaction.
    Hui-Fang Hung, Peng-Peng Zhu, Craig Blackstone.
      CEP68 is best known for its role at the centrosome linker, but its functions beyond the centrosome remain largely unexplored. Here, we show that CEP68 also localizes to the Golgi apparatus and nucleus, where it contributes to the stress response. CEP68 associates with stress response proteins, modulating eIF2α phosphorylation and stress granule (SG) formation during oxidative stress. In the nucleus, CEP68 forms liquid-like nuclear condensates adjacent to nuclear speckles (NSs), influencing their protein dynamics. The small heat shock protein HSP27, which translocates to NSs during stress, interacts with CEP68 under normal conditions, with this interaction markedly enhanced during stress. HSP27 regulates CEP68 condensate dynamics, while CEP68 nuclear condensates displace HSP27 from NSs. Both neuropathy-associated HSP27 mutants and a disease-linked CEP68 variant alter their interaction. These findings uncover a new role for CEP68 in stress response and provide insights into HSP27's functions in stress adaptation, neuropathy, and immune regulation.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116491
  3. bioRxiv. 2026 Jun 23. pii: 2026.06.21.733607. [Epub ahead of print]
    Dynamic redistribution of eIF4F controls cap-dependent translation initiation.
    Riley C Gentry, Nicholas A Ide, Victoria M Comunale, Colin Echeverría Aitken, Colin D Kinz-Thompson, Ruben L Gonzalez.
      Translation initiation requires messenger RNAs (mRNAs) to be recognized and loaded into ribosomes through a process catalyzed by the heterotrimeric eukaryotic initiation factor eIF4F. During this process, eIF4F engages the 7-methylguanosine cap at the 5' end of the mRNA and promotes productive engagement with the ribosomal pre-initiation complex (PIC) to facilitate PIC loading onto the mRNA. Although eIF4F is central to translation initiation and its regulation, the molecular mechanism by which eIF4F stimulates PIC loading, and the mechanistic role of the essential ATP hydrolysis step catalyzed by eIF4F, have remained unresolved. Here, we use single-molecule fluorescence microscopy to directly visualize the dynamics of eIF4F during cap recognition and PIC engagement. We show that ATP binding, but not ATP hydrolysis, promotes productive assembly of eIF4F on mRNA and enables dynamic redistribution of eIF4F along the transcript. In contrast, ATP hydrolysis is specifically required for recycling of cap-stalled eIF4F during productive PIC engagement. Furthermore, we identify eIF3 and eIF4B as the minimal PIC-associated factors required to stimulate ATP-hydrolysis-dependent recycling of eIF4F during PIC loading. Together, our results support a model in which productive PIC engagement stimulates ATP-hydrolysis-dependent recycling of eIF4F, thereby coupling eIF4F recycling to PIC loading during translation initiation. This mechanism provides a framework for understanding how mRNA topology, RNA-binding proteins, and the availability of initiation factors can control translational efficiency.
    DOI:  https://doi.org/10.64898/2026.06.21.733607
  4. bioRxiv. 2026 Jun 19. pii: 2026.06.19.733470. [Epub ahead of print]
    Remodeling of mRNA by eIF4F in human translation initiation.
    Carlos Alvarado, Christopher P Lapointe, Jinfan Wang, Masaaki Sokabe, Rosslyn Grosely, Ajinkya A Dhepe, Crystal I Stackhouse, Michael Z Palo, Adam Mamot, Jacek Jemielity, Christopher S Fraser, Joseph D Puglisi.
      For the ribosome to load onto an mRNA during the early steps of translation initiation, the mRNA must be activated by the eIF4F complex. The mechanism of this activation step has remained elusive. Here we employ multi-perspective real-time single-molecule assays to observe directly mRNA-eIF4F binding near the 5' end, mRNA conformational remodeling, and 40S ribosomal subunit loading. eIFs 4E, 4G, and 4B play distinct roles in promoting eIF4F association and stabilizing eIF4A binding. Binding of eIF4F is the rate-limiting step in mRNA activation: once bound, mRNA conformation is rapidly extended in an ATP-dependent manner. The mRNA extended state is the necessary substrate for 43S PIC loading and perturbations to extension delay loading. Features of the mRNA, such as the 7-methylguanosine cap at the 5' end and secondary structures, modulate these steps and regulate ribosome loading. Our results establish a kinetic and mechanistic framework for the early steps in translation initiation.
    DOI:  https://doi.org/10.64898/2026.06.19.733470
  5. Front Endocrinol (Lausanne). 2026 ;17 1834362
    Acute glucose stimulation drives coordinated translational reprogramming in primary pancreatic islets: from global remodeling to fine-tuned insulin synthesis.
    Yiqing Wang, Chunyang Shi, Yao Liu, Wenli Feng, Ming Liu, Xiaoxi Xu.
       Background: Pancreatic beta cells must rapidly escalate protein synthesis to maintain systemic glucose homeostasis. While the transcriptional responses are well characterized, the immediate translational dynamics governing this adaptive phase remain poorly defined.
    Methods: We performed high-resolution ribosome profiling (Ribo-seq) on primary mouse islets under acute low-glucose (2.5 mM) and high-glucose (25 mM) conditions and integrated analysis of the differential translation, functional enrichment, translational efficiency (TE), and ribosome kinetics. The protein levels and mRNA expression were validated using Western blot and quantitative PCR (qPCR), respectively.
    Results: We identified extensive translational reprogramming involving 1, 680 differentially translated genes. High glucose triggered a significant upregulation of immediate early genes (e.g., Fos and Nr4a1) and a concurrent inhibition of stress-related genes (e.g., Ddit3 and Trib3). On the other hand, beta cells prioritized the synthesis of cytosolic ribosomal proteins and elongation factors to expand the biosynthetic machinery. This was coordinated with a scale-up of the downstream secretory pathway (e.g., Sec61a1) and a metabolic realignment, characterized by the translational upregulation of mitochondrial enzymes (e.g., Cs and Fh1) despite the relative suppression of mitochondrial biogenesis genes. Furthermore, TE analysis revealed that several genes were regulated independent of their mRNA levels, such as Rpl3 and Atf4. Finally, kinetic analysis suggested that high glucose affected the ribosome occupancy density and distribution on specific transcripts, such as Ins1.
    Conclusion: Our research characterizes the translatome as a dynamic regulator of the glucose response. By revealing these rapid translational nodes, we provide potential targets to restore the insulin synthetic capacity and secretory function in T2DM, offering a mechanistic framework for the development of therapies centered on preserving β-cell proteostasis.
    Keywords:  insulin biosynthesis; pancreatic β cells; ribosome profiling; translational regulation; type 2 diabetes
    DOI:  https://doi.org/10.3389/fendo.2026.1834362
  6. ACS Omega. 2026 Jun 30. 11(25): 37332-37345
    Cannabidiol Activates Integrated Stress Response Signaling and Immune Trafficking Programs in an A375 Melanoma-Jurkat T Cell Coculture Model: A Multi-Omics Analysis.
    Ni Deng, Huifang Li, Ang Cai, Christopher L Hemme, Jonghae Youn, Ryan Janis, Matthew D Stone, Hang Ma, Chang Liu.
      Cannabidiol (CBD) is a nonpsychoactive cannabinoid with emerging anticancer and immunomodulatory properties; however, its systems-level mechanisms in tumor-associated immune cells remain incompletely defined. Here, we investigated CBD in a melanoma-T cell coculture model using integrated transcriptomic and proteomic analyses. At a subcytotoxic concentration (10 μM), CBD selectively induced apoptosis in melanoma while preserving T-cell viability and enhancing IL-2 secretion. RNA sequencing revealed coordinated activation of stress-adaptive, immune activation, and trafficking programs, including modulation of T-cell receptor signaling and cytokine networks. Data-independent acquisition proteomics identified activation of eukaryotic initiation factor 2 (EIF2) signaling, a central node of the integrated stress response (ISR) linking redox and endoplasmic reticulum stress to translational control. Multiomics integration converged on immune cell trafficking as a consistent outcome, with upregulation of ICAM1, ITGB1, and associated adhesion-related proteins. These findings suggest ISR-dependent translational reprogramming as a putative mechanistic axis by which CBD reshapes T-cell function in the melanoma microenvironment. Our study provides pharmacological insight into how CBD modulates tumor-immune interactions and suggests potential utility as an adjunct immunomodulatory agent in melanoma.
    DOI:  https://doi.org/10.1021/acsomega.6c01965
  7. J Physiol Biochem. 2026 Jul 01. pii: 62. [Epub ahead of print]82(1):
    METTL3 suppresses pyroptosis in obstructive sleep apnea-associated hypertension via YTHDF2-mediated SOX4 mRNA degradation.
    Wenjun Zhu, Yanyan Hou, Can Yang, Yaping Tian, Linna Cao, Wenjun Li, Liang Xie, Lirong He.
      Obstructive sleep apnea (OSA) is frequently complicated by hypertension, with approximately 60% of patients exhibiting both conditions. However, the epigenetic mechanisms underlying this comorbidity remain largely unexplored. N6-methyladenosine (m6A), the most abundant internal RNA modification, has emerged as a critical regulator of cardiovascular pathology, yet its role in OSA-associated hypertension (OSA-HTN) is unknown. Here, we investigated the contribution of m6A RNA methylation to OSA-HTN pathogenesis. In a chronic intermittent hypoxia (CIH) mouse model and hypoxia-stimulated aortic vascular smooth muscle cells (AVSMCs), we observed marked inflammatory injury, pyroptosis, and decreased expression of methyltransferase-like 3 (METTL3) along with global m6A levels. Overexpression of METTL3 significantly attenuated hypoxia-induced pyroptosis and inflammation by downregulating SRY-box transcription factor 4 (SOX4), a pro-inflammatory transcription factor. Mechanistically, CIH suppressed YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), an m6A reader that directly binds SOX4 mRNA, while METTL3-mediated m6A modification enhanced YTHDF2-dependent SOX4 mRNA degradation. Knockdown of YTHDF2 abolished the suppressive effect of METTL3 on SOX4 stability, confirming a METTL3-m6A-YTHDF2 regulatory axis. This METTL3-dependent regulation of YTHDF2-SOX4 interaction and SOX4 mRNA decay was also validated in mouse aortic endothelial cells. Furthermore, in vivo silencing of SOX4 alleviated CIH-induced pyroptosis and inflammation in cardiac and aortic tissues. Notably, pharmacological activation of METTL3 or METTL3 overexpression similarly attenuated CIH-induced cardiac and aortic tissue injury in OSA-HTN mice. In conclusion, our findings identify a novel METTL3-YTHDF2-SOX4 axis that governs hypoxia-induced pyroptosis and inflammation, providing new mechanistic insights into the epigenetic regulation of OSA-HTN and highlighting potential therapeutic targets.
    Keywords:  Chronic intermittent hypoxia; METTL3; N6-methyladenosine; Obstructive sleep apnea-associated hypertension; Pyroptosis; SOX4; YTHDF2
    DOI:  https://doi.org/10.1007/s13105-026-01200-3
  8. Oncogene. 2026 Jul 03.
    The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.
    Xiaozhen Yang, Shuming Wang, Yuzhong Yang, Aiyu Ma, Zhiyi Chen, Xuemei Zhang, Yan Zhang, Jinhua Zheng, Xiang Zheng.
      N6-methyladenosine (m6A) is one of the most important RNA modifications and is widely distributed across mRNAs and non-coding RNAs. Its deposition, removal, and recognition are dynamically regulated by a set of proteins, including methyltransferases (writers), demethylases (erasers), and binding proteins (readers). Through these regulators, m6A modifications influence key aspects of RNA metabolism, including stability, splicing, nuclear export, and translation efficiency, dynamically regulating cell fate. Protein lactylation is a reversible post-translational modification occurring on lysine residues of both histones and non-histones, with lactate or lactyl-CoA serving as the substrate. Lactylation modulates protein properties, including structure, function, and activity, thereby influencing gene expression. RNA m6A modifications and protein lactylation significantly regulate the biological behaviors of tumors, including proliferation, invasion, metastasis, metabolic reprogramming, immune evasion and treatment resistance. In recent years, their crosstalk has garnered increasing attention. On one hand, m6A regulatory proteins can be regulated by lactylation, either directly or via histone lactylation-mediated epigenetic regulation. On the other hand, m6A modifications may promote protein lactylation by regulating glycolysis and lactate production. This bidirectional interaction forms a regulatory loop that influences tumor progression. This review summarizes the emerging role of the crosstalk between RNA m6A modification and protein lactylation in tumor progression.
    DOI:  https://doi.org/10.1038/s41388-026-03878-7
  9. Cancer Lett. 2026 Jun 29. pii: S0304-3835(26)00461-1. [Epub ahead of print]657 218697
    The m6A epitranscriptome in cancer therapy resistance: From cellular plasticity and metabolic rewiring to immune escape and therapeutic targeting.
    Ying Yi, Jianhong Lai, Ling Jian, Yu Tian, Xiaoying Zhang, Rong Zhang.
      Cancer therapy resistance remains a major barrier to durable clinical benefit across chemotherapy, targeted therapy, cell-cycle-directed therapy, and immunotherapy. Although genetic alterations and epigenetic rewiring have long been recognized as major contributors to treatment failure, increasing evidence indicates that post-transcriptional regulation by the epitranscriptome represents an additional and highly dynamic layer of adaptive resistance. Among RNA modifications, N6-methyladenosine (m6A) has emerged as the most abundant internal modification in eukaryotic mRNA and a pivotal regulator of cancer progression, immune remodeling, and therapeutic response. Accumulating studies show that dysregulated m6A writers, erasers, and readers promote resistance by sustaining cellular plasticity and stemness, rewiring glucose and amino acid metabolism, reinforcing redox buffering and ferroptosis suppression, reshaping autophagy and mitochondrial homeostasis, and enhancing DNA damage repair and RNA processing programs. Beyond tumor-intrinsic survival, m6A also modulates immune escape by altering checkpoint responsiveness, immunometabolic suppression, and tumor-microenvironment communication. Recent advances have further expanded the conceptual framework of the field, revealing noncanonical functions of m6A regulators in adaptive translation, biomolecular condensate formation, and crosstalk with post-translational modifications such as lactylation. These findings position the m6A epitranscriptome not merely as a regulator of RNA fate, but as a systems-level coordinator of therapy-adaptive tumor states. In this review, we summarize current progress in understanding how m6A drives cancer therapy resistance across distinct therapeutic contexts, highlight emerging mechanistic frontiers, and discuss the translational potential and current challenges of targeting m6A regulators for overcoming resistant disease.
    Keywords:  Cancer therapy resistance; Cellular plasticity; Immune escape; Metabolic rewiring; m6A modification
    DOI:  https://doi.org/10.1016/j.canlet.2026.218697
  10. J Cell Mol Med. 2026 Jul;30(13): e71261
    The Role of Long Noncoding RNAs in Modulation of Stress Granules in Cancer.
    Nazlı Şevval Menemenli, Bünyamin Akgül.
