bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–06–21
fifty-six papers selected by
Cédric Chaveroux, CNRS
  1. The impact of psuedouridine modification on human tRNA.
  2. Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.
  3. Atypical Tetracyclines Promote Longevity and Ferroptotic Neuroprotection via Translation Attenuation.
  4. Post-transcriptional regulation of mRNA stability in pancreatic ductal adenocarcinoma.
  5. Click to Translate: Synthesis of Trans-Cyclooctene Modified 5' mRNA Caps for Bioorthogonal Activation.
  6. HNRNPA2B1 as an emerging coordinator of RNA fate in cancer: m6A reading, RNA export, translation reprogramming, and immune-metabolic adaptation.
  7. Integrating condensates into protein lifespan - from birth to death.
  8. Puf3 contributes to changes in mRNA solubility, translation elongation dynamics at rare arginine codons and loss of protein homeostasis in cells lacking Not4.
  9. m6A-Modulated RNF14 Favors Fatty Acid Oxidation to Drive Colorectal Cancer Progression via Regulation of TAF1/PINK1 Axis.
  10. Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.
  11. RNA acetylation modification ac4C: An emerging regulatory hub of RNA metabolism disruption in Alzheimer's disease.
  12. Staufen-swapping motif is crucial for Staufen dimerization, structure, and Staufen-mediated mRNA decay.
  13. m6A methylation of circKPNA2 promotes colorectal carcinogenesis by activating the RIN1-Ras pathway.
  14. Loss of Drosophila nucleostemin 1 disrupts ribosomal protein homeostasis and rRNA processing to trigger apoptosis via the Xrp1/Irbp18 complex.
  15. Stress granules as central players in the plant stress response.
  16. Anticodon loop remodeling and D-stem shape drive the specific recognition of ANN-decoding tRNAs for t6A modification.
  17. OTTR-seq profiling reveals dynamic tRNA modification landscapes across diverse archaeal species.
  18. Encapsulin-Protected Immunotherapeutic Complexes: Bacteria-Derived Nanoparticles for mRNA Delivery to Eukaryotic Cells.
  19. RNA-protein complexes as key regulators of plant secondary metabolism: Biophysical interactions and functional significance.
  20. Identification of SARS-CoV-2 proteins suppressing host protein synthesis.
  21. A-to-I RNA editing remodels 5'-UTR initiation codons to tune translational output.
  22. Alternative 3' UTRs and RNA-binding proteins Ewsr1b, HuR, and Syncrip organize sequential waves of translation to drive embryonic development.
  23. Rewriting the cancer proteome: targeting selective translation as a therapeutic frontier.
  24. Comparative analysis of the m6A epitranscriptome in HeLa-expressed HPV18 early transcripts reveals its potential impact on splicing.
  25. Tral tunes condensate phase behavior and mRNA partitioning to regulate P-body homeostasis during Drosophila melanogaster nurse cells.
  26. Riboregulation: a non-canonical tau function.
  27. Mass spectrometry proteomics for studying mitostasis.
  28. Revisiting the clastosome: a stress-induced nuclear proteolytic compartment of mammalian cells.
  29. Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.
  30. Regulation of EIF5A and hypusination by p53 determines colorectal cancer cell fitness.
  31. Oleanolic acid modulates neuronal regeneration through KLF5-mediated FGF13 mRNA degradation to alleviate Alzheimer's disease-like cognitive dysfunction.
  32. Mechanistic Exploration of Half-Sandwich Iridium(III) Anticancer Compounds through Integrated Cellular, Proteomic, and In Vivo Analyses.
  33. The Tor pathway, ribosome concentration, and wobble decoding mediate inhibitory effects of the Leu-Pro CUC-CCG codon pair in Saccharomyces cerevisiae.
  34. Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
  35. Quantitative comparison of methodologies for translation site imaging in living cells.
  36. Single-granule profiling reveals that RNP granule pH marks cellular translation.
  37. Cell-based screen identifies translation state modulators that extend lifespan in D. melanogaster and C. elegans.
  38. Stearoyl-CoA Desaturase-1 Drives Tumor Growth by Interacting With Histone Deacetylase-2 and Deacetylating Nucleophosmin-1.
  39. PRC2.1 Coordinates Peri-Nucleolar H3K27me3-Enriched Heterochromatin Organization and NPM1 Pentamerization to Maintain Nucleolar Integrity.
  40. Programming the translational landscape for predictable gene expression.
  41. The tRNA landscape in cancer: from pathogenesis to therapeutic interventions.
  42. Evolution of Hsp90 Targeting: From Stress Biology to Clinical Translation.
  43. P5CS represses tumor progression via inhibiting assembly of 48S pre-translation initiation complex.
  44. Anticodon-engineered tRNAs restore full-length MeCP2 expression and function in Rett syndrome nonsense mutations.
  45. Alternative ribosomal protein RpmE2 is produced under zinc limitation in Neisseria gonorrhoeae and slows translation and bacterial growth.
  46. Nucleotide-Level Chemical Reaction Network Modeling Enables Quantitative Prediction of Reconstituted Cell-Free Expression Systems.
  47. Stress granules go viral.
  48. The effects of rapid mitochondrial gene loss on organellar proteomes.
  49. The E3 ligase MKRN2 prevents DRiP accumulation in stress granules and maintains granulostasis.
  50. Cap in hand: giant viruses, stolen translation, and a road to endosymbiosis?
  51. rRNA intermediates associate with nucleolar reshaping in C. elegans.
  52. Decoding polyamine-ethylene dynamics: synergies at synthesis and signalling levels during osmotic stress and ripening.
  53. Visualization and Quantification of Intermolecular RNA Base Pairing in in vitro RNA Clusters Using Split Broccoli RNA Reporters.
  54. Prolonged heat stress induces autophagy in mouse skeletal muscle.
  55. Regulation of Fhl1 function through interactions with Hmo1 and Fpr1 at ribosomal protein gene promoters in Saccharomyces cerevisiae.
  56. PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1.
  1. Biochem Soc Trans. 2026 Jun 24. 54(6): 755-767
    The impact of psuedouridine modification on human tRNA.
    Yasmin Stone, Ethan Morgan, Yong-Han Su, Ching-Ying Kuo, Ting-Yu Lin.
      Transfer RNA (tRNA) is an important RNA in cells that decodes messenger RNA (mRNA) codons during protein translation to ensure correct amino acid sequences. The biogenesis of tRNA involves multiple processing steps to produce mature and functional molecules. Pseudouridine (Ψ), a derivative of uridine, is an abundant RNA modification and occurs at multiple positions within tRNAs. These modified sites are highly conserved across organisms. Classical biochemical studies have established that Ψ stabilises RNA-RNA interactions, but structural characterisations and molecular dynamics simulations reveal that Ψ can locally remodel tRNA architecture in ways that are dictated by where it is within tRNAs. Advances in transcriptome-wide Ψ mapping have uncovered additional modified sites beyond those previously described, with several novel sites appearing to be regulated in a cellular context-dependent manner. Furthermore, dysregulated pseudouridylation has been implicated in conditions ranging from cancer to inherited genetic disorders. Together, these developments reframe our understanding of Ψ from a well-established RNA stabiliser to a modification with roles far more dynamic, context-dependent, and clinically relevant than previously appreciated. The present review summarises and discusses the up-to-date developments in the impacts of pseudouridylation on human tRNA biogenesis, tRNA functions, and human health. More mechanistic questions remain open and will require further investigation. As pseudouridylation can also happen in mRNA and rRNA, exploring the interplay between these RNAs will be crucial for fundamental biology and advancing Ψ applications in biotechnology and biomedical uses.
    Keywords:  Pseudouridine; Pseudouridine synthases; RNA modifications; cancer; neurodevelopmental disorders; tRNA
    DOI:  https://doi.org/10.1042/BST20250258
  2. Protein Sci. 2026 Jul;35(7): e70682
    Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.
    Nikita A Kvasov, Yury S Bykov.
      Mitochondria import the majority of their proteins from the cytosol, creating a fundamental challenge: precursor proteins must be synthesized, maintained in an import-competent state, and delivered to mitochondrial translocases without premature folding or aggregation. While mitochondrial protein import has been considered a post-translational process, growing evidence shows that a subset of mitochondrial proteins is synthesized in proximity to the organelle. We term this process co-translational targeting, or local translation. It may lead to direct structural coupling of protein synthesis and import, which we term co-translational translocation. New approaches, including selective ribosome profiling, proximity labeling, and RNA imaging, reveal that mitochondrial mRNA localization is highly dynamic and can be driven by both RNA-based and translation-dependent mechanisms. In contrast to the well-defined signal recognition particle pathway at the endoplasmic reticulum, mitochondrial targeting appears to rely on more flexible mechanisms shaped by nascent-chain properties, translation elongation, and coding-sequence features beyond the targeting signal. We discuss how these processes may support mitochondrial biogenesis and proteostasis while also creating vulnerabilities associated with ribosome stalling and precursor quality control. Together, recent findings position mitochondrial protein targeting as an integral part of cellular protein biogenesis and highlight key open questions in the coordination of translation and organelle function.
    Keywords:  NAC; chaperones; co‐translational import; mRNA localization; mitochondria; protein targeting; translation
    DOI:  https://doi.org/10.1002/pro.70682
  3. Aging Cell. 2026 Jun;25(6): e70587
    Atypical Tetracyclines Promote Longevity and Ferroptotic Neuroprotection via Translation Attenuation.
    Khalyd J Clay, Manuel Sanchez-Alavez, Ian Newman, Na Na, Ana P Verduzco Espinoza, Alan To, Shannon Saad, Hollis T Cline, Michael Petrascheck.
      Reducing protein synthesis extends lifespan across taxa, but pharmacological strategies to safely attenuate translation remain limited. Tetracyclines are clinically used antibiotics long observed to exert beneficial effects in age-associated diseases and extend lifespan in model organisms, though the underlying mechanisms remain unclear. Here, we systematically profiled commercially available tetracyclines and show that translation attenuation is a general property of the tetracycline class. Importantly, we identify the atypical tetracyclines 4-epiminocycline and 12-aminominocycline, which attenuate translation independently of antibiotic activity and integrated stress response (ISR) activation. These compounds extend lifespan in C. elegans, attenuate translation in human induced neurons, reduce hippocampal protein synthesis in vivo, and protect neurons from ferroptotic stress. Together, our results demonstrate that pharmacological attenuation of translation is sufficient to promote longevity and establish translation attenuation as a druggable longevity mechanism in mammals.
    Keywords:  aging; ferroptosis; integrated stress response; longevity; neuroprotection; proteostasis; tetracyclines; translation inhibition
    DOI:  https://doi.org/10.1111/acel.70587
  4. Front Immunol. 2026 ;17 1861092
    Post-transcriptional regulation of mRNA stability in pancreatic ductal adenocarcinoma.
    Heyang Wang, Pan Liu, Juntaro Yamasaki, Tatsuhiko Harada, Tatsuya Sakaguchi, Tetsuya Takimoto, Hideyuki Saya, Osamu Nagano, Kazuhiro Fukumura.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies and is characterized by pronounced phenotypic plasticity, metabolic adaptation, and therapeutic resistance within a dense and desmoplastic tumor microenvironment. Although transcriptional deregulation has been extensively investigated, post-transcriptional regulation, particularly the control of mRNA stability, has emerged as a critical and previously underexplored contributor to PDAC progression. RNA-binding proteins (RBPs), together with cis-regulatory RNA elements and epitranscriptomic modifications such as N6-methyladenosine (m6A), form interconnected regulatory networks that dynamically modulate mRNA turnover and thereby shape protein output in response to microenvironmental stress. By selectively stabilizing transcripts encoding epithelial-mesenchymal transition (EMT) regulators, metabolic enzymes, and stress-response factors, these networks promote reversible, non-genetic adaptation without requiring permanent genetic alterations. This regulatory flexibility supports invasion, therapeutic tolerance, and intratumoral heterogeneity under hypovascular and nutrient-limited conditions. Recent advances further suggest that targeting mRNA stability through small molecules and RNA-directed strategies may provide new therapeutic opportunities in PDAC. In this review, we summarize current insights into post-transcriptional mechanisms regulating mRNA stability in PDAC, highlight key knowledge gaps, and discuss their potential translational implications.
    Keywords:  RNA-binding proteins (RBPs); epithelial–mesenchymal transition (EMT); m6A epitranscriptomics; mRNA stability; metabolic reprogramming; pancreatic ductal adenocarcinoma (PDAC); phenotypic plasticity; post-transcriptional regulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1861092
  5. Chembiochem. 2026 Jun 15. 27(11): e70420
    Click to Translate: Synthesis of Trans-Cyclooctene Modified 5' mRNA Caps for Bioorthogonal Activation.
    Niclas Zips, Ekaterina Kulko, Stephanie Kath-Schorr.
      mRNA translation can be controlled through chemical modification of the 5'-Cap, yet systematic insights into structure-reactivity relationships of bioorthogonally activatable Cap analogues remain limited. Here, we report the synthesis of trans-cyclooctene (TCO)-modified 5' mRNA caps (ZipCaps) and a comparative analysis of distinct TCO isomers. A controlled synthetic strategy enabled access to axial and equatorial derivatives, revealing stereochemical effects on click-to-release reactivity and stability. ZipCap-modified mRNA exhibits reduced translation that can be restored upon tetrazine addition, enabling reversible chemical control of protein expression in cells. In contrast to a recent report describing complete translational suppression, residual translation is observed, highlighting the sensitivity of Cap-dependent translation to structural variations.
    Keywords:  5′‐Cap; click‐to‐release; cyclooctene; mRNA; mRNA translation
    DOI:  https://doi.org/10.1002/cbic.70420
  6. Front Immunol. 2026 ;17 1805984
    HNRNPA2B1 as an emerging coordinator of RNA fate in cancer: m6A reading, RNA export, translation reprogramming, and immune-metabolic adaptation.
    Wentao Bo, Biao Zhao, Yali Wang, Quan Dai.
      Cancer progression and treatment failure are increasingly recognized as consequences of tumor plasticity rather than static genetic alterations. A key component of this plasticity is the ability of cancer cells to reprogram RNA fate, thereby reshaping gene expression outputs in response to microenvironmental stress, immune surveillance, infection, and therapeutic pressure. Among RNA-binding proteins involved in post-transcriptional regulation, heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) has been increasingly implicated in several cancer-associated RNA regulatory processes that extend beyond its initial characterization as an N6-methyladenosine (m6A) reader. In this review, we synthesize recent studies showing that HNRNPA2B1 participates in multiple aspects of RNA regulation, including m6A-dependent stabilization of oncogenic lncRNAs and mRNAs, ISGylation-associated selective nuclear export of m6A-tagged transcripts, cytoplasmic translation control, and extracellular vesicle-mediated RNA communication. We further discuss studies associating HNRNPA2B1 with immune-metabolic phenotypes and therapy response, including tumor acidosis, ferroptosis-related pathways, immune evasion, and altered sensitivity to chemotherapy, radiotherapy, endocrine therapy, and targeted treatments. Importantly, these mechanisms have largely been described in distinct tumor types, experimental systems, and biological contexts, and therefore should not yet be interpreted as a single universally established regulatory cascade. Instead, we organize current evidence within a context-aware framework in which HNRNPA2B1 is discussed as a possible regulator of selected RNA fate modules rather than as an established pan-cancer RNA fate hub. By distinguishing experimentally supported mechanisms from hypothesis-generating interpretations, this review provides a balanced assessment of the current evidence, limitations, and therapeutic implications of HNRNPA2B1-related RNA regulation in cancer.