      Stress granules are dynamic cellular structures that arise in response to stress. They play an important role in cancer cell survival by modulating multiple stress responses. Long noncoding RNAs (lncRNAs) have been identified as crucial regulators of stress granule (SG) dynamics, influencing cancer development and treatment resistance. LncRNAs play a role in the development and stability of stress granules, thereby enhancing cancer cells' ability to withstand severe conditions, such as chemotherapy. LncRNAs may promote the accumulation of pro-apoptotic proteins within stress granules, thereby contributing to cancer cell persistence and potentially serving as a barrier to effective treatment. Recent findings highlight the significance of intricate interactions among lncRNAs, stress granules, and the tumour microenvironment (TME), underscoring the importance of targeting lncRNAs within stress granules to enhance the efficacy of current therapies. This review examines the role of lncRNAs in SG dynamics and their implications for cancer, with a focus on how lncRNAs regulate SG formation, function, and cancer cell resilience to stress.
    Keywords:  cancer; chemotherapy; long noncoding RNAs; stress; stress granules
    DOI:  https://doi.org/10.1111/jcmm.71261
  11. Microb Cell. 2026 ;13 250-260
    Fungistatic effect of sorbic acid on yeast cells via translational repression involving eIF2 α phosphorylation and formation of Ded1- and eIF2B-granules.
    Haruka Yoshiyama, Wataru Nomura, Shingo Izawa.
      Sorbic acid is a lipophilic weak acid with fungistatic activity, and it has been widely used as a food preservative, along with its potassium and calcium salts. Although the fungistatic effect of sorbic acid is thought to be primarily due to acidification within fungal cells, the detailed fungistatic mechanism remains unclear. We investigated the effects of sorbic acid on yeast translation in Saccharomyces cerevisiae. At sublethal concentrations (2-4 mM), sorbic acid quickly repressed translation. Conversely, removal of sorbic acid restored translation activity, indicating that the sorbic acid-induced translational repression is reversible. Pronounced translational repression induced by various stress conditions or nutrient starvation is often accompanied by eIF2 α phosphorylation, eIF2B-body and stress granule (SG) formation, and the sequestration of Ded1 (which plays a role in translation initiation as a DEAD-box RNA helicase) into SGs. We found that sorbic acid stress also induces eIF2 α phosphorylation and the sequestration of Ded1 into SGs. In contrast, sorbic acid stress induced the formation of not eIF2B bodies but eIF2B granules, which colocalized with SGs. These results suggest that the functional arrest of translation-related factors, including eIF2 α , eIF2B, and Ded1, correlates strongly with the translational repression in the presence of sorbic acid. Notably, Gcn2 deficiency delayed translational repression and SG formation, and significantly suppressed eIF2B granule formation, suggesting the involvement of Gcn2 in these stress responses during sorbic acid stress. Our findings provide new insights into the physiological effects of sorbic acid on yeast cells, specifically regarding the regulation of translation-related factors.
    Keywords:  Ded1; Saccharomyces cerevisiae; eIF2B; fungistatic effect; sorbic acid; stress granules; translational repression
    DOI:  https://doi.org/10.15698/mic2026.06.880
  12. Front Neurosci. 2026 ;20 1854892
    The exercise-microbiota-queuine-tRNA axis in Parkinson's disease: evidence, uncertainties, and experimental priorities.
    Yang Zhou, Tao Jiang.
      Parkinson's disease (PD) is a multisystem neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic degeneration, α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammatory remodeling. Although these mechanisms have been extensively investigated, how systemic metabolic and microbiota-derived signals intersect with neuronal translational control remains incompletely understood. Queuosine (Q) modification of tRNAs is a distinctive RNA modification because its precursor, queuine, is not synthesized de novo by mammalian cells but is acquired from diet and gut microbial metabolism. Emerging evidence indicates that Q-tRNA modification can influence codon decoding, translational speed, proteostasis, oxidative stress responses, and mitochondrial function, but direct evidence linking Q-tRNA dysregulation to PD remains limited. In this narrative review, we propose a conceptual and hypothesis-generating framework in which the microbiota-queuine-Q-tRNA modification axis may contribute to neuronal translational buffering and stress adaptation in PD. We distinguish established mechanisms, emerging evidence, and speculative links, emphasizing that the complete causal chain from exercise-induced microbiota remodeling to altered queuine availability, Q-tRNA modification, mitochondrial translational recalibration, and dopaminergic neuroprotection has not yet been experimentally demonstrated. We further discuss tRNA-derived fragments (tRFs) as candidate biomarkers and potential effector molecules in PD-associated translational stress, neuroinflammation, and intercellular RNA communication. Finally, we outline experimental priorities for validating this model, including direct Q-tRNA profiling in PD tissues and biofluids, exercise-intervention studies in PD models, microbiota/queuine manipulation, and mechanistic testing of circulating RNA carrier transport across the blood-brain barrier. This framework does not establish a new pathogenic pathway, but provides a structured roadmap for investigating how exercise, microbial metabolism, and RNA modification biology may converge on selective neuronal vulnerability in PD.
    Keywords:  Parkinson's disease; Q-tRNA modification; evidence hierarchy; exercise; gut microbiota; mitochondrial translational stress; precision medicine; queuine
    DOI:  https://doi.org/10.3389/fnins.2026.1854892
  13. Nat Commun. 2026 Jul 03. pii: 5841. [Epub ahead of print]17(1):
    Cryo-EM structure of the naked mole-rat ribosome reveals a stabilized split 28S rRNA.
    Mehmet Gül, Alice Rossi, Christian M T Spahn, Gary R Lewin, Mikhail Kudryashev.
      The naked mole-rat (Heterocephalus glaber) is a long-lived mammal with resistance to cancer and hypoxia, suggesting the evolution of robust proteostasis networks. The ribosome, central for protein synthesis, is key to cellular stress responses and has an unusual feature: the 28S rRNA split; however, the details of its organization remain unknown. Here, we present high-resolution cryo-EM structures of the naked mole-rat 80S ribosome in four states of the elongation cycle. The structures reveal a conserved overall architecture and rRNA modification landscape compared to other mammals, and provide an atomic-level view of the distinct break in the 28S rRNA. This cleavage event, located in the D6 expansion segment, is structurally stabilized by a network of interactions with surrounding ribosomal proteins, maintaining the integrity of the large subunit. Our comparative analysis revealed that this compensatory network preserves a canonical architecture that is nearly indistinguishable from intact mouse and human ribosomes. These findings resolve the structural basis of this distinct cleavage, showing that it is a stable, integrated feature whose function is likely linked to more subtle regulatory mechanisms, rather than inducing major structural rearrangements.
    DOI:  https://doi.org/10.1038/s41467-026-75143-0
  14. Front Mol Neurosci. 2026 ;19 1816333
    The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention.
    Hua Huang, Yao Xu, Xingyi Li, Chenggang Li, Wuxue Peng.
      Activating transcription factor 4 (ATF4) functions as the central transcriptional arbiter of the integrated stress response (ISR) in neurons. Its translation is gated by diverse upstream kinases via the eIF2α pathway, while its functional output is critically shaped by context-dependent interactions with specific protein partners (e.g., C/EBPβ or CHOP). We conceptualize ATF4 as a spatiotemporal rheostat whose regulatory mandate is stage-specific: it acts as a physiological switch during neocortical development and maintains synaptic and mitochondrial integrity in the adult brain. However, this precise regulation fails in neurological disorders, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, and epilepsy. Chronic, maladaptive ATF4 signaling-often driven by pathological heterodimerization-catalyzes neuroinflammation, ferroptosis, and circuit failure. Crucially, contemporary challenges in clinical translation highlight a "therapeutic paradox," where broad or untimely pathway inhibition may inadvertently dismantle essential neuroprotective shields. We therefore advocate for a paradigm shift toward "kinetic recalibration"-the development of precision interventions designed to restore the proteostatic and information-processing homeostasis of the stressed nervous system.
    Keywords:  ATF4; homeostatic rheostat; integrated stress response; neurodegeneration; synaptic plasticity
    DOI:  https://doi.org/10.3389/fnmol.2026.1816333
  15. bioRxiv. 2026 Jun 24. pii: 2026.06.23.734070. [Epub ahead of print]
    40S ribosomal subunits move along the 5' UTR through an eIF4A-independent mechanism in higher eukaryotes.
    Thomas Ossevoort, Olga Chernaya, Angela Browning, Dave H Mathews, Dmitri N Ermolenko.
      During translation initiation, the 40S small ribosomal subunit is recruited to the mRNA 5' cap and scans the 5' untranslated region (UTR) to locate the start codon. While the mechanism of 40S translocation remains elusive, the RNA helicase eIF4A has long been suspected as the primary molecular motor driving 40S scanning. In this study, we utilized GFP reporter mRNAs to investigate the impact of 5' UTR length on translational efficiency. We found that an 8-fold variation in the length of unstructured 5' UTRs did not lead to substantial changes in translation efficiency in wheat germ extract (WGE) and human HEK293T cell lysate. By contrast, the presence of a stable stem-loop in the middle of the 5' UTR significantly reduced cap-dependent translation. These results suggest that mRNA scanning is not rate-limiting when the UTR is devoid of secondary structure. Inhibition of eIF4A by hippuristanol in cell-free protein synthesis systems yielded an equivalent decrease in translation for mRNAs with short and long unstructured 5' UTRs, indicating that eIF4A may be dispensable for 40S scanning. Our data suggest that helicase-independent one-dimensional diffusion may be the primary mechanism enabling 40S movement along the 5' UTR during initiation.
    DOI:  https://doi.org/10.64898/2026.06.23.734070
  16. Mol Biol Rep. 2026 Jul 03. pii: 1080. [Epub ahead of print]53(1):
    RNA modifications as innovative pharmaceutical targets: emerging drug delivery strategies and precision therapeutics for cancer immunotherapy and metabolic diseases.
    Satish Kumar Sharma, Dilip Kumar Chanchal, Jitendra Singh Chaudhary.
      RNA modifications have emerged as an important regulatory layer that influences gene expression beyond conventional genetic and epigenetic mechanisms. Among the various epitranscriptomic modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ) have been extensively investigated for their roles in RNA stability, splicing, translation, immune regulation, and metabolic homeostasis. Increasing evidence suggests that dysregulation of these modifications contributes to cancer progression, immune evasion, therapeutic resistance, and metabolic disorders, suggesting their potential as therapeutic targets. This review summarizes recent advances in endogenous epitranscriptomic RNA modifications and discusses their relevance in cancer immunotherapy and metabolic diseases. In addition, emerging therapeutic approaches targeting RNA-modifying enzymes, including writers, erasers, and readers, are discussed along with the development of antisense oligonucleotides, RNA-based therapeutics, and delivery systems. Recent progress in lipid nanoparticles, polymeric carriers, and targeted delivery platforms has improved the stability, specificity, and translational potential of RNA-targeted therapies. The review also highlights current challenges associated with clinical translation, including delivery efficiency, therapeutic specificity, and patient heterogeneity. Overall, epitranscriptomic RNA modifications may provide new opportunities for the development of precision therapeutic strategies for cancer and metabolic diseases.
    Keywords:  Cancer immunotherapy; Drug delivery systems; Metabolic disorders; Pharmaceutical innovation; RNA modifications; RNA-targeted therapeutics
    DOI:  https://doi.org/10.1007/s11033-026-12308-6
  17. Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 102979
    Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.
    Tristan N Samuels, Jenica H Kakadia, Cian Ward, Fatema Abdullatif, Marisa I Mendes, Desiree E Smith, Rachel Heilmann, Fanqi Wu, Jakub M Swiercz, Gajja S Salamons, Kyle Hoffman, Teklab Gebregiworgis, Patrick O'Donoghue, Ilka U Heinemann.
      Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant- and juvenile-onset disease, with no current disease-specific treatments. We developed a tractable human cell system to study disease-causing NARS1 alleles that can be adapted to investigate NARS1 and other aminoacyl-tRNA synthetase (ARS) alleles. We found that two dominant NARS1 nonsense alleles, R534X and R522X, cause a cytotoxic phenotype and elicit the integrated stress response (ISR). Proteomic and phenotypic changes were rescued by asparagine supplementation in the human cell model. Asparagine supplementation completely restored cell proliferation defects in patient-derived fibroblasts and prevented activation of the ISR. We also tested therapeutic cognate transfer RNA (tRNA) supplementation, which reduced the cytotoxicity of pathogenic NARS1 alleles but did not ameliorate activation of the ISR. A general control nonderepressible 2 (GCN2) inhibitor suppressed ISR activation and reduced cytotoxicity but did not restore changes to the proteome caused by the NARS1 nonsense alleles. The data reveal molecular and cellular defects caused by premature termination codons in NARS1 alleles. Our data also indicate asparagine supplementation as a feasible therapeutic approach to address the underlying cause of NARS1 disease, a rare disease for which currently no treatment is available.
    Keywords:  ARS disease; MT: non-coding RNAs; NARS1; amino acid supplementation; aminoacyl-tRNA synthetase; integrated stress response; premature termination codon; tRNA
    DOI:  https://doi.org/10.1016/j.omtn.2026.102979
  18. NAR Genom Bioinform. 2026 Sep;8(3): lqag069
    The role of ATF4 in neurons under mitochondrial stress.
    Maria Bilen, Yubing Liu, Imane Chakroun, Mohamed Ariff Iqbal, Bensun C Fong, Jingwei Chen, Smitha Paul, Alexandre Blais, Ruth S Slack.
      Mitochondrial dysfunction and fragmentation are observed in various circumstances, such as neurodegeneration and aging. Studies have shown that altered mitochondrial function activates the integrated stress response (ISR), with ATF4 serving as a major mediator of adaptation to stress. Presently, little is known about the role of ATF4 in neurons under mitochondrial stress. Using primary cortical neurons, we demonstrate that inhibiting ATF4 under OPA1-mediated mitochondrial stress accelerates the impairment of neuronal differentiation, as evidenced by smaller dendrites and lower dendritic spine density. To better understand the role of ATF4 in this context, we investigated the global binding sites of ATF4 using chromatin immunoprecipitation sequencing (ChIP-seq) and examined the chromatin accessibility changes that occur following the loss of ATF4 in neurons under conditions of mitochondrial stress. We found that ATF4 binds to a wide range of targets and alters the chromatin accessibility of genes involved in metabolism, neuronal fate, and neuron maturation. The downstream targets of ATF4 identified in this study can reveal novel and direct targets of ATF4 in neuronal survival and maturation. These adaptations are the hallmarks of stress response in mitochondrial dysfunction-mediated neurodegeneration.
    DOI:  https://doi.org/10.1093/nargab/lqag069
  19. Nat Chem Biol. 2026 Jun 29.
    Allosteric disordering of eIF2B regulates the integrated stress response.
    Udit Dalwadi, Advait Subramanian, Aniliese Deal, Julia E Conrad, Tamara Nadjsombati, Meera Venkatesh, Morgane Boone, Pascal F Egea, Lingjie He, Nimit Jain, D John Lee, Yuwei Liu, Lucas C Reineke, Kazuki Saito, Nathaniel Talledge, Hannah Toutkoushian, Maxence Le Vasseur, Francesca Zappa, Raoul J de Groot, Diego Acosta-Alvear, Christopher P Arthur, Jodi Nunnari, Susan Marqusee, Rosalie E Lawrence, Mauro Costa-Mattioli, James J Crawford, Frank J M van Kuppeveld, Tristan I Croll, Peter Walter, Adam Frost.
      The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.
    DOI:  https://doi.org/10.1038/s41589-026-02256-4
  20. J Proteome Res. 2026 Jun 29.
    Phosphorylation Patterns of Preribosomal Proteins Associated with the RNA Exosome.