    Keywords:  HNRNPA2B1; RNA fate regulation; immune–metabolic adaptation; m6A modification; therapy resistance
    DOI:  https://doi.org/10.3389/fimmu.2026.1805984
  7. J Biol Chem. 2026 Jun 19. pii: S0021-9258(26)02143-5. [Epub ahead of print] 113271
    Integrating condensates into protein lifespan - from birth to death.
    Chloe A Langridge, Emily M Sontag.
      Proper protein production is an essential biological process for all known living organisms. The cell depends on a functional protein homeostasis, or proteostasis, network to facilitate proper gene expression, transcription, translation, polypeptide folding, and degradation. Several condensates are involved in the "birth" and maturation of newly synthesized proteins. In conditions of cellular stress, gene expression and protein production are altered, and protein degradation often increases. Under various types of cellular stress, new condensates often form. This review will highlight the condensates that are involved in the protein lifespan. This includes condensates that regulate gene expression, protein translation, sequester misfolded proteins, and those associated with protein degradation. We will summarize what is known about these condensates under unstressed conditions, and how their regulation changes under stressed conditions. Understanding the functions and regulation of condensates during the protein life cycle will be critical to determining how things go awry in disease.
    Keywords:  aging; misfolded protein clearance; molecular chaperones; neurodegenerative diseases; phase separation; protein aggregation; protein quality control; proteostasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.113271
  8. RNA. 2026 Jun 18. pii: rna.080953.126. [Epub ahead of print]
    Puf3 contributes to changes in mRNA solubility, translation elongation dynamics at rare arginine codons and loss of protein homeostasis in cells lacking Not4.
    Léna Audebert, George E Allen, Siyu Chen, Olesya O Panasenko, Susanne Huch, Christine Polte, Zoya O Ignatova, Vicent Pelechano, Martine A Collart.
      The Not proteins of the Ccr4-Not complex regulate translation elongation dynamics, essential for proper folding and assembly of new proteins. In yeast, ribosomes with non-optimal codons in the A-site are enriched within the pool of ribosomes bound by Not4 and Not5. Such ribosomes accumulate in cells lacking Not4 or Not5 that show defects in co-translational assembly and aggregation of new proteins. Recently we observed that depletion of Not1 and Not4 inversely regulate changes in mRNA solubility, correlating with inverse codon-specific changes in A-site ribosome dwelling occupancies (RDOs). Here we describe that mRNAs less soluble upon Not4 depletion are enriched for targets of the RNA-binding protein Puf3. We determine that Puf3 contributes to differential changes of A-site RDOs upon Not1 and Not4 depletion, in particular at rare arginine codons, and it contributes to changes in mRNA solubility in not4Δ Moreover, deletion of Puf3 suppresses temperature sensitivity and protein aggregation in the not4Δ strain, while overexpression of Puf3 is toxic. Interestingly the Puf3 interactome is altered in not4Δ. Taken together, our results associate alterations in Puf3 to not4 mutant phenotypes, in particular to changes in translation elongation dynamics and protein aggregation.
    Keywords:  Not4 and Puf3; Ribosome dwelling and translation elongation; mRNA solubility; protein homeostasis; rare arginine codons
    DOI:  https://doi.org/10.1261/rna.080953.126
  9. FASEB J. 2026 Jun 30. 40(12): e72060
    m6A-Modulated RNF14 Favors Fatty Acid Oxidation to Drive Colorectal Cancer Progression via Regulation of TAF1/PINK1 Axis.
    Lv Lv, Fayou Lv, Binfeng Li, Guoqing Li, Huijun Yi.
      The contribution of fatty acid oxidation (FAO) to colorectal cancer (CRC) progression has been recognized. However, the detailed mechanisms underlying FAO remain obscure. This study explored the influence of ring finger protein 14 (RNF14) on FAO and its related mechanisms in CRC. We found that RNF14 was up-regulated in CRC, which was positively associated with FAO level. High expression of RNF14 promoted FAO to facilitate growth of CRC cells in vitro and in vivo. Mechanistically, RNA binding motif protein 15 (RBM15)/YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-mediated N6-methyladenosine (m6A) modification enhanced RNF14 translation. RNF14 reduced TATA-box binding protein associated factor 1 (TAF1) protein stability via promoting its ubiquitination. Moreover, TAF1 bound to PTEN-induced kinase 1 (PINK1) promoter to trigger its transcription. RNF14 knockdown or TAF1 overexpression repressed FAO of CRC cells, which was overturned by TAF1 or PINK1 silencing, respectively. In conclusion, RBM15/YTHDF1-mediated m6A modification of RNF14 mRNA contributed to FAO enhancement via ubiquitination of TAF1 to transcriptionally inhibit PINK1, thus promoting CRC progression.
    Keywords:  PINK1; RNF14; TAF1; colorectal cancer; fatty acid oxidation; m6A modification
    DOI:  https://doi.org/10.1096/fj.202504954RR
  10. FEBS J. 2026 Jun 16.
    Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.
    Tony Avril, Matthieu Le Gallo, Elodie Lafont.
      The endoplasmic reticulum (ER) is a cellular organelle frequently subjected to stress under both physiological and pathological circumstances, associated with the accumulation of mis/unfolded proteins in its lumen. To cope with this stress, cells have evolved an adaptive program called the unfolded protein response (UPR), whose primary function is to restore ER proteostasis. When the stress is prolonged, the UPR can also trigger cell death. The UPR controls multiple machineries involved in pre-emptive quality control (QC) of proteins prior to ER entry, ribosome-associated QC, protein folding within the ER, protein degradation through various processes, and export from the ER for secretion. Because the UPR and the machineries it controls play fundamental roles in determining cell fate, they are finely regulated, including through post-translational modifications (PTMs). In this review, we focus on the role of the ubiquitin and ubiquitin-like PTMs in the regulation and mediation of ER proteostasis. We specifically focus on three core processes: the UPR, ER-associated ribosome QC and ER-associated degradation. Lastly, we briefly discuss how Ub and Ubl also control the integrated stress response and the formation of inter-organelle membrane contact sites and thus act as general regulators of responses to cellular stresses beyond ER proteotoxicity.
    Keywords:  ER stress; ERAD; ER‐ribosomal quality control; endoplasmic reticulum; integrated stress response; ubiquitin; ubiquitin‐like; unfolded protein response
    DOI:  https://doi.org/10.1111/febs.70622
  11. Mol Biol Rep. 2026 Jun 19. pii: 968. [Epub ahead of print]53(1):
    RNA acetylation modification ac4C: An emerging regulatory hub of RNA metabolism disruption in Alzheimer's disease.
    Liping Xing, Annan Liu, Jianhui Li, Kexin Jiang, Honglin Li.