    Felipe A Almeida, Valdir Gomes Neto, Rebeca B Jantsch, Moises R A Barros, L Paola P Cepeda, Bruno R S Queiroz, Anna B Machado, Ana P J Menezes, Julia P C Da Cunha, Carla C Oliveira.
      The RNA exosome is an essential and ubiquitous RNase with exonucleolytic activity that is involved in ribosome biogenesis and RNA quality control in eukaryotes. It is present both in the nucleus and cytoplasm and interacts with specific cofactors in each cell compartment, which are essential for the recruitment and activity control of the exosome. Post-translational modifications are known to regulate enzyme activity and protein interaction, although their precise roles are individually specific. In this study, we investigated the phosphorylation status of proteins associated with the nuclear (Rrp6) and core (Rrp46) subunits of the RNA exosome in Saccharomyces cerevisiae. Using coimmunoprecipitation followed by phosphopeptide enrichment and high-resolution mass spectrometry, we identified 114 phosphorylation sites on proteins functionally related to rRNA processing. Differential phosphorylation patterns between Rrp6 and Rrp46 coimmunoprecipitations are consistent with distinct exosome assemblies and suggest potential regulatory roles for phosphorylation. Several phosphosites were identified in exosome subunits and cofactors, revealing potential regulatory mechanisms for fine-tuning exosome function. The results shown here highlight the role of phosphorylation in the recruitment and control of the exosome in RNA processing and degradation, offering new insights into the post-transcriptional control of gene expression.
    Keywords:  RNA exosome; Saccharomyces cerevisiae; nucleolar proteins; protein interactions; protein phosphorylation; protein-RNA interactions; proteomic analysis; rRNA processing; ribosome biogenesis; affinity purification
    DOI:  https://doi.org/10.1021/acs.jproteome.6c00095
  21. Int J Biol Macromol. 2026 Jun 29. pii: S0141-8130(26)03211-3. [Epub ahead of print]373 153271
    Silencing of human RNA polymerase I subunit A34 influences multiple cellular processes including rDNA transcription and cell migration.
    Xiaoye Song, Huating Zeng, Jiandong Zhang, Cheng Zhang, Shasha Zhao, Xiaomei Yin, Zhouliang Han, Yuwen Dong, Baoqiang Guo, Wensheng Deng.
      Human RNA polymerase I (Pol I) is responsible for the synthesis of 18S, 28S, and 5.8S rRNA in cells. These rRNAs are essential to ribosome assembly and play a critical role in protein synthesis. However, the roles of Pol I specific subunits in many cellular processes remain unknown. Here, we found that human Pol I specific subunit A34/G (hRPA34/POLRG) participates in the regulation of multiple molecular and cellular processes, including rDNA transcription, cell migration, and others. We show that hRPA34 depletion inhibited rRNA synthesis, protein synthesis, and cell growth, but it promoted cell migration. In contrast, up-regulating hRPA34 expression exhibited an adverse effect on these processes. The inhibition of rRNA synthesis caused by hRPA34 depletion induces nucleolar stress and cell apoptosis. We show that hRPA34 silencing reduced the occupancies of components of the Pol I transcription machinery at the rDNA promoter and down-regulated hRPA49 expression. It indicates that hRPA34 silencing can affect rDNA transcription by changing RPA49 expression and the recruitment of the Pol I transcription machinery factors at the rDNA promoter. We demonstrate that hRPA34 depletion increased cell migration by up-regulating the expression of c-Jun and Integrin-β1 proteins. hRPA34 silencing caused cell growth arrest by activating p21 expression and increasing Caspase-3 and cleaved Caspase-3 levels. Collectively, these findings indicate that hRPA34 is required for the regulation of multiple molecular and cellular processes, extending the understanding of hRPA34 functions in human cells.
    Keywords:  Cell apoptosis; Cell migration; Human RPA34; Nucleolar stress; R-loop; rDNA transcription
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153271
  22. Biochim Biophys Acta Rev Cancer. 2026 Jun 29. pii: S0304-419X(26)00122-8. [Epub ahead of print]1881(4): 189650
    Post-transcriptional regulation in cancer chemoresistance.
    Sabrina De Lella, Franca Esposito, Danilo Swann Matassa, Rosario Avolio.
      Cancer remains the second leading cause of death worldwide, surpassed only by cardiovascular diseases. Although cancer-specific mortality rates have declined due to advances in early detection and therapeutic strategies, the absolute number of cancer-related deaths continues to rise, driven by increasing disease incidence associated with population aging and lifestyle factors. A substantial proportion of cancer mortality is attributable to the development of resistance to anticancer therapies, making drug resistance a critical barrier to durable treatment efficacy and a major focus for clinical and translational research. Drug resistance arises from a wide spectrum of molecular and microenvironmental adaptations that enable cancer cells to limit drug uptake, neutralize or bypass drug activity, and evade therapy-induced cell death. These adaptive processes are orchestrated by extensive rewiring of gene expression programs, regulatory networks, and signaling pathways, ultimately reshaping cellular metabolism and stress responses. Traditionally, such adaptations have been primarily ascribed to genetic alterations and transcriptional reprogramming. However, growing evidence indicates that posttranscriptional regulatory mechanisms play a pivotal and previously underappreciated role in modulating gene expression and protein activity during the acquisition of drug-resistant phenotypes. RNA-mediated mechanisms, including regulation of mRNA stability, translation, subcellular localization, and RNA-protein interactions, introduce a dynamic and reversible level of control over protein expression and activity. In particular, non-canonical RNA-binding proteins, diverse classes of non-coding RNAs, and riboregulatory mechanisms have emerged as critical modulators of pathways involved in drug transport, DNA damage response, apoptosis, and metabolic adaptation. These processes allow cancer cells to rapidly fine-tune functional proteomes without requiring permanent genetic changes, thereby facilitating phenotypic plasticity and therapeutic escape. In this review, we summarize recent advances in the field, with a particular emphasis on emerging posttranscriptional mechanisms of gene regulation that contribute to anticancer drug resistance. By highlighting the dynamic and multilayered nature of RNA-mediated regulatory processes, we aim to provide a comprehensive framework for understanding how cancer cells adapt to therapeutic pressure and to identify novel avenues for therapeutic intervention in the context of drug-resistant disease.
    Keywords:  Anticancer drug resistance; Post-transcriptional regulation; RNA modifications; RNA-binding proteins; Riboregulation; ncRNAs
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189650
  23. BMC Genomics. 2026 Jun 29. pii: 562. [Epub ahead of print]27(1):
    Evaluation of Dorado v5.2.0 de novo basecalling models for the detection of tRNA modifications using RNA004 chemistry.
    Bhargesh Indravadan Patel, Franziskus N M Rübsam, Yu Sun, Ann E Ehrenhofer-Murray.
      Direct RNA sequencing with Oxford Nanopore Technologies (ONT) captures nucleotide-specific current signals that reflect both sequence and chemical modifications, offering the potential to detect RNA modifications directly from native RNA molecules. To interpret such signals, ONT provides modification-aware basecalling models that estimate the probability of selected modifications at each nucleotide. In May 2025, ONT released updated modification-calling models (Dorado v5.2.0) for pseudouridine (Ψ), inosine, m6A and m5C, alongside new models for 2'O-ribose-methylations, necessitating independent validation. Here, we benchmark Dorado v5.2.0 against v5.1.0 using ex cellulo tRNAs from Schizosaccharomyces pombe, leveraging their well-defined modification landscape. We generated modification probability profiles at single-nucleotide resolution and quantified model performance using curated sets of annotated and validated modification sites. Our results reveal that, despite notable improvements in Ψ detection, most modification callers remain challenged by the dense and heterogeneous modification environments of tRNAs. This work provides the first comprehensive evaluation of Dorado v5.2.0 on native tRNAs and establishes a methodological framework for benchmarking future ONT modification models in complex RNA modification contexts.
    Keywords:  Dorado v5.2.0; Nanopore sequencing; SQK-RNA004; dRNA-seq
    DOI:  https://doi.org/10.1186/s12864-026-12893-7
  24. J Gastroenterol. 2026 Jul 01.
    METTL3/FTO drives ferroptosis in colorectal cancer by targeting m6A modification of MUC1 mRNA and YTHDF2-dependent SLC7A11/GSH pathway.
    Zili Zhang, Kaiwen Cheng, Yuyao Wei, Yuqi Sun, Chun Zhang, Yang Wu, Mei Guo.
       BACKGROUND: Ferroptosis is a newly defined form of programmed cell death and is associated with the progression of colorectal cancer (CRC). Abnormal levels of N6-methyladenosine (m6A) modification are frequently identified in CRC, but its regulation of ferroptosis is still unclear. In this study, we report that the m6A modification modulates ferroptotic susceptibility to inhibit CRC progression by targeting m6A-YTHDF2-mediated regulation of MUC1 mRNA stability.
    METHODS: CRC cell lines were treated with ferroptosis inducers, and m6A methylation assay kit and dot blot were employed to assess m6A methylation status. Transcriptomic sequencing and immunoprecipitation were employed to elucidate the molecular mechanisms by which m6A modification modulates ferroptotic susceptibility. The CRC mouse tumor models were used to validate the regulatory mechanisms of m6A methylation on ferroptosis in vivo. The CRC patient-derived organoid models (PDOs) were applied to determine the regulatory role of m6A methylation-mediated ferroptosis. Clinical CRC specimens were analyzed to evaluate the relationship between m6A modification and ferroptosis.
    RESULTS: The upregulation of METTL3 and downregulation of FTO enhanced m6A methylation levels, while disruption of m6A methylation conferred resistance to ferroptosis in CRC cells. Mechanistic investigations through transcriptome sequencing and bioinformatics identified MUC1 as a key target for m6A methylation regulation of ferroptosis. YTHDF2 promoted the decay of MUC1 mRNA by recognizing the m6A-binding site at A1078 within 3'UTR regions, which can inhibit the function of SLC7A11 and thereby enhance susceptibility to ferroptosis. Ferroptosis inducer erastin augmented YTHDF2-mediated ferroptotic susceptibility to inhibit the growth of CRC by suppressing MUC1/SLC7A11 signaling in PDOs. Clinically, YTHDF2 was negatively correlated with MUC1 expression in CRC specimens, which was associated with poor prognosis.
    CONCLUSIONS: Our findings unveil a crucial mechanism through which YTHDF2 facilitates ferroptotic susceptibility via MUC1 destabilization and subsequent SLC7A11 downregulation. These discoveries open up new possibilities for ferroptosis-regulated therapeutics by offering targets and approaches for the treatment of CRC.
    Keywords:  Colorectal cancer; Ferroptosis; M6A methylation; MUC1; SLC7A11; YTHDF2
    DOI:  https://doi.org/10.1007/s00535-026-02474-6
  25. Elife. 2026 Jul 03. pii: RP109452. [Epub ahead of print]14
    Non-canonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy.
    Hao Chen, Haocheng Wang, Yu-Ning Lu, Peng Chen, Zhongfan Zheng, Tao Zhang, Jiou Wang.
      We report a minimally disruptive labeling strategy for stress granule protein, G3BP Stress Granule Assembly Factor 1 (G3BP1), and ALS-linked protein, TAR DNA-binding protein 43 (TDP-43), using the fluorescent non-canonical amino acid Anap. By integrating the genetic code expansion (GCE) with rational site selection, we achieved precise incorporation of Anap that preserves protein structure and function. In live cells and neurons, Anap labeling faithfully recapitulated localization, stress-induced dynamics, and recovery behavior, outperforming conventional fluorescent tags, and enabling physiologically relevant visualization of protein pathobiology.
    Keywords:  TDP-43; anap labeling; biochemistry; cell biology; chemical biology; genetic code expansion; human; mouse; stress granule
    DOI:  https://doi.org/10.7554/eLife.109452
  26. J Neurochem. 2026 Jul;170(7): e70507
    Norepinephrine Couples Astrocytic Metabolism to mTOR-Driven Protein Synthesis.
    Florencia Cabrera-Cabrera, Helena Tull, Giulia Urone, Age Utt, Maria Kuhtinskaja, Robert Zorec, Indrek Koppel.
      Norepinephrine is a neuromodulator that regulates diverse physiological processes in the central nervous system, including astrocytic metabolism. While its metabolic actions in astrocytes are well characterised, its role in regulating protein synthesis remains unknown. Here, we show that norepinephrine robustly stimulates protein synthesis in rat primary cortical astrocytes in a time-dependent manner, comparable to that of insulin and serum. This effect is mediated predominantly by β-adrenergic receptors and is accompanied by activation of the mTOR-S6K signalling pathway. We further demonstrate that this translational response requires glycolytic activity and is preceded by a rapid depletion of astrocytic glycogen stores and a transient reduction in ATP levels. Together with growth factors, these findings identify protein synthesis as a previously unrecognised physiological target of norepinephrine in astrocytes and reveal a mechanism linking neuromodulatory signalling, metabolic state and mTOR-dependent translational control in the brain.
    Keywords:  ATP; astrocytes; glycogen; mTOR; norepinephrine; translation
    DOI:  https://doi.org/10.1111/jnc.70507
  27. Plant J. 2026 Jul;127(1): e71015
    Multi-layered RNA decay mechanisms underlie subgenome-biased homoeologous mRNA stability in salt-stressed allopolyploid plants.
    Pengfei Xu, Yaobin Wang, You Wu, Shuhua Huang, Xiang Yu.
      Many crop species are polyploid plants, yet how post-transcriptional regulation influences the RNA abundance of homoeologous genes from different subgenomes under stress conditions remains poorly understood. In this study, we systematically investigated transcriptional and post-transcriptional regulation in the allopolyploid crop Brassica napus under salinity stress. Integrated transcriptome and degradome profiling on hypocotyl and cotyledon revealed tissue-specific gene expression and mRNA stability associated with their developmental changes under salt stress. Notably, mRNAs undergoing exon junction complex (EJC)-marked RNA decay (EMRD) and co-translational RNA decay (CTRD) exhibited higher degradation propensity. Transcriptome-wide profiling of mRNA abundance and mRNA decay in homoeologous genes revealed subgenome-specific patterns in both gene expression and mRNA stability. Dual-luciferase assays confirmed that the 3' UTR mediates the divergent mRNA stability observed between homoeologous gene pairs. Further analysis revealed that EMRD, CTRD, and miRNA cleavage are associated with asymmetric RNA degradation across subgenomes. These findings provide comprehensive insights into the multi-layered regulation of transcript stability under salt stress and reveal a critical role for RNA degradation in shaping tissue-specific and subgenome mRNA asymmetry in polyploid crops.
    Keywords:  Brassica napus; allopolyploid; homoeologous gene pairs; post‐transcriptional regulation; salt stress; subgenome
    DOI:  https://doi.org/10.1111/tpj.71015
  28. J Vis Exp. 2026 Jun 12.
    Cell-Free In Vitro mRNA Translation In Drosophila Lysates.
    Noemi Baranda-Ávila, Mariana Valdes-Barreto, Patricio Reza, Dora Emma Vélez, Greco Hernández.