      RNA metabolic dysregulation is a key pathological mechanism underlying the onset and progression of Alzheimer's disease (AD), involving multiple aspects such as abnormal RNA splicing, loss of function in RNA-binding proteins, dysregulation of non-coding RNAs, and impaired nuclear-cytoplasmic transport. In recent years, the emergence of epigenome research has revealed the critical role of RNA chemical modifications in regulating RNA metabolism at the post-transcriptional level. N4-acetylcytidine (ac4C) is the only known RNA acetylation modification in eukaryotes and is specifically catalyzed by N-acetyltransferase 10 (NAT10). The ac4C modification is widely found in tRNA, rRNA, and mRNA, and by influencing RNA stability, translation efficiency, and ribosome assembly, it participates in various biological processes such as the cell cycle, differentiation, aging, and stress responses. In AD, the ac4C modification profile undergoes significant changes, involving GABAergic synapses, the PI3K-AKT signaling pathway, and various lncRNAs. Although indirect evidence from progeria and tumor models suggests that via α-tubulin acetylation and intersect with AD pathology via the p53 pathway and regulation of autophagy, these mechanisms currently lack direct experimental validation in NAT10 may participate in axonal transport through α-tubulin acetylation and intersect with AD pathology via the p53 pathway and autophagy regulation, these mechanisms currently lack direct experimental validation within the AD system. This article systematically summarizes the molecular basis and regulatory networks of ac4C modification, integrates existing evidence and unresolved questions regarding its role in AD, and explores its potential value as a diagnostic biomarker and therapeutic target, with the aim of providing guidance for future research in this field.
    Keywords:  Alzheimer's disease; Epitranscriptomics; NAT10; RNA acetylation; RNA metabolism; ac4C
    DOI:  https://doi.org/10.1007/s11033-026-12148-4
  12. Protein Sci. 2026 Jul;35(7): e70669
    Staufen-swapping motif is crucial for Staufen dimerization, structure, and Staufen-mediated mRNA decay.
    Andrea Tripepi, Huma Shakoor, Maria Zlobina, Tomáš Klumpler, Monika Kubíčková, Josef Houser, Petr Klapetek, Peter Josef Lukavsky.
      Human Staufen1 (hStau1, UniProt O95793.2) is a double-strand RNA (dsRNA) binding protein that modulates gene expression via mRNA-dependent mechanisms such as Staufen-mediated mRNA decay (SMD). This modular protein is dynamic and binds to both messanger RNA (mRNA) targets and proteins. The Staufen-swapping motif (SSM) domain is reported to play a key role in hStau1 dimerization. Our data confirm that SSM deletion decreases hStau1 dimerization. This protein shows higher protein disorder in the absence of SSM. Thus, SSM plays not only a key role in hStau1 dimerization but also modulates its tertiary structure. Surprisingly, increased disorder upon SSM deletion does not affect affinity for mRNA targets or protein/RNA stoichiometry but SMD efficiency since SMD targets are upregulated upon SSM deletion. In conclusion, hStau1 dimerization via SSM affects the overall structure and dynamics of the protein required for efficient regulation of gene expression via SMD.
    Keywords:  Staufen dimerization; Staufen‐binding site; Staufen‐mediated mRNA decay; Staufen‐swapping motif; protein disorder; protein oligomer
    DOI:  https://doi.org/10.1002/pro.70669
  13. Epigenetics. 2026 Dec;21(1): 2672219
    m6A methylation of circKPNA2 promotes colorectal carcinogenesis by activating the RIN1-Ras pathway.
    Jinhai Tian, Zongying Jiang, Qi Huang, Jia Wang, Yaqin He.
      Colorectal cancer (CRC) is a prevalent and highly lethal malignancy. However, the molecular mechanisms underlying its progression remain incompletely understood. Therefore, this study aimed to investigate the role and mechanisms of circKPNA2 in CRC progression. We used various techniques, including RNA sequencing, functional assays, RNA pull-down, and mass spectrometry, to examine the expression and function of circKPNA2. Our findings indicate that circKPNA2 is significantly upregulated in CRC tissues and cell lines. It contributes to tumour growth by promoting cell proliferation, migration, and invasion. We found that circKPNA2 specifically binds to the RIN1 protein and increases its levels, thereby activating the Ras signalling pathway and facilitating CRC progression. Additionally, we identified that METTL3 regulates the expression of circKPNA2 through N6-methyladenosine (m6A) methylation, which in turn affects CRC cell proliferation, migration, and invasion. These results deepen our understanding of CRC biology and underscore the potential of targeting circKPNA2 as both a therapeutic target and a diagnostic biomarker to improve CRC diagnosis and treatment.
    Keywords:  Colorectal cancer; METTL3; RIN1; Ras signaling pathway; circKPNA2
    DOI:  https://doi.org/10.1080/15592294.2026.2672219
  14. Cell Death Discov. 2026 Jun 14.
    Loss of Drosophila nucleostemin 1 disrupts ribosomal protein homeostasis and rRNA processing to trigger apoptosis via the Xrp1/Irbp18 complex.
    Xiuxiu Liu, Min Hou, Yuanyuan Zhang, Huan Liu, Xiaojiao Li, Yuanlin Su, Huiyuan Ding, Yanqin Gong, Qiao Liu, Yaoqin Gong, Gongping Sun.
      Ribosome biogenesis, a process of producing ribosomes, plays an essential role in cell survival, proliferation and apoptosis. Nucleostemin (NS) is a conserved nucleolar protein highly expressed in proliferating cells but markedly reduced in differentiated cells. Previous studies on mammalian systems have shown that loss of NS triggers p53-dependent apoptosis and impairs ribosomal RNA (rRNA) processing. In this study, using the Drosophila wing imaginal disc, which is a proliferating epithelial tissue, we demonstrate that depletion of Ns1, the Drosophila homolog of mammalian NS, induces extensive p53-independent apoptosis and suppresses global translation. Notably, we find that Ns1 is required not only for rRNA processing but also for maintaining global ribosomal protein (RP) abundance. Loss of Ns1 leads to a reduction in 65 RPs. Furthermore, we show that Ns1 deficiency upregulates the Xrp1/Irbp18 complex, an effector mediating cellular response to ribosomal deficiency, which in turn activates JNK to trigger apoptosis and suppresses global translation through a mechanism independent of eIF2α phosphorylation and JNK. Our work establishes Ns1 as a critical regulator of ribosome biogenesis and cell survival in proliferating epithelia.
    DOI:  https://doi.org/10.1038/s41420-026-03205-9
  15. J Exp Bot. 2026 Jun 16. pii: erag300. [Epub ahead of print]
    Stress granules as central players in the plant stress response.
    Jorge Solis-Miranda, Santiago Gonzalez-Rodriguez, Rafael Rubio-Ramos, David Delgado-Romero, Emilio Gutierrez-Beltran.
      Stress granules (SGs) are conserved biomolecular condensates that assemble in response to environmental stress. SGs were initially described as sites of translational arrest containing stalled mRNAs and RNA-binding proteins (RBPs). However, accumulating evidence indicates that SGs play a broader and more active role during stress responses. Rather than acting as passive repositories, SGs have emerged as dynamic hubs that contribute to the coordination of multiple cellular processes, enabling rapid adjustment to adverse conditions. In this context, studies in animal systems have redefined SGs as central hubs that coordinate key cellular processes, including signalling, cellular homeostasis, and metabolic adaptation. Similarly, emerging evidence in plants suggests that SGs function as important regulators of stress responses, contributing to the reorganization of cellular activities required for adaptation. Despite these advances, key questions remain regarding the mechanisms underlying SG assembly, selectivity, and functional outputs in plant cells.
    Keywords:  biomolecular condensates; central hubs; liquid-liquid phase separation; plant stress response; stress granules
    DOI:  https://doi.org/10.1093/jxb/erag300
  16. Nucleic Acids Res. 2026 Jun 08. pii: gkag599. [Epub ahead of print]54(11):
    Anticodon loop remodeling and D-stem shape drive the specific recognition of ANN-decoding tRNAs for t6A modification.
    Ana Kutchuashvili, Erik Scheleen, George Guynes, Junzhou Wu, Chi-Kong Chan, Peter Dedon, Dirk Iwata-Reuyl, Manal A Swairjo.
      N6-threonylcarbamoyladenosine (t6A) is a universal transfer RNA (tRNA) modification essential for translational fidelity. The modification is installed at position 37 of ANN-decoding tRNAs (N is A, U, G, or C) by transfer of a threonylcarbamoyl moiety from a pathway intermediate, catalyzed in bacteria by the TsaBD complex. Despite the strict requirement for the 36-UAA-38 sequence in substrate tRNAs, the structural basis for this specificity has remained unclear. We determined cryo-EM structures of the Thermotoga maritima t6A synthase bound to unmodified and to natively modified tRNA carrying the t6A37 modification, at a nominal resolution of 3.2 Å. In both structures, A37 is positioned in the active site, and the anticodon loop is remodeled into a zig-zag conformation not previously observed in tRNA, stabilized by conserved interactions with the RNA backbone at the TsaD/TsaB interface. The wobble and middle anticodon bases occupy shallow surface pockets without base-specific contacts, explaining tolerance to base identity at these positions. In contrast, U36 and A38 are recognized indirectly through formation of a base triple with U32. Additional D-stem contacts provide a second mode of indirect readout. Together with mutagenesis data, the structures reveal the molecular basis for restriction of t6A37 to ANN-decoding tRNAs and the requirement for A38.
    DOI:  https://doi.org/10.1093/nar/gkag599
  17. Genome Biol. 2026 Jun 18.
    OTTR-seq profiling reveals dynamic tRNA modification landscapes across diverse archaeal species.
    Jesse S Leavitt, Henry T Moore, Thomas J Santangelo, Todd M Lowe.
       BACKGROUND: Transfer RNA (tRNA) modifications are essential for structural integrity, decoding fidelity, and stress adaptation, yet their evolutionary dynamics remain poorly characterized in archaea. Here, we apply Ordered Two-Template Relay sequencing (OTTR-seq), a high-throughput approach that captures full-length tRNAs and modification-sensitive reverse transcription signatures, to systematically profile tRNA modification landscapes across diverse archaeal species.
    RESULTS: Across nine archaeal species spanning thermophilic, acidophilic, halophilic, and mesophilic environments, we identify position-specific and clade-dependent patterns of tRNA modifications. We detect coordinated and mutually exclusive methylation at acceptor stem positions 6 and 67 in hyperthermophiles, as well as clade-specific co-modification at positions 10 and 26, which are typically known as tRNA modification anti-determinants. Comparative analyses also reveal lineage-specific divergence in the domain architectures of tRNA methyltransferases, including Trm1, Trm10, Trm11, and Trm14, linking enzymatic evolution to substrate specificity. We further refine known identity elements, such as the G10oU25 pairing, and identify novel structural features that may facilitate or prevent modification.
    CONCLUSIONS: These findings exemplify the co-evolution of tRNAs and their modifying enzymes, providing new insights into how archaea may fine-tune translation in extreme environments. The broad scope of data and comparative analyses establishes a multispecies framework for future biochemical, mechanistic, and predictive modeling efforts.
    Keywords:  Archaea; Enzyme–substrate coevolution; High-throughput RNA modification mapping; tRNA modification
    DOI:  https://doi.org/10.1186/s13059-026-04158-z
  18. ChemMedChem. 2026 Jun 15. 21(11): e202501050
    Encapsulin-Protected Immunotherapeutic Complexes: Bacteria-Derived Nanoparticles for mRNA Delivery to Eukaryotic Cells.
    Carlos Francisco Coffeen, Maribel Cayetano-Cruz, Damaris Ilhuicatzi-Alvarado, Carmen Méndez, Leticia Moreno-Fierros, Ismael Bustos-Jaimes.
      Encapsulins are protein nanocompartments that self-assemble into icosahedral structures that capture cargo proteins through a cargo-loading peptide (CLP). Here, we aimed to develop an mRNA delivery vector for eukaryotic cells by fusing the CLP from Myxococcus xanthus encapsulin cargoes with a short peptide that binds to a complementary RNA aptamer, creating an encapsulin-RNA adaptor peptide (ERAP). Additionally, we designed a chimeric mRNA (CmRNA) molecule for translation in eukaryotic cells, featuring an internal ribosome entry site (IRES) in the 5'-UTR to enable cap-independent translation. Downstream of the IRES, genes coding for model proteins were included. Finally, an aptamer that binds the Rev-derived peptide was added to the 3'-UTR of the RNA molecule. The CmRNA, ERAP, and encapsulin were coexpressed in Escherichia coli, and it was demonstrated that the produced nanocompartments contained the ERAP and bacterial RNA. The RNA was reverse-transcribed and identified by nested PCR, confirming that the encapsulin captured the CmRNA. qPCR analysis of encapsulin-protected immunotherapeutic complexes (EPICs) demonstrated the loading of 2.9 CmRNA molecules per particle. These RNA-loaded encapsulins were taken up by macrophage cells, and the expression of model proteins was confirmed. Finally, immunization of mice with these particles induced IgG antibodies against the model proteins.
    Keywords:  encapsulin; internal ribosome entry site; mRNA vaccine; nanoparticles; synthetic biology
    DOI:  https://doi.org/10.1002/cmdc.202501050
  19. Biochem Biophys Rep. 2026 Sep;47 102664
    RNA-protein complexes as key regulators of plant secondary metabolism: Biophysical interactions and functional significance.
    Okechukwu Paul-Chima Ugwu, Melvin Nnaemeka Ugwu, Hope Onohuean, Hilal Ahmad Rather, Ibe Michael Usman.
      RNA-protein complexes (RNPs) are central regulators of post-transcriptional gene expression and are increasingly implicated in controlling when, where and to what extent specialised (secondary) metabolic pathways operate in plants. Relative to transcription factor-centred regulation, RNPs can modify pathway output rapidly by modulating mRNA processing, stability, localisation and translation, thereby enabling plants to adjust metabolite production on developmentally and environmentally relevant timescales. Many regulatory RNPs assemble into membraneless biomolecular condensates (e.g., stress granules and processing bodies) via liquid-liquid phase separation (LLPS), providing reversible mechanisms to sequester, protect or degrade transcripts, including those encoding enzymes and regulators of specialised metabolism. In addition, small RNA-guided silencing complexes (e.g., AGO-containing RISC) form well-defined RNP modules that post-transcriptionally regulate transcription factors and biosynthetic genes involved in phenylpropanoid/flavonoid and other pathways. Here, we synthesise current evidence linking RNP biology to specialised metabolism, explicitly distinguishing mechanistic evidence (e.g., direct binding with functional perturbation) from associative evidence (e.g., co-localisation or proteomic enrichment). We also summarise experimental and computational approaches for mapping plant RNA-protein interactions, including key limitations (crosslinking bias, antibody specificity and contamination) and emerging tools (enhanced RNA interactome capture, proximity labelling and deep-learning-assisted binding prediction). Finally, we highlight evidence gaps in non-model medicinal plants and propose a framework that integrates spatiotemporal transcriptomics, structural biology and RNP-centred engineering to improve plant biofactories and stress-resilient phytochemical production.