      Cell-free mRNA in vitro translation has played a crucial role in the understanding of the protein synthesis process during gene expression across eukaryotes. The development of lysates from different systems for in vitro translation has been instrumental in studying the roles of most components of the translation machinery and in dissecting many steps of the protein synthesis process. Different aspects of translation and translational control have been studied using Drosophila melanogaster lysates. This paper provides detailed protocols for preparing synthetic mRNA templates, growing large-scale living fly cultures, preparing translation-competent lysates from Drosophila embryos, and performing cell-free in vitro translation reactions. This protocol is suitable for any species of the Drosophila genus-melanogaster, virilis, pseudoscura, grimshawi, hydei, etc. We further compare this protocol to other translation systems and discuss limitations, critical steps, and troubleshooting. Representative outcomes are included to help assess protocol performance and reproducibility. Finally, we discuss potential applications in biotechnology and research.
    DOI:  https://doi.org/10.3791/70844
  29. Pharmacol Res Perspect. 2026 Aug;14(4): e70292
    Deciphering the Functional Mechanisms of eIF3f in Tumors and Exploring Targeted Therapies.
    Yujinpeng Hao, Jun Shao, Naqi Lian, Mianli Bian.
      Eukaryotic translation initiation factor 3 subunit F (eIF3f) is a critical component of the eIF3 complex and plays a pivotal role in diverse biological processes, including cell proliferation, apoptosis, adhesion, and transcriptional regulation. Recent studies have revealed that eIF3f is aberrantly expressed in multiple malignancies and exhibits a striking context-dependent functional profile. In solid tumors such as hepatocellular carcinoma (HCC), colorectal cancer (CRC), and prostate cancer (PCa), elevated eIF3f expression correlates with poor patient prognosis, indicating an oncogenic role. Conversely, in pancreatic cancer (PC) and melanoma (MM), reduced or absent eIF3f expression promotes tumor progression, suggesting a tumor-suppressive function. This functional plasticity indicates that eIF3f is not a simple oncogenic driver but rather a molecular hub that integrates diverse cellular signals. This review systematically delineates the structural characteristics and biological functions of eIF3f, summarizing its expression patterns and underlying molecular mechanisms across various malignancies. Building on this, we propose an integrated mechanistic framework that attributes the functional plasticity of eIF3f to differential upstream signaling networks, heterogeneity in post-translational modification profiles, and the remodeling status of the tumor microenvironment (TME). Furthermore, we critically evaluate the strength of evidence supporting eIF3f as a diagnostic and prognostic biomarker, identify methodological bottlenecks and translational challenges in current targeting strategies, and outline priority research directions, including elucidating the structural biological basis of its functional plasticity and developing context-specific intervention strategies. By integrating mechanistic insights with clinical relevance, this review aims to establish a conceptually coherent and mechanistically testable theoretical framework for eIF3f research, guiding the design of precision stratified therapeutic approaches and facilitating its substantive translation from basic research to clinical application.
    Keywords:  biological functions; cancer; eIF3f; molecular mechanisms; targeted intervention
    DOI:  https://doi.org/10.1002/prp2.70292
  30. Autophagy. 2026 Jun 29.
    Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.
    Gayatri Mohanan, Kumkum Nag, Harsh Singh Senger, Parvathy J, Purusharth I Rajyaguru.
      The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating autophagy during hydroxyurea (HU)-induced replication stress. We observe that Sbp1 localizes to reversible, mRNA-containing cytoplasmic granules specifically upon HU treatment in an RGG motif-dependent manner. Loss of Sbp1 leads to selective translational upregulation of key autophagy genes ATG1, ATG2, and ATG9. Consistent with these translational changes, sbp1∆ cells exhibit increased selective macroautophagy/autophagy and enhanced bulk autophagy, whereas Sbp1 overexpression suppresses both processes. Interestingly, overexpression of Sbp1 shifts DNA repair toward non-homologous end joining (NHEJ) repair, linking altered autophagy to genome maintenance. Together, these findings identify Sbp1 as a negative regulator of autophagy during replication stress and suggest a regulatory axis linking granule-mediated mRNA sequestration, translational control of autophagy factors, and the cellular response to genotoxic stress.Abbreviations: CHX: cycloheximide; CPT: camptothecin; DDR: DNA damage response; GTA: genotoxin-associated targeted autophagy; HR: homologous recombination; HU: hydroxyurea; MMS: methyl methanesulfonate; mRNPs: mRNA-protein complexes; NHEJ: non-homologous end joining; P-bodies: processing bodies; RBPs: RNA binding proteins.
    Keywords:  Autophagy; DNA repair; Sbp1; hydroxyurea; mrnps; translation regulation; yeast
    DOI:  https://doi.org/10.1080/15548627.2026.2694657
  31. Basic Res Cardiol. 2026 Jun 30.
    Peroxisomal catalase and plasmalogen biosynthesis protect from oxidative stress in Barth syndrome cardiomyopathy.
    Elsie Kajese, Malte Hachmann, Katharina J Ermer, Manuela Erk, Lin Alhasaan, Michael Kohlhaas, Heike Bömmel, Lisa Berberich, Christopher Carlein, Hanna Eberl, Katrin Streckfuß-Bömeke, Leticia Prates Roma, Süleyman Ergün, Christoph Maack, Srikanth Karnati, Jan Dudek.
      Barth Syndrome (BTHS) is an inherited mitochondrial cardiomyopathy caused by variants in the gene encoding TAFAZZIN (Taz), a transacylase catalyzing the synthesis of the essential mitochondrial phospholipid cardiolipin (CL). Although defects in Taz deteriorate mitochondrial respiration, Ca2+-uptake, and redox regulation in cardiac myocytes, we previously observed an unexpected lack of oxidative cardiac damage, despite the development of cardiomyopathy in a BTHS mouse model with Taz-knockdown (KD). Furthermore, we revealed that the integrated stress response (ISR) governs metabolic rewiring in Taz-KD hearts to compensate for deficient mitochondrial FAO and to support GSH production. Here, we interrogated whether adaptive mechanisms in peroxisomes, which are closely associated with mitochondria and harbor antioxidative enzymes, can also compensate for the mitochondrial defects. We identified alterations in the peroxisomal biogenesis factors PEX14 and PEX19, indicating changes in the peroxisomal proteome in Taz-KD vs. WT hearts. While the enzymes of peroxisomal FAO were unchanged, levels of Lon Protease 2 (LONP2) and catalase were elevated in Taz-KD hearts. Inhibition or siRNA-mediated knockdown of catalase increased reactive oxygen species (ROS) and blunted the protection of mouse embryonic fibroblasts (MEF) with Taz-knockout (KO), but not in WT, from ROS-induced activation of the apoptotic caspase 3. Furthermore, we observed that the increase in plasmalogen synthesis in cardiac Taz-KD peroxisomes contributes to the activation of the ISR, since siRNA-mediated knockdown of the key enzyme GNPAT blunted the ISR and thereby increased cellular ROS in Taz-KO, but not WT MEFs. In conclusion, peroxisomes facilitate a counterregulatory response to dysfunctional mitochondria by activating a catalase-driven ROS defense and maintaining ISR-mediated metabolic alterations, both of which compensate for mitochondrial dysfunction and oxidative stress. Therefore, the so far poorly investigated mitochondrial-peroxisome crosstalk may represent a novel therapeutic target in an orphan disease with a poor prognosis.
    Keywords:  Apoptosis; Barth syndrome; Catalase; Integrated stress response; Mitochondria; Peroxisomes; Plasmalogens
    DOI:  https://doi.org/10.1007/s00395-026-01197-2
  32. Chembiochem. 2026 Jul 14. 27(13): e202500445
    RNAGEN: A Generative Adversarial Network-Based Model to Generate Synthetic RNA Sequences to Target Proteins.
    Furkan Ozden, Sina Barazandeh, Dogus Akboga, Sobhan Shokoueian Tabrizi, Urartu Ozgur Safak Seker, A Ercument Cicek.
       BACKGROUND: RNA-protein binding plays an important role in regulating protein activity by affecting localization and stability. While proteins are usually targeted via small molecules or other proteins, easy-to-design and synthesize small RNAs are a rather unexplored and promising venue. The problem is the lack of methods to generate RNA molecules that have the potential to bind to certain proteins.
    RESULTS: Here, we propose a method based on generative adversarial networks that learn to generate short RNA sequences with natural RNA-like properties such as GC content and free energy. Using an optimization technique, we fine-tune these sequences to have them bind to a target protein. We use RNA-protein binding prediction models from the literature to guide the model. We show that even if there is no available guide model trained specifically for the target protein, we can use models trained for similar proteins, such as proteins from the same family, to successfully generate a binding RNA molecule to the target protein. Using this approach, we generated piRNAs that are tailored to bind to SOX2 protein using models trained for its relative (SOX15, SOX14, and SOX7) and experimentally validated in vitro that the top-2 molecules we generated specifically bind to SOX2.
    CONCLUSIONS: We demonstrate that our generative model matched with the gradient-based optimization method is capable of generating piRNA sequences with high expected binding scores to the target protein. State-of-the-art RNA-Protein binding prediction models validate our results.
    Keywords:  RNA design; RNA‐protein binding; deep learning; generative models
    DOI:  https://doi.org/10.1002/cbic.202500445
  33. Nat Commun. 2026 Jun 30. pii: 5552. [Epub ahead of print]17(1):
    Gravitational and mechanical forces shape mitochondrial translation.
    Taisei Wakigawa, Yusuke Kimura, Mari Mito, Toshiya Tsubaki, Muhoon Lee, Koki Nakamura, Abdul Haseeb Khan, Hironori Saito, Tohru Yamamori, Tomokazu Yamazaki, Akira Higashibata, Tatsuhisa Tsuboi, Yusuke Hirabayashi, Nono Takeuchi-Tomita, Taku Saito, Atsushi Higashitani, Yuichi Shichino, Shintaro Iwasaki.
      Life on Earth has evolved in a form suitable for the gravitational force. Although the pivotal role of gravity in gene expression has been suggested, the molecular details remain unclear. Here, we show that mitochondria utilize gravity to activate protein synthesis within the organelle. Genome-wide ribosome profiling reveals reduced mitochondrial translation in mammalian cells and Caenorhabditis elegans under microgravity. We found that attenuation of cell adhesion through laminin-integrin interactions caused the phenotype. Mitochondrial translation is activated by a signal relayed by FAK, RAC1, PAK1, BAD, and Bcl-2 family proteins in the cytosol, and the mitochondrial fatty acid synthesis (mtFAS) pathway in the matrix. Consumption of mitochondrial malonyl-CoA by mtFAS reduces the malonylation of the translational machinery and accelerates the rates of translational initiation and elongation. Physiologically, this system operates in mechano-response of skeletal muscles. Our work provides mechanistic insights into how cells convert gravitational and mechanical forces into translation in mitochondria.
    DOI:  https://doi.org/10.1038/s41467-026-74493-z
  34. bioRxiv. 2026 Jun 26. pii: 2026.06.25.734654. [Epub ahead of print]
    Evolution of a core ribosomal innovation in octopus.
    Rishav Mitra, Richard Han, Trey J Scott, Anik G Grearson, Jessica A Willi, Christina G Liu, Hyeongju Kim, Michael C Jewett, Nicholas W Bellono, Amy Sy Lee.
      Much of biology focuses on how genetic changes mediate new functions, but less attention is given to adaptations in other steps of the central dogma. Octopuses exhibit complex nervous systems and sophisticated behaviors that rival vertebrates, but via an entirely divergent evolutionary history. Here, we serendipitously discovered that octopus ribosomes contain a structural break in the core ribosomal RNA that is unique among all animals. This break site enhances translation fidelity to reduce miscoding and subsequent protein aggregation, even when engineered into evolutionarily distant bacterial ribosomes. Furthermore, high fidelity translation by octopus ribosomes supports proteomic stability during extensive RNA editing observed in cephalopods, suggesting synergy between distinct non-canonical modes of gene regulation. This adaptation emerged in recently derived octopuses with expanded nervous systems, thereby revealing a mechanism that could broadly support the evolution of novel organismal traits.
    DOI:  https://doi.org/10.64898/2026.06.25.734654
  35. mBio. 2026 Jun 23. e0130526
    Bridging two hosts: how intracellular environments shape flaviviral infection.
    Pavithra Umashankar, Shwetha Shivaprasad.
      Mosquito-borne flaviviruses replicate in physiologically and biochemically distinct host environments in humans and mosquitoes, providing a unique window into conserved and host-specific mechanisms shaping viral infection efficiencies and outcomes. This review focuses specifically on intracellular factors, including proteins, metabolites, innate immune effectors, and stress sensors in human and mosquito cells that collectively regulate the flaviviral life cycle and host cell survival, with specific emphasis on dengue virus. We discuss both conserved dependencies and species-specific differences in receptor usage, membrane remodeling, RNA translation, and replication strategies that influence viral dynamics across hosts. We further highlight how host metabolism, innate immune sensing, and stress response pathways drive divergent outcomes in virus-infected cells. In mammalian cells, rapid viral replication activates interferon-mediated antiviral responses that limit viral infection, but also lead to cytopathic effects and apoptosis. In contrast, mosquito cells support persistent, non-cytopathic infection mediated by RNA interference-dependent control of viral replication, coupled with antioxidant and anti-apoptotic defenses that maintain cellular homeostasis. This comparative perspective integrates insights from mammalian and mosquito systems to illustrate how host environments shape flaviviral infection, host susceptibility, and infection outcomes. Identifying these intracellular determinants of infection and persistence will be critical for defining host susceptibility, understanding barriers to cross-species transmission, and predicting viral emergence potential.
    Keywords:  flavivirus; host-virus interactions; mosquito; stress response
    DOI:  https://doi.org/10.1128/mbio.01305-26
  36. Cell Biochem Funct. 2026 Jul;44(7): e70255
    The Role of RNA Helicase DHX33 in Tumorigenesis.
    Xingshun Wang.
      RNA helicases are a large family of enzymes crucial for virtually all aspects of RNA metabolism, forming the backbone of gene expression regulation. Among them, DEAH-box helicase 33 (DHX33) has emerged as a pivotal player in fundamental cellular processes, including ribosomal biogenesis, transcription, and translation initiation. A compelling body of evidence now positions DHX33 as a significant oncoprotein, with its overexpression documented in a wide spectrum of human cancers such as lung carcinoma, hepatocellular carcinoma, glioblastoma, and acute myeloid leukemia. Its oncogenic drive is mediated through the transcriptional regulation of genes governing the cell cycle and apoptosis, its interplay with major signaling pathways like Wnt/β-catenin and PI3K/Akt/mTOR, and its role in metabolic reprogramming, notably the Warburg effect. Furthermore, DHX33 acts as a key downstream effector of potent oncogenes like c-Myc. Genetic or pharmacological inhibition of DHX33 consistently impedes tumor growth, underscoring its non-redundant role in oncogenesis. This review systematically synthesizes the current understanding of the mechanisms by which DHX33 promotes tumorigenesis. It delves into its regulation of core cellular processes, its integration into oncogenic signaling networks, and its recently discovered functions in epigenetic and metabolic reprogramming. By consolidating this knowledge, we aim to highlight the multifaceted nature of DHX33 in cancer biology and firmly establish its potential as a viable and promising therapeutic target for future anticancer strategies.
    Keywords:  DHX33; RNA helicase; therapeutic target; tumorigenesis
    DOI:  https://doi.org/10.1002/cbf.70255
  37. Front Physiol. 2026 ;17 1873221
    When mitochondria lose their fold: matrix proteostasis and stress signaling.
    Nils Bertram, Dejana Mokranjac.
      A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.
    Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis
    DOI:  https://doi.org/10.3389/fphys.2026.1873221
  38. Commun Biol. 2026 Jun 29.
    A nucleolar stress gene signature enables quantitative scoring across multi-omics contexts.
    Jianxiong Chen, Shuai Xiao, Zhe Hao, Huimeng Xu, Xuemei Xu, Jun Zhou.
      The nucleolus is essential for ribosome biogenesis and cellular homeostasis, and its dysfunction can induce nucleolar stress, a process implicated in cancer and other diseases. However, nucleolar stress is commonly inferred from morphological changes or a limited set of functional assays, and quantitative approaches based on gene expression profiles remain lacking. Here, we integrate literature curation with multi-dataset screening to define a nucleolar stress gene signature and develop a nucleolar stress score (NuS) applicable to bulk transcriptomics, single-cell transcriptomics, proteomics, and spatial transcriptomics. Using this framework, we show in colorectal cancer models that oxaliplatin induces nucleolar stress, suppresses nascent rRNA synthesis, and activates p53 signaling, whereas these responses are attenuated in oxaliplatin-resistant cells. Combined with a ribosome biogenesis activity score (RiboSis), NuS captures related but distinct dimensions of nucleolar function and stratifies tumors into functional states associated with clinical outcomes. NuS-based analysis of perturbational transcriptomes further prioritizes compounds with putative nucleolar stress-inducing activity. Collectively, this study provides a quantitative framework for evaluating nucleolar stress and illustrates its applications in disease stratification and drug mechanism discovery.
    DOI:  https://doi.org/10.1038/s42003-026-10528-x
  39. Nat Rev Mol Cell Biol. 2026 Jul 03.
    Human aminoacyl-tRNA synthetases as integrators of translation and cell signalling networks.
    Ina Yoon, Haissi Cui, Sunghoon Kim.
      Aminoacyl-tRNA synthetases (ARSs) are best known for their central role in translation, where they attach specific amino acids to their matching tRNAs to ensure accurate protein synthesis. However, in humans, these enzymes have evolved far beyond this textbook function. Emerging research reveals that ARSs have versatile roles in cells, acting as sensors, signalling hubs and regulators of cellular and systemic homeostasis. The structural adaptability of ARSs enables them to connect metabolic cues with gene expression, protein networks and stress responses. Disruptions in ARS functions are increasingly linked to a wide range of diseases, from cancer to neurodegeneration. In this Review, we examine how ARSs operate at the intersection of translation and signalling networks: we discuss their catalytic regulation functions, structural diversification, non-canonical functions such as in transcription and translation regulation, protein degradation and signal transduction and their disease relevance. By bringing these insights together, we offer a unified view of ARSs as multifaceted proteins and open new avenues for discoveries in molecular biology, pathophysiology and drug design.
    DOI:  https://doi.org/10.1038/s41580-026-00980-2
  40. Bio Protoc. 2026 Jun 20. 16(12): e5504
    Visualizing Diverse RNA Functions in Living Cells With SpinachTM Family of Fluorogenic Aptamers.
    Ryan O'Hanlon, Karen Y Wu.
      RNA is now recognized as a highly diverse and dynamic class of molecules whose localization, processing, and turnover are central to cell function and disease. Live-cell RNA imaging is therefore essential for linking RNA behavior to mechanism. Existing approaches include quenched hybridization probes that directly target endogenous transcripts but face delivery and sequestration issues, protein-recruitment tags such as MS2/PP7 that add large payloads and can perturb localization or decay, and CRISPR-dCas13 imaging that requires substantial protein cargo and careful control of background and off-target effects. Here, we present a protocol for live-cell RNA imaging using the SpinachTM family of fluorogenic RNA aptamers. The method details the design and cloning of SpinachTM-tagged RNA constructs, selection and handling of cognate small-molecule fluorophores, expression in mammalian cell lines, dye loading, and image acquisition on standard fluorescence microscopes, followed by quantitative analysis of localization and dynamics. We include controls to verify aptamer expression and signal specificity, guidance for multiplexing with related variants (e.g., Broccoli, Corn, Squash, Beetroot), and troubleshooting for dye permeability and signal optimization. Application examples illustrate use in tracking cellular delivery of mRNA therapeutics, monitoring transcription and decay in response to perturbations, and the forming of toxic RNA aggregates. Compared with prior methods, SpinachTM tags are compact, genetically encodable, and fluorogenic, providing high-contrast imaging in both the nucleus and cytoplasm with single-vector simplicity and multiplexing capability. The protocol standardizes key steps to improve robustness and reproducibility across cell types and laboratories. Key features • This protocol demonstrates the usage of the SpinachTM technology in different RNA-focused applications. • The protocol can be used to fluorescently image most RNA types in live cells. • This protocol requires pre-existing experience in molecular cloning, cell culturing, and fluorescence microscopy. • Requires at least seven days to complete from beginning to end.
    Keywords:  Fluorescence microscopy; Fluorogenic RNA; Live-cell imaging; RNA aggregation; RNA degradation; RNA imaging; Single-molecule resolution; Transcription
    DOI:  https://doi.org/10.21769/BioProtoc.5504
  41. Mol Cell. 2026 Jul 02. pii: S1097-2765(26)00376-X. [Epub ahead of print]86(13): 2449-2451
    Tweezing apart ribosome heterogeneity.
    Jakub Zeman, Leo Kurian.
      In this issue of Molecular Cell, Chen et al.1 introduce Ribo-Tweezer: a modular platform for conditionally and selectively depleting proteins from mature ribosomes, enabling direct tests of their ribosome-bound roles in translation regulation.
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.005
  42. Zhonghua Kou Qiang Yi Xue Za Zhi. 2026 Jul 02. 61(7): 1081-1088
    [Clinical significance and molecular mechanisms of m6A modification in oral squamous cell carcinoma].
    Z C Wang, C P Qiu, L T Li, S Y Liu, Y C Yang, J Wang.
      Oral squamous cell carcinoma (OSCC) represents the most prevalent primary malignant neoplasm within the head and neck region. The elevated rates of recurrence and metastasis, coupled with resistance to conventional therapies, significantly compromise patient prognosis, thereby necessitating the identification of novel molecular regulatory targets. N6-methyladenosine (m6A) modification emerges as the most widespread post-transcriptional RNA modification in eukaryotic organisms. This modification operates through a dynamic regulatory network involving methyltransferases (Writers), demethylases (Erasers), and recognition proteins (Readers), which collectively orchestrate precise regulation of RNA functionality and are intricately involved in oncogenic processes. Current research indicates that m6A modification and its associated regulatory factors exhibit aberrant dysregulation in OSCC. By modulating critical biological processes such as tumor cell proliferation, invasion, metastasis, autophagy, ferroptosis, and the characteristics of OSCC tumor stem cells, these modifications influence both the progression and therapeutic responsiveness of OSCC. This article systematically reviews the core regulatory mechanisms of m6A modification, focusing on its functional effects and molecular pathways in the malignant progression of OSCC. It summarizes the clinical translational value of m6A regulatory factors as diagnostic and prognostic biomarkers as well as targets for targeted therapy, and outlines future research directions in this field, aiming to provide important theoretical references for the precision diagnosis and treatment of OSCC.
    DOI:  https://doi.org/10.3760/cma.j.cn112144-20260117-00029
  43. Exp Brain Res. 2026 Jun 30. pii: 146. [Epub ahead of print]244(8):
    Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.
    Sule Terzioglu-Usak, Merve Zaim, Merve Beker, Sevim Isik, Birsen Elibol.
      Reelin signaling regulates multiple pathways in neurodegenerative conditions, including neuronal migration, synaptic plasticity, tau phosphorylation, and amyloidogenic processing of amyloid precursor protein (APP). This study aimed to investigate the impact of reelin downregulation on the expression of topoisomerase IIβ (topo IIβ), given its crucial role in neuronal differentiation and its established association with neurodegenerative disorders such as Alzheimer's disease (AD). Furthermore, we sought to elucidate the potential relationship between reelin downregulation and proteins implicated in the pathophysiology of AD. Firstly, the optimum concentration of small interfering RNAs (siRNA) targeting reelin was transfected into SH-SY5Y cells using Lipofectamine RNAiMAX reagent. The downregulation of reelin was confirmed at the mRNA level by real-time quantitative polymerase chain reaction (qRT-PCR). Reelin-mediated molecular alterations at both the mRNA and protein levels were analyzed by qRT-PCR and Western blotting. Reelin downregulation led to a decrease in the number of viable cells as determined by the MTT assay. Consistent with the downregulation of reelin gene expression, topo IIβ, Psen1, and BACE1 expressions were also reduced, whereas tau and APP expressions were upregulated. Although siRNA treatment effectively decreased reelin mRNA levels and the proteolytic fragment of reelin protein, no significant change was observed in total full-length reelin protein levels, suggesting the involvement of post-transcriptional regulatory mechanisms. Moreover, pTAU and APP protein expressions were increased, while Nurr1 protein was decreased in reelin-silenced cells. These findings suggest that downregulation of reelin gene expression may contribute to neurodegeneration through alterations in topo IIβ and nurr1 expression, in addition to changes in proteins associated with AD pathology.
    Keywords:  Neuropathology; Reelin; Small interference RNA
    DOI:  https://doi.org/10.1007/s00221-026-07339-1
  44. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2026 Apr 28. pii: 1672-7347(2026)04-0781-18. [Epub ahead of print]51(4): 781-798
    [Mechanisms of RNA-binding protein phase separation in steroid-associated necrosis of the femoral head].
    Tianfa Hu, Jie Han, Yachao Wu, Guojun Yao, Kebin Shang, Zhen Liao, Bin Nong, Kailong Yu.
      Steroid-associated necrosis of the femoral head (SANFH) is a refractory osteoarticular disease induced by glucocorticoids, characterized by a complex pathogenesis and limited clinical treatment options. Recent studies have demonstrated that RNA-binding proteins (RBPs) play crucial roles in post-transcriptional regulation, cell signal transduction, and metabolic homeostasis through liquid-liquid phase separation (LLPS). In the pathogenesis of SANFH, RBPs participate in the regulation of key processes involved in bone metabolism via LLPS and may represent potential therapeutic targets. The phase-separation behavior of RBPs can be dynamically regulated by factors such as domain characteristics, RNA-binding status, and the adenosine triphosphate (ATP) microenvironment. These regulatory mechanisms subsequently influence DNA damage repair, ferroptosis, exosome biogenesis, the transforming growth factor-beta (TGF-β)/Sma- and Mad-related protein 7 (Smad7) signaling pathway, inflammasome activation, and m6A modification, all of which are closely associated with the initiation and progression of SANFH. Targeted regulation of RBP phase separation may provide a promising strategy to restore bone metabolism homeostasis, inhibit cell death, and alleviate inflammatory responses through multiple mechanisms. By integrating the emerging cell-biological mechanism of RBP phase separation with the multistage and multipathway pathological progression of SANFH, a novel mechanistic framework is proposed, offering new perspectives for the prevention and treatment of SANFH. Further studies are warranted to elucidate the precise roles of RBP phase separation in SANFH and to explore phase separation-based precision therapeutic strategies.
    Keywords:  RNA-binding protein; exosome; ferroptosis; glucocorticoid; m 6 A modification; phase separation; steroid-associated necrosis of the femoral head
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2026.250687
  45. J Biochem Mol Toxicol. 2026 Jul;40(7): e71004
    METTL3 Promotes Castration-Resistant Prostate Cancer Progression by Enhancing AKR1C3 Expression.
    Qihong Nie, Xiaoyuan Wu, Xin Huang, Min Zeng, Zhongsheng Yang, Hailin Luo, Chuance Du.
      Castration-resistant prostate cancer (CRPC) is a lethal stage of prostate cancer (PC). This research sought to examine the functions and underlying mechanisms of N6-methyladenosine (m6A) methyltransferases in CRPC. Transcriptomic datasets from the Gene Expression Omnibus and The Cancer Genome Atlas were analyzed to identify dysregulated m6A methyltransferases. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, wound healing, Transwell, enzyme-linked immunosorbent assay, reverse transcription quantitative polymerase chain reaction, western blot, m6A RNA immunoprecipitation quantitative PCR, co-immunoprecipitation, and m6A quantification assays were performed to evaluate the phenotypic and molecular effects of methyltransferase-like 3 (METTL3). A xenograft tumor model was constructed by subcutaneous injection of lentivirus-transduced LNCaP cells into BALB/c nude mice. Hematoxylin and eosin staining was utilized to detect histopathological alterations, and immunohistochemistry was applied to measure Ki67 expression. METTL3 and methyltransferase-like 5 were upregulated, whereas methyltransferase-like 4 was downregulated. METTL3 knockdown suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition in LNCaP and C4-2 cells and suppressed xenograft tumor growth. METTL3 knockdown reduced dihydrotestosterone production and suppressed the protein expression of androgen receptor, kallikrein-related peptidase 3, and FK506 binding protein 5. METTL3 enhanced the m6A methylation and transcript stability of aldo-keto reductase family 1 member C3 (AKR1C3). AKR1C3 overexpression notably reversed the anti-tumor effects induced by METTL3 knockdown. METTL3 acts as an epigenetic driver of CRPC by promoting AKR1C3 expression in an m6A-dependent manner, highlighting the METTL3/AKR1C3 axis as a promising treatment target.
    Keywords:  aldo‐keto reductase family 1 member C3; androgen receptor signaling; castration‐resistant prostate cancer; methyltransferase‐like 3
    DOI:  https://doi.org/10.1002/jbt.71004
  46. Int J Biol Macromol. 2026 Jun 29. pii: S0141-8130(26)03191-0. [Epub ahead of print]373 153251
    YTHDC2 suppresses oral squamous cell carcinoma progression by inhibiting glutaminolysis via VHL/HIF-1α axis.
    Xi Chen, Bin Yang, Zhenzhong Liu, Fang Wang, Yang Li, Ronghui Wu, Liqin Mao, Ting Zhao, Yu Gao, Yulin An.
      Oral squamous cell carcinoma (OSCC), a highly prevalent and poor-prognosis malignancy, is closely associated with tumor metabolic reprogramming, particularly the glutamine-dependent metabolic phenotype. This study systematically investigates the role of N6-methyladenosine (m6A) modification in OSCC through integrated bioinformatics analysis and functional experiments, focusing on the tumor-suppressive function of the m6A reader YTHDC2 and its regulation of glutaminolysis. Analysis based on The Cancer Genome Atlas (TCGA) datasets revealed that YTHDC2 expression was significantly inversely correlated with OSCC malignancy and patient survival. Functional validation showed that YTHDC2 depletion promoted OSCC cell proliferation and stem-like properties, whereas YTHDC2 overexpression markedly suppressed these malignant phenotypes. Mechanistic studies demonstrated that YTHDC2 stabilized VHL mRNA by recognizing m6A modification sites, enhancing VHL protein expression. This promoted VHL-mediated ubiquitin-dependent degradation of HIF-1α, leading to transcriptional repression of its downstream target GLS1. Consequently, this blocked glutaminolysis, tricarboxylic acid (TCA) cycle-driven energy production, and glutathione (GSH)-mediated antioxidant pathways. Additionally, low YTHDC2 expression in OSCC tissues was closely associated with DNA hypermethylation at CpG islands in its promoter, an epigenetic silencing mechanism that sustains the glutamine-addicted phenotype. This study first uncovers the core role of the YTHDC2/m6A/VHL/HIF-1α/GLS1 signaling axis in metabolic regulation of OSCC, providing new insights into the molecular basis of glutamine addiction. YTHDC2 not only serves as a prognostic biomarker for OSCC but also highlights its-mediated metabolic pathway as a theoretical basis for developing targeted therapies against glutaminolysis.