    Keywords:  RNA-Protein complexes; RNA-binding proteins; Secondary (specialised) metabolism; Stress granules; and liquid-liquid phase separation
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102664
  20. Virology. 2026 Jun 09. pii: S0042-6822(26)00221-7. [Epub ahead of print]623 111006
    Identification of SARS-CoV-2 proteins suppressing host protein synthesis.
    Zhen Wang, Qinghua Pan, Ariana Arduini, Chen Liang.
      Viruses hijack cellular resources in order to produce large quantities of progenies in a short period of time. One viral strategy to achieve this goal is to shut off host gene expression, including cellular protein synthesis. To gain insights into the host shutoff mechanism employed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we determined which of its viral proteins have the capacity to inhibit the synthesis of nascent host proteins. Our results revealed that, in addition to the non-structural protein NSP1, well-documented for inhibiting translation by binding to the mRNA entry channel in the 40S ribosomal subunit, viral proteins NSP5, NSP13 and NSP15 also markedly suppress host protein synthesis. Further experiments showed that the enzymatic activities of these three latter viral proteins are required for translation inhibition, and that NSP1, NSP5 and NSP13 markedly diminish the formation of polysomes, suggesting a mechanism of disrupting the initiation stage of translation. Interestingly, no stress granule formation was detected in cells expressing these translation inhibitory viral proteins. Together, our data support a multi-pronged strategy SARS-CoV-2 uses to achieve optimal shutoff of host gene expression.
    Keywords:  COVID-19; Host shut-off; SARS-CoV-2; Translation suppression; Virus-host interactions
    DOI:  https://doi.org/10.1016/j.virol.2026.111006
  21. Sci Rep. 2026 Jun 17.
    A-to-I RNA editing remodels 5'-UTR initiation codons to tune translational output.
    Yuki Ogata, Asuka Ichinomiya, Momoko Tomikura, Masatora Fukuda.
      A-to-I RNA editing is a prevalent post-transcriptional modification in higher eukaryotes that converts adenosine to inosine within RNA molecules. Because inosine is interpreted as guanosine during translation, editing can alter codon identity and potentially influence translation initiation signals. Here, we examined whether A-to-I editing within the 5' untranslated region (5'-UTR) can remodel upstream initiation codons and thereby tune downstream translation. Using luciferase-based reporter systems, we show that AUA-to-AUI editing generates an initiation-competent inosine-containing codon, whereas AUG-to-IUG editing markedly attenuates initiation and can relieve uORF-mediated repression. Quantitative in vitro and cellular assays establish the initiation hierarchy AUA < AUI < AUG, with IUG exhibiting strongly reduced initiation efficiency. Importantly, AUI-mediated upstream initiation did not behave like a canonical AUG-initiated uORF in the tested contexts; its effect on downstream ORF translation was modest and context-dependent. Transcriptome-wide bioinformatic analysis identified endogenous human transcripts whose 5'-UTRs harbor editing sites compatible with initiation-codon gain or attenuation. Reporter validation using native 5'-UTR sequences supports the possibility that editing-dependent initiation-codon remodeling can tune translational output in living cells, particularly through AUG-to-IUG-mediated derepression. Together, these findings establish a reporter-based framework in which A-to-I editing can remodel 5'-UTR initiation codons, while highlighting the need for endogenous protein-level and native-locus validation to determine physiological relevance.
    Keywords:  ADAR; Post-transcriptional regulation; RNA editing; Translational control
    DOI:  https://doi.org/10.1038/s41598-026-57909-0
  22. Cell Rep. 2026 Jun 13. pii: S2211-1247(26)00635-2. [Epub ahead of print]45(6): 117557
    Alternative 3' UTRs and RNA-binding proteins Ewsr1b, HuR, and Syncrip organize sequential waves of translation to drive embryonic development.
    Keisuke Sato, Ludivine Fierro, Anyu Suginishi, Takahiro Sanada, Tomoya Kotani.
      Eggs of many species accumulate thousands of dormant mRNAs that are translated after fertilization at specific times and locations to direct development. However, how embryos coordinate translation of these mRNAs remains unclear. In this study, we identify sequential waves of translation critical for proper development progression. The first wave occurs within 1 h and includes translation of ewsr1b mRNA that harbors a short 3' untranslated region (UTR) comprising 16 nucleotides. The resulting Ewsr1b protein triggers the second translation wave through binding cytoplasmic mRNAs, including pou5f3, which encodes a transcription factor promoting zygotic genome activation. In contrast, HuR and Syncrip repress translation until the first and second waves, respectively. ewsr1b mRNA that has a long 3' UTR is translated in the second wave, and the 3' UTR's length determines protein localization and function. Overall, our findings reveal previously unknown molecular principles that coordinate translation timings and protein functions to drive long-term, multilayered processes.
    Keywords:  3′ UTR; CP: developmental biology; CP: molecular biology; Ewsr1b; HuR; RNA granule; RNA-binding protein; Syncrip; embryo; subcellular compartment; translation; vertebrate
    DOI:  https://doi.org/10.1016/j.celrep.2026.117557
  23. J Clin Invest. 2026 06 15. pii: e207335. [Epub ahead of print]136(12):
    Rewriting the cancer proteome: targeting selective translation as a therapeutic frontier.
    Davide Ruggero.
      Cancer proteogenomics has revealed that RNA abundance often poorly predicts protein output, highlighting translation as a central determinant of malignant identity. In this issue of JCI, Mishra et al. showed that pharmacologic inhibition of eIF4E cap binding selectively rewired the prostate cancer translatome, suppressing basal keratin translation while promoting luminal features and renewed sensitivity to hormone therapy. More broadly, the study illustrates how tumors exploit selective translation to maintain lineage plasticity, survival, and therapeutic resistance. Targeting translational dependencies may therefore offer a powerful strategy to dismantle cancer-specific proteomic programs and convert resistant cell states into druggable vulnerabilities.
    DOI:  https://doi.org/10.1172/JCI207335
  24. RNA. 2026 Jun 16. pii: rna.080698.125. [Epub ahead of print]
    Comparative analysis of the m6A epitranscriptome in HeLa-expressed HPV18 early transcripts reveals its potential impact on splicing.
    Ida Rye Hellebek, Malte Storm Lau Schlosser, Johanna Jonsson, Jamie Yam Auxillos, Sarah Rennie.
      Human papillomavirus (HPV)-driven cancers remain a major global health burden, and understanding how post-transcriptional regulation shapes viral gene expression may inform new therapeutic strategies. Here, we reanalysed independently generated public HeLa datasets to identify candidate RNA modification sites on integrated HPV18 transcripts expressed from the HeLa genome. Using Oxford Nanopore direct RNA sequencing of native RNAs and in vitro transcribed controls, together with GLORI, eTAM-seq and staged 4sU-GLORI datasets, we identified a set of candidate m6A sites on HPV18 early transcripts. m6A levels at a subset of these sites were reduced following perturbation of the m6A pathway, most clearly after METTL3 inhibition, WTAP knockdown or FTO overexpression. We further show that the E6*I-proximal m6A site at position 224 is enriched on unspliced transcripts in direct RNA sequencing, eTAM-seq and staged 4sU-GLORI data. In contrast, we find no convincing evidence for m5C or pseudouridine within the HPV18 regions covered by these datasets. Together, our analyses provide a prioritized candidate map of RNA modifications on HeLa-expressed HPV18 early transcripts.
    Keywords:  HPV; Nanopore direct RNA sequencing; bioinformatics; epitranscriptomics; m6A
    DOI:  https://doi.org/10.1261/rna.080698.125
  25. RNA. 2026 Jun 15. pii: rna.081011.126. [Epub ahead of print]
    Tral tunes condensate phase behavior and mRNA partitioning to regulate P-body homeostasis during Drosophila melanogaster nurse cells.