    Keywords:  Glutaminolysis; Metabolic reprogramming; Oral squamous cell carcinoma; YTHDC2; m6A modification
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153251
  47. Res Sq. 2026 Jun 17. pii: rs.3.rs-9927381. [Epub ahead of print]
    Diversion of Arginine's dietary metabolic fate in proteinuric kidney disease.
    Markus Rinschen, Maria Chrysopoulou, Xavier de la Rosa, Yifan Tan, Elina Kovalenko, Oliver Hahn, Jesper Frank Andersen, Moritz Lassé, Vladimir Matchkov, Vera Wulfmeyer, Johannes Jaegers, Anja Billing, Elizabeth Colby, Markus Bleich, Bernhard Schermer, Sarantos Kostidis, Martin Giera, Janos Peti-Peterdi, Meryl Waldman, Nicola Tomas, Moin Saleem, Insa Schmidt, Nina Himmerkus, Peder Berg, Fatih Demir, Eugene Rhee, Morgan Grams, Sushrut Waikar.
      Proteinuria predicts chronic kidney disease progression and cardiometabolic mortality, yet how sustained urinary protein loss reshapes interorgan metabolism remains unclear. Here, we tested whether proteinuric kidney disease alters whole-body amino-acid and nitrogen handling by applying long-term dietary arginine isotope tracing in a proteinuric podocin-mutant mouse model, complemented by ex vivo nephron-segment metabolism and human cohort analyses. Because arginine connects amino acid use in protein synthesis, amino acid catabolism, and the urea cycle, the dietary isotope label allowed us to follow both metabolite flux and protein incorporation across organs over time. Proteinuria did not trigger a broad compensatory increase in protein synthesis. Instead, it caused a kidney-centered rerouting of arginine metabolism. Arginine use shifted away from hepatic ureagenesis and toward renal glutamate-, proline-, and aspartate-linked fate. Across organs, most proteins incorporated recycled arginine, whereas albumin preferentially incorporated diet-derived arginine, identifying albumin as a major non-recycled arginine sink during proteinuric disease. In the kidney, proximal nephron segments showed coordinated remodeling of arginine and proline metabolism in association with tubular albumin handling. This rerouting favored proline synthesis and early collagen incorporation before overt fibrosis was established. Isotope-resolved nitrogen tracing indicated that this renal diversion of arginine occurs at the expense of coordinated nitrogen and acid handling, as reflected by reduced urinary ammonium excretion, tissue accumulation of arginine-derived ammonia, and altered abundance of enzymes involved in ammonium detoxification. In humans, circulating aspartate was elevated during active proteinuric disease and decreased in remission, independently of glomerular filtration rate, and both aspartate and proline associated with histological markers of fibrotic remodeling in biopsies from glomerular disease patients. Consequently, in proteinuric mice, a high dietary content of aspartate/asparagine further aggravated collagen accumulation and fibrosis-related remodeling of high-proline-content proteins, while impairing acid excretion. Together, these findings define proteinuric kidney disease as a chronic interorgan nitrogen-redistribution state that links selective protein turnover, impaired ammonium disposal, acid retention, and a renal profibrotic metabolic environment.
    DOI:  https://doi.org/10.21203/rs.3.rs-9927381/v1
  48. Nat Metab. 2026 Jun 29.
    Mitochondrial quality control in human ageing and longevity.
    Anna Picca, Luigi Ferrucci.
      Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.
    DOI:  https://doi.org/10.1038/s42255-026-01563-3
  49. Curr Med Chem. 2026 Jul 01.
    HRI Kinase Modulation by BTdCPU as a Therapeutic Strategy for Bortezomib Resistance in Prostate Cancer.
    Semih Seker, Emrah Okur, Azmi Yerlikaya.
       BACKGROUND: Heme-Regulated Inhibitor (HRI) kinase is a key serine-threonine kinase that regulates eIF2α phosphorylation and Integrated Stress Signaling (ISR). The present study used parental and bortezomib-resistant PC3 prostate cancer cells to examine whether pharmacologic modulation of this pathway, particularly with BTdCPU, retains activity in a resistant setting and how it relates to stress-signaling markers.
    MATERIALS AND METHODS: We initially assessed the cytotoxic effects of the HRI activator BTdCPU, along with its inhibitors hemin and ZnPP, in bortezomib-resistant cells using the MTT assay. A single BTdCPU + bortezomib concentration pair was then examined using the real-time iCELLigence system and AO/EB morphology. Western blotting was performed to evaluate total HRI, phosphorylated eIF2, Hsp70, Hsp60, and polyubiquitin (PolyUb) conjugates. Public-dataset analyses were used to provide descriptive clinical context.
    RESULTS: The IC50 values for bortezomib in parental and resistant cells were 44.34 nM and 1.151 µM, respectively, indicating that the resistant cells were approximately 26 times more resistant to bortezomib than the parental cells. The IC50 of BTdCPU in parental and resistant cells was found to be 1.268 µM and 1.971 µM, respectively. Notably, BTdCPU-induced HRI activation appears to act through a mechanism distinct from classical proteasome inhibition, as it promotes eIF2α phosphorylation independently of stress markers such as Hsp70 and polyubiquitin (PolyUb) conjugate accumulation, which are observed in parental cells treated with bortezomib, but not in resistant cells treated similarly. Descriptive bioinformatic analyses also indicated differential HRI expression across prostate cancer subgroups and according to TP53 status.
    DISCUSSION: The current findings suggest that cancer cell resistance may, in part, arise from the overactivation of the HRI/eIF2α signaling pathway, which is likely triggered by the increased expression of PolyUb conjugates and Hsp70. These findings support further investigation of HRI/ISR-related signaling in proteasome-inhibitor resistance; however, the present data are pharmacologic and associative rather than causal, and they do not establish direct HRI dependence or downstream ISR effector involvement.
    CONCLUSION: The findings indicate that BTdCPU, either alone or in combination with bortezomib, warrants further investigation as a potential strategy for overcoming bortezomib resistance in both p53-wild type and p53-mutant cancer cells.
    Keywords:  BTdCPU; Bortezomib; HRI; eIF2; proteasome; ubiquitin
    DOI:  https://doi.org/10.2174/0109298673465659260612050156
  50. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2601775123
    Dynamic positioning of Rpc34 winged helix in RNA polymerase III elongation complex for its stability with implications for reinitiation.
    Jheng-Syong Wu, Yu-Chun Lin, Yi-Yu Wei, Hsin-Hung Lin, Yang-Chih Liu, Jen-Wei Chang, I-Ping Tu, Hung-Ta Chen, Wei-Hau Chang.
      RNA polymerase III (Pol III) is specialized for the high-throughput synthesis of short RNAs, a capability linked to its unique TFIIE- and TFIIF-like subcomplexes that are stably associated through different stages of transcription. To date, the role of a winged helix domain (WH2) of Rpc34 subunit in the TFIIE-like subcomplex during elongation has remained a conundrum because its density is consistently absent in cryo-EM structures of Pol III elongation complexes (ECs), suggesting its high conformational mobility. In this study, we employed single-molecule Förster resonance energy transfer (smFRET) and nano-positioning triangulation to characterize the dynamics and determine the position of the Rpc34-WH2 domain within transcription-competent but nontranslocating Pol III ECs. To achieve the required site-specific labeling, we developed a chemical biology framework that utilizes azido-carrying unnatural amino acid incorporation and a thiol-capping strategy to eliminate off-target alkyne-thiol cross-reactivity. With the acceptor at Rpc34-WH2 and the donor at a defined position on the DNA template as the reference point, our smFRET results reveal that Rpc34-WH2 dynamically transitions among three discrete states, corresponding to preferred positional sites in downstream, middle, and upstream regions across the DNA-binding cleft. One of these sites coincides with Rpc34-WH2's position in the preinitiation complex, indicating positional similarity across transcriptional states. Together with prior Pol I and Pol II studies, these findings establish Rpc34-WH2 as a mobile regulatory element that engages the Pol III EC through transient, weak interactions. Additionally, the bio-orthogonal labeling strategy presented here provides a robust, generalizable route for smFRET studies of large, multisubunit protein assemblies.
    Keywords:  RNA polymerase; bio-orthogonal chemistry; protein dynamics; single-molecule FRET; transcription elongation
    DOI:  https://doi.org/10.1073/pnas.2601775123
  51. Hematol Oncol. 2026 Jul;44(4): e70216
    Integrated Glycoproteomics Identifies Dynamic IgA1 N-Glycosylation and FUT8 as a Functional Mediator in Multiple Myeloma.
    Xu Si, Rui Zhao, Yichuan Song, Wenxuan Fu, Jing Zhao, Yahan Gong, Rui Zhang.
      Aberrant protein glycosylation is pivotal in cancer progression. However, the IgA glycosylation landscape in multiple myeloma (MM) and its regulatory mechanisms remain uncharacterized. We conducted a comprehensive glycoproteomic analysis of site-specific N-glycosylation at IgA1-Asn144 across a large cohort, including newly diagnosed MM patients (n = 50), healthy controls (n = 38), and longitudinal samples from various remission stages. Analysis was performed using Zeno trap-equipped time-of-flight mass spectrometry. We identified a significant upregulation of fucosylated N-glycopeptides in MM. A diagnostic model based on two fucosylated glycopeptides showed potential diagnostic utility (AUC = 0.808). Attaining deep therapeutic remission was associated with a marked loss of fucosylation and downregulation of hypersialylated glycans. Bioinformatics analysis pinpointed the fucosyltransferase FUT8 as a key differentially expressed regulator, which was subsequently validated to be elevated in MM at both RNA and protein levels. FUT8 promotes tumor progression by activating Wnt/β-catenin signaling and EMT-associated pathways, thereby enhancing MM cell proliferation, migration, and invasiveness. These findings identify FUT8 as a potential prognostic biomarker and a therapeutic target in MM.
    Keywords:  FUT8; N‐glycosylation; glycoproteomics; immunoglobulin A; multiple myeloma
    DOI:  https://doi.org/10.1002/hon.70216
  52. J Proteome Res. 2026 Jun 29.
    Proteomic Impact of Peripheral Expression of Mutant Huntingtin in C. elegans.
    Ephraim Ezeigbo, Alyssa Stonebraker, Herbi Yuliantoro, Anjola Adewoye, Anthony Debastiani, Emily Roefer, Pritom Kumar Biswas, Peng Li, Justin Legleiter, Stephen J Valentine.
      Huntington's Disease (HD), a neurodegenerative disorder, is caused by the expansion of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin protein (HTT), resulting in HTT aggregation. While associated with neurodegeneration, HTT is expressed ubiquitously throughout the body, leading to potential peripheral consequences of aggregation. However, the impact on peripheral tissues remains poorly understood in comparison to the central nervous system. Here, a Caenorhabditis elegans (C. elegans) HD model that expresses an N-terminal HTT fragment (nonpathogenic 15Q or pathogenic 128Q) in body-wall muscle cells was used to evaluate proteome remodeling. Four conditions (15Q and 128Q on days 2 and 7 of adult worms, denoted as 15D2, 15D7, 128D2, and 128D7) were evaluated. In comparison to 15D2, 128D2 worms displayed decreased expression of ribosomal proteins and cytoskeletal components such as actin, profilin, calponin, and myosin, as well as overexpression of galectin, a stress- and inflammation-associated protein. By day 7, the 15D7 animals exhibited developmental signatures related to ribosome biogenesis, signal transduction, and vesicle trafficking, whereas abundance levels of proteins associated with stress response pathways such as proteostasis, protein folding, and cytoskeletal remodeling were observed to be increased in the 128D7 worms. These findings demonstrate the stage-dependent, nonlinear nature of HD-associated proteome disruption associated with peripheral expression of HD.
    Keywords:  C. elegans; DIA-PASEF; proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00850
  53. Front Immunol. 2026 ;17 1817305
    p53-associated regulation of COX17 enhances elesclomol-induced copper-associated cytotoxicity and suppresses gastric cancer growth.
    Qianling Li, Xiaoyin Dong, Yu Zhao, Yun Shen, Chenyang Yang, Yu Xi.
       Background: Cuproptosis is a copper-dependent form of regulated cell death with emerging relevance to cancer therapy. However, the upstream determinants of copper-associated cytotoxicity and cuproptosis-related sensitivity in gastric cancer remain incompletely defined.
    Methods: Using AGS gastric cancer cells with genetic gain- and loss-of-function of COX17 and p53, we assessed viability using CCK-8 assays, cell death using TUNEL staining, intracellular copper levels, migration and invasion using wound healing and Transwell assays, and the expression of copper handling and cuproptosis-associated proteins by Western blotting. The potential transcriptional regulation of COX17 by p53 was evaluated using ChIP-qPCR. Paracrine effects on angiogenesis-related phenotypes were evaluated in HUVECs exposed to tumor-cell-conditioned media, followed by tube formation, ROS, GSH, SOD, and MDA measurements. In vivo relevance was examined in a subcutaneous AGS xenograft model treated with elesclomol.
    Results: COX17 alone had only a modest effect on basal cell viability but markedly increased the sensitivity of AGS cells to elesclomol-induced copper-associated cytotoxicity, accompanied by increased intracellular copper accumulation and TUNEL positivity, whereas COX17 knockdown attenuated these effects. Elesclomol treatment with COX17 modulation was associated with increased SLC31A1 expression and decreased ATP7A expression. p53 overexpression suppressed malignant phenotypes and increased COX17 expression. ChIP-qPCR showed the enrichment of p53 at the COX17 promoter region, suggesting that p53 may participate in the transcriptional regulation of COX17. Functional rescue experiments further indicated that COX17 is an important downstream mediator of p53-associated sensitivity to elesclomol. Conditioned media from elesclomol-treated, COX17-overexpressing tumor cells inhibited HUVEC tube formation and proliferation and increased oxidative stress. In xenografts, elesclomol reduced tumor growth, which was further suppressed by COX17 overexpression and partially attenuated by COX17 silencing, accompanied by increased tumor copper accumulation, upregulation of p53/COX17/SLC31A1, and downregulation of ATP7A.
    Conclusion: These findings suggest that the p53-COX17 axis links copper metabolism to elesclomol-associated antitumor activity in gastric cancer. COX17 may enhance copper accumulation, oxidative stress, tumor-cell-death-associated changes, and angiogenesis-related phenotypic inhibition. Further studies using canonical cuproptosis markers, copper chelator rescue experiments, additional gastric cancer cell lines with different p53 backgrounds, and clinical validation are required to confirm the translational significance of this pathway.
    Keywords:  COX17; angiogenesis-related phenotype; copper metabolism; cuproptosis; elesclomol; gastric cancer; p53
    DOI:  https://doi.org/10.3389/fimmu.2026.1817305
  54. FEMS Yeast Res. 2026 Jun 29. pii: foag027. [Epub ahead of print]
    Nutrient sensing and transceptor-mediated metabolic control in yeast.
    Ryoya Tanahashi, Hiroshi Takagi, Akira Nishimura.
      The yeast Saccharomyces cerevisiae coordinates growth, metabolism, and stress adaptation through signaling pathways that respond to changes in nutrient availability. Classical nutrient-sensing systems, including the cAMP-protein kinase A (PKA), Snf1/AMP-activated protein kinase, target of rapamycin complex 1 (TORC1)-Sch9, Ssy1-Ptr3-Ssy5, and general amino acid control pathways, have revealed how yeast senses and responds to extracellular carbon, nitrogen, phosphate, and amino acid levels. In addition to these established pathways, plasma-membrane nutrient transporters also function in signaling rather than solely mediating substrate uptake. These dual-function proteins, termed nutrient transceptors, couple nutrient transport or extracellular nutrient recognition to rapid intracellular responses, often activating PKA without detectable changes in cAMP levels. This review focuses on yeast nutrient transceptors, specifically Gap1, Mep2, Pho84, Sul1/Sul2, Can1, Ftr1, and Zrt1. These proteins link extracellular nutrient availability to intracellular regulatory responses, including trehalose mobilization, stress resistance, growth resumption, filamentous development, and, in some cases, TORC1-Sch9 signaling. Mechanistic insights, including transport-signaling uncoupling and potential physical association with downstream protein kinases, are also discussed. Collectively, this evidence establishes nutrient transceptors as an essential additional layer of nutrient sensing in yeast, highlighting their role in translating extracellular nutrient cues into cellular responses.
    Keywords:   Saccharomyces cerevisiae ; Nutrient sensing; Nutrient signaling; PKA pathway; Plasma-membrane transporters; transceptor
    DOI:  https://doi.org/10.1093/femsyr/foag027
  55. Nat Commun. 2026 Jul 03. pii: 5845. [Epub ahead of print]17(1):
    Structural basis of the regulation by CDK11 kinase of early spliceosome activation and evidence for its proofreading by DHX15 helicase.
    Zhenwei Zhang, Vinay Kumar, Sumeru Panta, Jiayun Zhong, Olexandr Dybkov, Haohao Dong, Berthold Kastner, Henning Urlaub, Holger Stark, Reinhard Lührmann.
      Formation of the activated human spliceosome (Bact) involves major structural rearrangements, leading to the catalytically active U2/U6 RNA core. This process involves at least two intermediates, pre-Bact-1 and pre-Bact-2, and is regulated by CDK11-mediated phosphorylation of the U2 snRNP protein SF3B1. However, the mechanisms of this essential step are poorly understood. Here we present the cryo-EM structure of a spliceosome stalled - by the CDK11 inhibitor OTS964 - in a previously undescribed early-activated state, termed pre-Bact-OTS, shortly after dissociation of U4 snRNP. In pre-Bact-OTS, the U2-SF3B6 protein is retained in a C-terminal region of the super-helical U2-SF3B1 HEAT domain (SF3B1HEAT) that clamps the U2/branch-site helix. In contrast, in pre-Bact-1, SF3B6 is repositioned to SF3B1's N-terminal HEAT repeats, thereby preventing a steric clash of SF3B6 with PRP8 during the pre-Bact-OTS-to-pre-Bact-1 transition. We infer that the CDK11-mediated phosphorylation of SF3B1 drives the relocation of SF3B6, gating progression to Bact formation. In pre-Bact-OTS, we also located the RNA helicase DHX15 at the N-terminal region of SF3B1HEAT, assisted by the SR140/SPF45/CHERP/SUGP1 protein complex. These results suggest the involvement of DHX15 in kinase-mediated proofreading of the early-activated spliceosome, by competing with CDK11's phosphorylation of SF3B1, and thus with relocation of SF3B6 at SF3B1HEAT.
    DOI:  https://doi.org/10.1038/s41467-026-75109-2
  56. Front Mol Biosci. 2026 ;13 1867214
    MBNL1-mediated alternative splicing in cancer: underlying mechanism, isoform regulation, and translational perspectives.
    Huidan Tan, Rongyan Zhao, Bo Liu, Leilei Fu.
      Alternative splicing (AS) is a major mechanism that expands proteomic diversity and fine-tunes gene expression in eukaryotic cells. Its dysregulation is now recognized as a hallmark of cancer and contributes to tumor initiation, progression, metastasis, and therapeutic resistance. Muscleblind-like splicing regulator 1 (MBNL1) is a highly conserved RNA-binding protein (RBP) that controls AS, RNA stability, and other aspects of transcript processing. Increasing evidence indicates that MBNL1 expression, isoform composition, and subcellular localization are frequently altered in multiple cancer types. Through these changes, MBNL1 reshapes the splicing programs of cancer-related genes and exerts context-dependent tumor-suppressive or tumor-supportive effects. This review summarizes the structure and biological functions of MBNL1, the major mechanisms through which it regulates cancer-associated AS, its expression and isoform-specific features across different tumor types, and emerging therapeutic strategies targeting MBNL1 and its downstream splicing network. Current challenges and future directions are also discussed. Overall, MBNL1 represents a promising splicing regulator with potential value for biomarker development and precision cancer therapy.
    Keywords:  MBNL1; RNA-binding protein; alternative splicing; cancer; isoform regulation
    DOI:  https://doi.org/10.3389/fmolb.2026.1867214
  57. J Math Biol. 2026 Jul 03. pii: 12. [Epub ahead of print]93(1):
    Dynamic resource allocation in eukaryotic Resource Balance Analysis.
    Saeed Sadeghi Arjmand.
      Resource Balance Analysis (RBA) is a framework for predicting steady-state cellular growth under resource constraints. However, classical RBA formulations are static and do not capture the dynamic regulation of biosynthetic resources or macromolecular turnover, which is particularly important in eukaryotic cells. In this work, we propose a dynamic extension of eukaryotic RBA based on an optimal control formulation. Cellular growth is modeled as the result of a time-dependent allocation of translational capacity between metabolic enzymes and macromolecular machinery, aimed at maximizing biomass accumulation over a finite time horizon. Using Pontryagin's Maximum Principle, we characterize optimal allocation strategies and show that steady-state RBA solutions arise as limiting regimes of the dynamic problem.
    Keywords:  Convex optimization; Eukaryotic cells; Macromolecular turnover; Optimal control; Resource Balance Analysis
    DOI:  https://doi.org/10.1007/s00285-026-02436-9
  58. Biochem Soc Trans. 2026 Jul 29. 54(7): 873-885
    Mechanisms influencing transient cytoplasmic protein targeting to intracellular lipid droplets.
    Jay L Laws, Ebony A Monson, Lachlan A Wallace, Karla J Helbig, Cameron J Reddington.
      Lipid droplets (LDs) have a multitude of functions ranging from lipid storage to fighting infection and are decorated with a variety of proteins on their surface that determine their functions and behaviours. Mass spectrometric analysis has identified the vast array of LD-localised proteins, which have recently been shown to be dynamic, changing in response to cellular stress, infection, and altered homeostasis. Here, we review the key mechanisms of cytoplasmic protein interactions with the LD, highlighting conventional features like amphipathic helices, atypical sequence-based motifs, protein-protein interactions, and post-translational modifications that confer dynamic targeting of proteins to the surface of the LD. A better understanding of the transient LD proteome and the mechanisms that confer LD protein targeting will allow researchers to develop a more thorough understanding of LD biology, and the role of LDs in cellular homeostasis and disease.
    Keywords:  CYTOLD; Lipid droplets; Membrane targeting; Post-translational modifications
    DOI:  https://doi.org/10.1042/BST20250461
  59. Chem Biol Interact. 2026 Jul 01. pii: S0009-2797(26)00338-8. [Epub ahead of print] 112230
    Arsenic Promotes Nonalcoholic Steatohepatitis via MCFD2-Induced PERK/eIF2α-Mediated Integrated Stress Response.
    Yingyue Yuan, Tianming Qiu, Huilin Luo, Wenjuan Tan, Jingyuan Zhang, Ningning Wang, Jie Bai, Xiaofeng Yao, Xiance Sun.
      Arsenic exposure, a typical environmental stressor, is closely associated with nonalcoholic steatohepatitis (NASH), but the definite mechanism remains elusive. The integrated stress response (ISR) acts as a core signaling cascade that mediates cellular stress responses and is implicated in the development of multiple metabolic disorders. Nevertheless, the critical regulatory role of ISR in the progression of arsenic-associated NASH has not been definitively clarified. In the present study, we verified the activation of ISR in arsenic-induced NASH by detecting the expression of ISR-related markers through in vivo and in vitro. Notably, the majority of the downstream impacts of the ISR were modified after arsenic exposure. However, of the four upstream ISR signaling initiators, only Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) was influenced, as evidenced by a marked elevation in PERK phosphorylation levels following arsenic treatment. Furthermore, we demonstrated that NaAsO2 downregulated the protein levels of multiple coagulation factor deficiency protein 2 (MCFD2), which is localized on the endoplasmic reticulum and Golgi apparatus, in vivo and in vitro. Notably, overexpression of MCFD2 markedly attenuated PERK-eIF2α-mediated ISR, inflammation and lipid accumulation caused by arsenic in vitro. In conclusion, our findings reveal that arsenic exposure triggers the activation of PERK-eIF2α-mediated ISR and NASH by suppressing MCFD2. These findings may provide insights into the underlying mechanisms of NASH.
    Keywords:  Integrated stress response; MCFD2; NASH; NaAsO(2)
    DOI:  https://doi.org/10.1016/j.cbi.2026.112230
  60. Theranostics. 2026 ;16(13): 7196-7243
    GRP78 in human diseases: From molecular chaperone to therapeutic target.
    Yang Li, Dan Mu, Jiajie Feng, Zhijia Li, Lan Zhang, Lei Wang.
      Glucose-regulated Protein 78 (GRP78, also known as BiP/HSPA5) is a central member of the Hsp70 family. As a key molecular chaperone in the endoplasmic reticulum (ER), it plays an important role in cell survival and biological function by maintaining protein folding homeostasis and regulating endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR). Its function is precisely regulated by various post-translational modifications (PTMs), including phosphorylation and acetylation. In addition, GRP78 can translocate to subcellular locations such as the cell membrane and nucleus, where it performs non-classical functions under stress conditions. Under pathological states, the aberrant expression and function of GRP78 are extensively involved in the onset and progression of diverse human diseases, including cancer, neurodegenerative diseases, infectious diseases, cardiovascular diseases, inflammatory diseases and metabolic diseases, and often exhibit a dual role dependent on tissue specificity and disease stage. To date, a variety of intervention strategies have been developed, such as small-molecule modulators, antibodies and genetic intervention approaches. These strategies have demonstrated promising potential in preclinical studies, yet are confronted with challenges including insufficient specificity and delayed clinical translation. This paper systematically elucidates the structure, PTMs, biological functions and disease regulatory mechanisms of GRP78, summarizes the existing intervention strategies, and discusses the unresolved issues and future research directions in this field. Future research should focus on developing highly specific regulatory tools and integrating precision medicine strategies to advance the clinical translation and application of GRP78 as a therapeutic target.
    Keywords:  GRP78; human diseases; molecular chaperone; post-translational modifications; structure and function; targeted therapy
    DOI:  https://doi.org/10.7150/thno.136060
  61. Mol Biol Rep. 2026 Jul 02. pii: 1076. [Epub ahead of print]53(1):
    ATPR promotes differentiation in gastric cancer cells by endocan.
    Jian Zhong, Qingya He, Xiaoli Jiang, Wenjing Zhou, Zihan Wang, Shengquan Zhang, Sumei Zhang.
       BACKGROUND: ATPR (4-amino-2-trifluoromethyl-phenyl retinate), a derivative of ATRA (all-trans retinoic acid), exhibits potent anti-cancer activity by restoring the differentiation capacity of tumor cells. It has lower cytotoxicity compared to ATRA, making it a clinically valuable therapeutic agent. Endocan, encoded by ESM-1, a glycoprotein secreted by endothelial cells, is involved in multiple cellular proliferation processes. The high invasive capacity of gastric cancer is associated with abnormal differentiation. This study aims to investigate the mechanism by which ATPR modulates the differentiation capacity of gastric cancer cells and to elucidate the critical role of endocan in this process.
    METHODS: Gastric cancer cells (SGC-7901) were cultured and treated with a specific concentration of ATPR. We then performed Hoechst dye staining to assess cell viability, measured the activities of alkaline phosphatase (AKP) and lactate dehydrogenase (LDH) and examined endocan mRNA and protein levels. Subsequently, SGC-7901 cells cultured with ATPR were transfected with small interfering RNA (siRNA) targeting endocan. Changes in LDH and AKP activities were compared between the control group and the endocan knockdown group.
    RESULTS AND CONCLUSIONS: In gastric cancer cells treated with ATPR, there was a significant reduction in the activities of LDH and AKP, accompanied by a marked increase in endocan expression at both mRNA and protein levels. In stable endocan-knockdown gastric cancer cells, the activities of LDH and AKP were significantly restored. These results suggest that ATPR promotes gastric cancer cell differentiation via endocan.
    Keywords:  4-amino-2-trifluoromethyl-phenyl retinate (ATPR); Cell differentiation; Endocan; Gastric cancer
    DOI:  https://doi.org/10.1007/s11033-026-12235-6
  62. Front Plant Sci. 2026 ;17 1868690
    SbHsp70 overexpression enhances drought and salinity tolerance in wheat through improved cellular stability and stress-associated structural adaptations.
    Sruthy Maria Augustine, Nayyer Abdollahi Sisi, Lennart Scheer, Annabelle Heid, Babette Knoblauch, Stjepan Vukasovic, Stavros Tzigos, Rod J Snowdon.
       Introduction: Drought and salinity are major constraints to wheat productivity worldwide. Heat shock protein 70 (Hsp70) is a conserved molecular chaperone implicated in plant stress responses, but its role in cellular stability and structural adaptation in wheat remains poorly understood.
    Methods: To investigate its function, the sorghum-derived SbHsp70 gene was constitutively overexpressed in durum wheat (cv. Kofa) and bread wheat (cv. Bobwhite) via particle bombardment. Transgenic lines were evaluated under controlled drought and salinity stress conditions using physiological, cellular, molecular, and agronomic analyses.
    Results: SbHsp70 overexpression enhanced drought and salinity tolerance in both wheat backgrounds. Transgenic plants maintained higher membrane stability, relative water content, and photosynthetic activity under stress. Enhanced interlocking marginal lobe formation, altered actin organization, and modulation of stress-responsive gene expression were also observed. Importantly, transgenic lines maintained agronomic performance under drought without yield penalties under well-watered conditions.
    Discussion: These findings suggest that SbHsp70 contributes to abiotic stress tolerance through improved cellular stability and stress-associated structural adaptations. While the observed cytoskeletal and transcriptional changes indicate a coordinated stress response, further studies are required to elucidate the underlying molecular mechanisms.
    Keywords:  Hsp70; Kofa; biolistics; bobwhite; durum wheat; heat shock protein; interlocking marginal lobe
    DOI:  https://doi.org/10.3389/fpls.2026.1868690
  63. Nucleic Acids Res. 2026 Jun 22. pii: gkag664. [Epub ahead of print]54(12):
    Defective queuosine and i6A/ms2i6A modification of tRNATyr cause frameshifting and protein aggregation.