    Samantha N Milano, Livia V Bayer, Julie J Ko, Gwendolyn S Posner, Caroline E Casella, Diana P Bratu.
      Processing bodies (P-bodies) are cytoplasmic granules that regulate mRNA storage, repression, and decay, yet how their internal organization supports selective mRNA regulation remains poorly understood. Here, we show that the conserved LSm protein Trailer Hitch (Tral) is a key organizer of P-body architecture and function in Drosophila melanogaster nurse cells. Using quantitative confocal imaging, super-resolution microscopy, and chemical perturbation of intermolecular interactions, we demonstrate that Tral coordinates the incorporation and spatial organization of the core P-body proteins Me31B and Cup. Loss of Tral alters their partitioning into P-bodies, promotes demixing into distinct subdomains, and shifts condensates toward a less dynamic, structurally heterogeneous state. These organizational changes have functional consequences for mRNA storage: Tral depletion selectively releases maternal mRNA bicoid, while nanos mRNA remains P-body associated and stable. We further identify twinstar mRNA, encoding the actin regulator Cofilin, as a Tral-dependent P-body client whose localization and organization within P-bodies requires Tral:RNA interactions and electrostatic forces. Reduced twinstar mRNA levels in the absence of Tral are associated with decreased nuclear G-actin and altered transcription of me31B and cup, revealing a potential feedback mechanism that links cytoplasmic P-body organization to nuclear gene expression. Together, these findings establish Tral as a central regulator of P-body architecture that couples condensate organization to selective mRNA regulation and transcriptional homeostasis in D. melanogaster nurse cells.
    Keywords:  Drosophila melanogaster; Nuclear Actin; P-bodies; RNA; oogenesis
    DOI:  https://doi.org/10.1261/rna.081011.126
  26. Mol Neurodegener. 2026 Jun 19.
    Riboregulation: a non-canonical tau function.
    Katherine R LeBlanc, Randall J Eck, Sarah J Benbow, Brian C Kraemer.
      Almost since its discovery, tau protein has perplexed scientists and clinicians with its varied roles in physiology as well as its appearance as phosphorylated protein aggregates of various structures in many neurodegenerative diseases. Tau plays a role in microtubule stabilization, but from the earliest of studies, tau has also been observed to bind to RNA, with recent research suggesting tau has a higher affinity for some RNA species compared to microtubules. In the context of disease, tau dysfunction potentiates disruptions to RNA metabolism, including the perturbation of mRNA splicing, impairment of translation, de-repression of transposable elements, and alteration of RNA export and degradation. Tau aggregates directly sequester diverse RNA species and RNA binding proteins. Emerging evidence reinforces the characterization of tau as an RNA binding protein, highlighting questions about both the physiological and disease-related functions of this direct RNA binding. The disparate structure of tau in normal and various disease states makes teasing apart the various impacts on RNA and regulation a more difficult puzzle requiring future study. In this review, we summarize the evidence for tau's role in RNA biology, including as an RNA binding protein.
    Keywords:  Alzheimer’s disease; RNA metabolism; Tauopathy
    DOI:  https://doi.org/10.1186/s13024-026-00949-x
  27. Protein Sci. 2026 Jul;35(7): e70673
    Mass spectrometry proteomics for studying mitostasis.
    Lakshita Sharma, Sristi Chakroborty, Hirak Das, Silke Oeljeklaus, Julian Bender, Bettina Warscheid.
      Maintaining mitochondrial integrity and function is fundamental to cellular homeostasis. Cells rely on coordinated protein quality control (QC) systems-including intricate chaperone-protease networks, the ubiquitin-proteasome system, and cytosolic surveillance pathways-that together form a dynamic, cell-wide mitostasis network governing the import, folding, synthesis, and degradation of mitochondrial proteins. Disruption of mitochondrial homeostasis, for example, by impairing mitochondrial protein import, induces proteotoxic stress and contributes to human disease. Mass spectrometry (MS)-based proteomics has established itself as an indispensable method to dissect mitostasis at unprecedented depth by enabling systematic quantitative analysis of protein abundance, localization, interactions, stability, and dynamics. In this review, we highlight state-of-the-art MS technologies and multifaceted proteomics approaches used to study mitostasis on a proteome-wide level. These functional analysis approaches build on quantitative MS methods employing label-free, metabolic, and chemical labeling strategies, which allow precise tracking of proteome dynamics in response to different cellular conditions including stress. Spatial and interaction-based approaches, such as affinity purification-MS, proximity labeling, and complexome profiling, provide detailed insight into the organization and regulation of the complex mitochondrial organizing system, chaperone networks, and protein QC pathways. Furthermore, we discuss advanced methodologies such as nascent chain and dynamic proteomics strategies, which offer a proteome-wide comprehension of early stress responses and fast regulation. The skillful integration of temporal, spatial subcellular, interaction, nascent, and dynamic proteomics approaches now enables a systems-level assessment of mitostasis, paving the way for a holistic while nuanced understanding of this essential cellular process and the underlying molecular mechanisms.
    Keywords:  complexome profiling; dynamic SILAC; interactome analysis; mitochondria; nascent proteomics; protein import stress; proteome dynamics; proteostasis; proximity labeling; quantitative mass spectrometry
    DOI:  https://doi.org/10.1002/pro.70673
  28. Front Neuroanat. 2026 ;20 1839944
    Revisiting the clastosome: a stress-induced nuclear proteolytic compartment of mammalian cells.
    Miguel Lafarga, María T Berciano, Noemí Rueda, Sofía Cardona-Cortés, Olga Tapia.
      The nuclear ubiquitin proteasome system (UPS) is fundamental to maintaining proteostasis and ensuring the quality control of nuclear proteins. Within the nucleus, proteasomes are distributed throughout the nucleoplasm and can aggregate into nuclear bodies. In 2002, our group provided the first description in mammalian cells of a specific subtype of nuclear body highly enriched in: (i) ubiquitin conjugates, (ii) the proteolytically active 20S and 19S regulatory complexes of the 26S proteasome, (iii) the molecular chaperone Hsp70, and (iv) proteasome substrates. We coined the term clastosome to define this nuclear proteolytic center of the UPS. Clastosomes exhibit dynamic behavior, and their formation is transiently and robustly induced in mammalian neurons during osmotic stress, coinciding with enhanced proteasomal activity. Subsequent studies have confirmed and mechanistically expanded our understanding of these nuclear proteolytic centers, which are now recognized as nuclear condensates formed via liquid-liquid phase separation mechanisms. Notably, PML nuclear bodies can establish interactions with clastosomes, thereby linking the PML protein and the SUMOylation pathway with UPS-mediated protein degradation. The association between PML nuclear bodies and clastosomes has been implicated in the clearance of toxic mutant proteins associated with certain neurodegenerative diseases. This review examines the structure, composition, and dynamic regulation of clastosomes, focusing on their modulation during stress responses and neurodegeneration. Given the essential role of nuclear proteolytic centers in proteostasis regulation, a better understanding of mechanisms that modulate their assembly may offer therapeutic strategies for neurodegenerative proteinopathies and other pathologies.
    Keywords:  PML nuclear bodies; cellular stress; clastosomes; down syndrome; mammalian neurons; nuclear condensates; nuclear proteolytic centers; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3389/fnana.2026.1839944
  29. Infect Immun. 2026 Jun 15. e0017826
    Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.
    Zachary M Powers, Michael J McFadden, Gi Young Lee, Tracey Schultz, Luiza A Castro Jorge, Daniel F Edwards, Simon Sanchez-Paiva, Jonathan Z Sexton, Katherine R Spindler, Jeongmin Song, Mary X O'Riordan.