    Yu Sun, Navpreet Kaur, Hina Zain, Rodrigo Arias-Cartin, Bibek Hamal, Caroline Kühne, Marc Erhardt, Frédéric Barras, Patrick A Limbach, Ann E Ehrenhofer-Murray.
      Queuosine (Q) modification at the wobble position (Q34) of tRNAs fine-tunes translational speed but is not essential for viability, leaving its physiological role unclear. In bacteria, Q34 is synthesized de novo, whereas eukaryotes obtain queuosine (Q) or its precursor queuine (q) from external sources. Q34 uniquely co-occurs with N6-isopentenyladenosine (i6A) or its derivative 2-methylthio-N6-isopentenyladenosine (ms2i6A) at position 37 of tRNATyr. We show that loss of Q34 (∆tgt) causes a severe growth defect in Escherichia coli lacking ms2i6A due to deletion of the MiaA isopentenyltransferase (∆miaA), which is rescued by tRNATyr overexpression. Simultaneous absence of Q34 and ms2i6A37 increases +1 frameshifting at tyrosine codons and promotes protein aggregation, indicating impaired tRNATyr function. This functional interplay is evolutionarily conserved: Q34 deficiency aggravates the growth defect of Schizosaccharomyces pombe lacking the isopentenyltransferase Tit1 and thus i6A. In S. pombe, Q34 enhances tRNATyr abundance in tit1∆ cells and reduces i6A37 levels in wild-type, revealing reciprocal regulation. Together, these findings demonstrate a synergistic role of Q34 and (ms2)i6A37 in maintaining translational fidelity and proteostasis, with potential implications for human health when Q availability is limited.
    DOI:  https://doi.org/10.1093/nar/gkag664
  64. Front Plant Sci. 2026 ;17 1871251
    FgMob1 is involved in mitotic exit and regulates the development, abiotic stress response, and pathogenicity of Fusarium graminearum.
    Zenghong Luo, Qihao Xu, Xintong Wu, Xuzhao Mao, Usama Amin, Yakubu Saddeeq Abubakar, Wenhui Zheng, Zonghua Wang, Huawei Zheng.
      Fusarium graminearum is a plant pathogenic fungus that causes wheat scab. This pathogen is distributed worldwide and produces deoxynivalenol, which significantly affects humans and animals. Mob1 belongs to the MOB (Mps One Binder) family, whose members are present in a wide variety of eukaryotes, and is a core component of the MEN (mitotic exit network) pathway, regulating the mitotic exit process in yeast. However, the roles of Mob1 in pathogenic fungi remain poorly understood. In this study, we investigated the roles of FgMob1 in the development and pathogenicity of F. graminearum. Functional analyses showed that FgMob1 is important for vegetative growth, conidiation, ascospore formation, DON production, and pathogenicity. Subcellular localization results revealed that FgMob1 localizes to the spindle pole bodies. Furthermore, the average number of nuclei was significantly increased in the hyphae and conidia of the FgMOB1 deletion mutant, suggesting that FgMob1 is involved in MEN. Additionally, FgMob1 plays a significant role in the response to abiotic stress, deletion of the FgMOB1 gene affected sensitivity to cell wall, plasma membrane and oxidative stresses. In summary, this study demonstrates that FgMob1 is involved in MEN and is required for vegetative growth, asexual and sexual development, abiotic stress response, and pathogenicity in F. graminearum.
    Keywords:  FgMob1; Fusarium graminearum; abiotic stress; mitotic exit; pathogenicity
    DOI:  https://doi.org/10.3389/fpls.2026.1871251
  65. Immunobiology. 2026 Jun 25. pii: S0171-2985(26)00057-4. [Epub ahead of print]231(4): 153211
    Chronic stress promotes colorectal cancer progression by inducing M2 macrophage polarization and activating the CCL2-CCR2 axis.
    Mengyun Wang, Jiayu Pang, Wenbin Wang, Qian Xu, Yanjie Lu, Yanzhen Zuo, YuHong Li.
      Chronic stress is associated with poor prognosis in colorectal cancer (CRC), but the underlying immune mechanisms remain poorly defined. This study investigates how β-adrenergic signaling, a key component of the stress response, modulates the tumor microenvironment. We demonstrate that stressed CRC patients have elevated serum CCL2, and high tumoral expression of CCL2 and its receptor CCR2 predicts poor survival. Single-cell analysis reveals that within the tumor microenvironment of colorectal cancer, macrophages constitute the primary subset of immune cells responsible for CCL2 secretion. Mechanistically, we demonstrate that stimulating macrophages with isoproterenol, a well-established in vitro method to mimic chronic stress signaling, induces their polarization toward an M2-like phenotype and significantly increases CCL2 secretion. Functionally, conditioned media from these "stressed" macrophages enhanced CRC cell proliferation and invasion in a CCR2-dependent manner, an effect abrogated by pharmacological CCR2 blockade. Collectively, our findings pinpoint the CCL2-CCR2 pathway as the central mediator of a 'stress-macrophage-tumor' axis, validating it as a key therapeutic target to intercept CRC progression driven by a chronic stress state elicited by β-adrenergic activation.
    Keywords:  CCL2-CCR2; Chronic stress; Colorectal cancer; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.imbio.2026.153211
  66. J Toxicol Sci. 2026 ;51(7): 379-391
    Protein homeostasis disruption in cisplatin-induced skeletal muscle atrophy: toxicological insights from experimental studies.
    Hiroyasu Sakai, Risako Kon, Nobutomo Ikarashi, Kumiko Ogawa.
      Cisplatin is a widely used platinum-based chemotherapeutic agent whose dose-limiting toxicities, including nephrotoxicity, neurotoxicity, and myelosuppression, have been extensively characterized. In contrast, skeletal muscle has not traditionally been regarded as a primary target of cisplatin toxicity. However, accumulating experimental evidence indicates that cisplatin administration leads to a significant reduction in skeletal muscle mass and fiber size, even in the absence of tumor burden or overt cachexia. These findings suggest that cisplatin itself can directly induce skeletal muscle atrophy as a form of drug-induced toxicity. Animal and cell-based studies have demonstrated that cisplatin activates catabolic signaling in skeletal muscle, most notably through enhanced protein degradation via the ubiquitin-proteasome system. This response is accompanied by increased expression of muscle-specific E3 ubiquitin ligases, including muscle RING finger 1 (MuRF1) and muscle atrophy F-box protein (MAFbx/atrogin-1), which are established mediators of skeletal muscle atrophy. In parallel, suppression of anabolic signaling, particularly impairment of the insulin-like growth factor-1/Akt/mechanistic target of rapamycin complex 1 (mTORC1) pathway, has been reported, indicating a shift in muscle protein turnover toward a catabolic state. Recent studies suggest that cellular stress responses, such as endoplasmic reticulum stress, may be involved in regulating these processes. This review summarizes experimental evidence supporting cisplatin-induced skeletal muscle atrophy and discusses the underlying toxicological processes from a muscle-centered perspective. By distinguishing drug-induced muscle toxicity from cancer cachexia and other wasting conditions, we propose that skeletal muscle should be recognized as a clinically relevant but underestimated target organ of cisplatin toxicity. Improved understanding of these processes may support the development of strategies to preserve muscle mass and function during cancer chemotherapy.
    Keywords:  Atrogin-1; Cisplatin; MuRF1; Skeletal muscle atrophy; Ubiquitin–proteasome system
    DOI:  https://doi.org/10.2131/jts.51.379
  67. Curr Opin Biomed Eng. 2026 Jun;pii: 100668. [Epub ahead of print]38
    Beyond The Nucleus: Translating Engineered Protein Localization To Chromatin Modifying Enzymes.
    Zanir Hirani, Rabindra Tirouvanziam, Karmella A Haynes.
      Chromatin-modifying enzymes (CMEs) have traditionally been studied in their nuclear context for regulating gene expression. However, recent evidence points to the significant non-canonical functions that they perform in the cytoplasm, mitochondria, and plasma membrane, which can contribute to disease progression and alter cell phenotypes. This review surveys emerging engineering approaches to control protein localization, which could be applied to CMEs, particularly histone-modifying enzymes. Natural regulatory mechanisms include nuclear import/export signals and mechanical force-mediated translocation. Engineering strategies encompass diverse approaches: synthetic localization signals for directional transport, RNA editing systems like SNAP-ADAR, and small molecule platforms including bifunctional compounds, self-localizing ligands, and nanobody-mediated translocation. Optogenetic tools provide spatiotemporal control through light-inducible trapping, while inducible condensates enable reversible protein sequestration. Additional tools provide extra control via protease-based cleavage mechanisms and endogenous secondary messenger coupling. Despite significant advances in protein relocalization technologies, their application to CMEs remains largely unexplored, which would allow us to decode mechanisms of disease and develop targeted therapeutic interventions for those diseases. Future applications of these tools to CMEs will elucidate our understanding of epigenetic regulation and expand how we conceptualize CMEs.
    Keywords:  Histone-modifying enzyme; epigenetic engineering; nanobody; protein localization; sequestration; synthetic biology
    DOI:  https://doi.org/10.1016/j.cobme.2026.100668
  68. Yakugaku Zasshi. 2026 ;146(7): 617-624
    [Development of Protein and RNA Degraders for Drug Discovery].
    Yukihiro Itoh.
      Targeted protein degradation (TPD) is an emerging approach that selectively eliminates specific proteins using synthetic molecules, such as proteolysis-targeting chimeras (PROTACs). It has attracted increasing attention in medicinal chemistry and chemical biology, with several PROTACs being tested in clinical settings. Unlike traditional small molecules, such as enzyme inhibitors and receptor antagonists, PROTACs exhibit a fundamentally different mechanism. Conventional drugs block enzymatic activities or receptor interactions, whereas PROTACs induce the degradation of target proteins, decreasing their cellular levels and abolishing all associated functions. PROTACs targeting enzymes in protein complexes disrupt both their catalytic activity and involvement in complex formation. In some cases, they also degrade other proteins in complexes, facilitating the elimination of entire assemblies. Our study leverages these unique features of TPD. We are currently developing various PROTACs targeting the enzymes responsible for lysine acetylation or methylation in proteins. Recently, the TPD concept has been extended beyond proteins to include nucleic acids, and ribonuclease-targeting chimeras (RIBOTACs) that selectively degrade RNA have been developed. We are also actively exploring new RNA-targeted degradation strategies. Herein, we highlight our recent work on TPD-inducing small molecules and provide an overview of RIBOTACs, which represent an area of growing research interest.
    Keywords:  RNA; histone deacetylase; target protein degradation
    DOI:  https://doi.org/10.1248/yakushi.25-00183-1
  69. Theriogenology. 2026 Jun 29. pii: S0093-691X(26)00245-1. [Epub ahead of print]265 118055
    Interaction of ARA54 with androgen receptor in mediating testosterone-dependent regulation of caput epididymal GPX5 expression in mice.
    Dong-Li Liu, Xin Gao, Yi-Ying Wang, Yu-Qing Lin, Si-Han Yu, Zhao-Jin Luan.
      Glutathione peroxidase 5 (GPX5), a highly expressed antioxidant enzyme in the caput epididymis, is pivotal for sperm maturation and storage. Exploring its expression regulatory mechanisms is significant for maintaining normal sperm motility, but such mechanisms remain elusive. In this research, we examined the role of androgen receptor (AR) and its co-regulator androgen receptor-associated protein 54 (ARA54) in testosterone-mediated regulation of epididymal GPX5 expression using in vivo and in vitro models. The results indicated that in the castrated mouse model, epididymal expression of GPX5, AR, and ARA54 proteins was markedly downregulated following testosterone deprivation. Exogenous testosterone supplementation restored their expression to near-normal levels. Cellular experiments confirmed the positive regulation of these proteins by testosterone. Mechanistically, AR knockdown not only reduced ARA54 protein levels but also suppressed GPX5 transcription and translation. Similarly, ARA54 knockdown downregulated both mRNA and protein expression of GPX5. Our present study elucidated that ARA54 acts in concert with the AR to mediate the testosterone-induced upregulation of GPX5, offering novel insights for a deeper understanding of the hormonal regulatory network governing the antioxidant microenvironment in the epididymis.
    Keywords:  AR; ARA54; Epididymis; GPX5; Testosterone
    DOI:  https://doi.org/10.1016/j.theriogenology.2026.118055
  70. Exp Mol Med. 2026 Jul 03.
    Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function.
    Ju-Hyeon Bae, Chang-Lim You, Jeongmin Park, Jong-Sun Kang.
      Sarcopenia and neuromuscular degeneration are key drivers of functional decline during ageing and arise not solely from muscle loss but also from failure of mitochondrial and metabolic stress adaptation across the neuromuscular system. Mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, defective quality control and redox imbalance, contributes directly to muscle weakness, neuromuscular junction instability and motor unit degeneration. However, the upstream mechanisms governing the transition from adaptive remodelling to degenerative collapse remain incompletely defined. Protein arginine methyltransferases (PRMTs) have emerged as critical modulators of mitochondrial and metabolic stress signalling. Beyond epigenetic regulation, PRMTs influence signalling pathways that intersect with AMP-activated protein kinase (AMPK)-Forkhead box O (FOXO) and mechanistic target of rapamycin (mTOR), thereby regulating mitochondrial biogenesis, selective autophagy and mitophagy, proteostatic balance, and anabolic restraint. Distinct PRMT family members exert non-redundant functions across muscle fibres, satellite cells and motor neurons, collectively shaping neuromuscular stress resilience. We propose that PRMTs act as molecular rheostats that bias cellular responses to mitochondrial stress towards adaptive resolution or progression to neuromuscular degeneration, thereby positioning PRMT-regulated metabolic signalling as a unifying mechanism underlying sarcopenia and compromised healthspan.
    DOI:  https://doi.org/10.1038/s12276-026-01762-8
  71. Bone Res. 2026 Jun 29. pii: 68. [Epub ahead of print]14(1):
    Angiogenin mediates cell-cell fusion as a mitochondrial RNA processing enzyme.
    Ke Shen, Yixiang Zeng, Jiekang Wang, Kangping Song, Surendra Kumar, Peisong Gao, Guo-Fu Hu, Xu Cao, Mei Wan.
      Cell-cell fusion, essential for diverse physiological events, requires high ATP levels. While mitochondrial activity increases in fusing cells, the mechanism driving mitochondrial ribosome (mitoribosome) biogenesis to support these energy demands remains unclear. Here, we identify angiogenin (ANG) as a mitochondrial tRNA (mt-tRNA) processing enzyme critical for mitoribosome biogenesis during myoblast and osteoclast fusion. Upon fusion initiation, ANG translocates to mitochondria, promoting mitoribosome biogenesis to support translation of respiratory complex proteins for ATP production. Using transcriptome-wide PARE and 5' RACE analyses, we show that ANG cleaves the tRNA 3'-end in mitochondrial pre-RNA transcripts bordering rRNAs and mRNAs, enabling their release for translation. Loss of ANG or disruption of its ribonucleolytic activity impairs osteoclast and myoblast fusion, disrupting bone and muscle homeostasis and skeletal muscle regeneration post-injury. Our findings establish ANG as an essential mitoribosome biogenesis regulator and highlight a novel mechanism of mitochondria energy regulation in high-energy-demand biological processes.
    DOI:  https://doi.org/10.1038/s41413-026-00545-1
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