      Many intracellular pathogens stimulate host cell stress by directly or indirectly causing an imbalance in host nutrients. Depletion of amino acid pools, in particular, can act as a danger signal to infected cells. Using a restrictive host model of Salmonella enterica serovar Typhi (S. Typhi) infection, we identify early induction of the integrated stress response (ISR) by viable bacteria, but not by heat-killed bacteria. Genetic deletion of the amino acid-sensing ISR kinase GCN2 (also known as EIF2AK4) prevented early ISR activation during S. Typhi infection and murine macrophages lacking GCN2 show impaired bacterial clearance and decreased cytokine output. Supplementation of wild-type C57BL/6 murine macrophages with only the non-essential amino acid asparagine was sufficient to suppress S. Typhi-induced ISR activation, and deletion of S. Typhi ansB, encoding an asparaginase, prevented ISR activation during infection. Pharmacological inhibition of mammalian target of rapamycin (mTOR), the other major amino acid-sensing pathway in eukaryotic cells, prevented GCN2 activation and ISR induction in murine macrophages, indicating an upstream role for mTOR in signaling to GCN2. These findings suggest a role for the ISR in macrophage innate immune responses to S. Typhi infection and highlight a potential difference in nutrient-dependent signaling between the S. Typhi-susceptible human host and the restrictive murine host centered around asparagine, mTOR, and GCN2.
    Keywords:  gram-negative bacteria; innate immunity; nutritional immunity
    DOI:  https://doi.org/10.1128/iai.00178-26
  30. Cancer Lett. 2026 Jun 15. pii: S0304-3835(26)00446-5. [Epub ahead of print]656 218682
    Regulation of EIF5A and hypusination by p53 determines colorectal cancer cell fitness.
    Alain P Gobert, Caroline V Hawkins, Mohammad Asim, Daniel P Barry, Alberto G Delgado, Regina N Tyree, Kate S Carson, Nikhil P S Kahlon, Mark V Ciampa, Kristie L Rose, Purvi Patel, Ganesh V Pusapati, Rajat Rohatgi, Wang Yu, Shilin Zhao, Lori A Coburn, M Blanca Piazuelo, Keith T Wilson.
      Hypusination of eukaryotic translation initiation factor 5 A (EIF5A) by the enzyme deoxyhypusine synthase (DHPS) is a mechanism of regulation of translation that plays a role in cell proliferation. Herein, we assessed the role of hypusination in established colorectal cancer (CRC). Using molecular and biochemical approaches in established CRC cell lines and human colon organoids, we found that the tumor suppressor p53 is a critical regulator of expression of the gene EIF5A1 in the colon, thus supporting EIF5A synthesis and hypusination. Therefore, tissues and cells isolated from patients with CRC harboring TP53 mutation associated with loss of function of p53 exhibited a marked reduction of EIF5A and hypusine level. Further, TP53 mutant CRC cells remained unresponsive to a DHPS inhibitor. However, restoration of wild-type TP53 in these mutated cells supported hypusination-dependent translation of proteins involved in cell growth and rendered them susceptible to DHPS inhibition. Our studies show that loss of EIF5A is an unrecognized molecular feature of TP53 mutation in CRC cells and patients with WT TP53 CRC may benefit from drugs that can inhibit hypusination.
    Keywords:  Colon; Colorectal cancer; Deoxyhypusine synthase; Hypusine; Polyamine; Tumor suppressor p53
    DOI:  https://doi.org/10.1016/j.canlet.2026.218682
  31. J Mol Med (Berl). 2026 Jun 15. pii: 85. [Epub ahead of print]104(1):
    Oleanolic acid modulates neuronal regeneration through KLF5-mediated FGF13 mRNA degradation to alleviate Alzheimer's disease-like cognitive dysfunction.
    Dan Ren, Jiangxi Xu, Lan Xiao, Ting Zhang, Biyan Li, Ruomeng Li, Hong Zhu.
      Despite understanding the pathophysiology of Alzheimer's disease (AD), the mechanisms of neuronal regeneration mediated by oleanolic acid (OA) through m6A RNA methylation remain unexplored, forming the crux of this study. In a streptozotocin (STZ)-induced AD rat model, we administered OA and conducted behavioral tests to evaluate cognitive functions. We employed BrdU incorporation assays and immunofluorescence to investigate NSC proliferation, and Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays to analyze protein expression and RNA stability. Bioinformatic predictions focused on the interaction between KLF5, YTHDF2, and FGF13. OA significantly reversed cognitive impairment and enhanced NSC differentiation in the AD model. The modulation of OA on KLF5 expression led to the repression of YTHDF2, which was pivotal in the m6A-dependent RNA decay of FGF13, promoting axonal regeneration. Furthermore, FGF13 harbors multiple m6A modification sites, which contribute to its mRNA stability and translation, thereby influencing neuronal polarization and migration. In addition, the neuroprotective mechanism of OA also involved the upregulation of NSCs, while impaired neurogenesis and reduced NSC function are known to be associated with AD pathology. This research reveals that OA's therapeutic potential in AD is mediated through a previously unidentified mechanism involving modulation of m6A-dependent RNA regulation, highlighting the significance of m6A RNA methylation in neuronal regeneration. The findings pave the way for new therapeutic strategies targeting RNA modifications in neurodegenerative diseases.
    Keywords:  Alzheimer’s Disease; Krüppel-like Factor 5; Neuronal Regeneration; Oleanolic Acid; m6A RNA Methylation
    DOI:  https://doi.org/10.1007/s00109-026-02691-9
  32. J Med Chem. 2026 Jun 16.
    Mechanistic Exploration of Half-Sandwich Iridium(III) Anticancer Compounds through Integrated Cellular, Proteomic, and In Vivo Analyses.
    Pavel Štarha, Jaroslava Friedecká, Renata Héžová, Ondřej Bárta, Rea Jarošová, Josef Mašek, Ivan Nemec, David Milde, Adam Novobilský, Ladislav Novotný, Jaroslav Ondruš, Slavomíra Šterbinská, Nicol Straková, René Lenobel, Jan Hošek.
      New half-sandwich iridium(III) compounds [Ir(η5-Cpx)Cl(L1-3)]PF6 (1-6), combining Cp* or Cpph with N,P-coordinated phosphinoalkylamines L1-L3, were tested in different cancer cells (2D and 3D cultures), including MOR/CPR cisplatin-resistant lung carcinoma. Best-performing compound 3 outperformed its Cpph analogue 6 and cisplatin in MOR/CPR cells while sparing noncancerous cells. Multiomics profiling shows a non-DNA-targeted mechanism: rapid integrated stress response with ER stress (DDIT3/CHOP) and oxidative stress (HMOX1, ATF3), nucleolar stress, and primary inhibition of ribosome biogenesis and mitochondrial translation. These changes drive translational shutdown, suppression of oxidative phosphorylation with a glycolytic shift, and G1 arrest, alongside endolysosomal remodeling (enhanced vesicular uptake, reduced degradative capacity) that favors intracellular retention. The phenotype is predominantly cytostatic with apoptotic priming. In vivo, 3 suppressed tumor growth and activated apoptosis with low systemic toxicity. Compound 3 thus emerges as a promising prototype Ir(III) metallodrug that disrupts nucleolar, mitochondrial, and lysosomal homeostasis to overcome resistance.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03448
  33. RNA. 2026 Jun 16. pii: rna.081015.126. [Epub ahead of print]
    The Tor pathway, ribosome concentration, and wobble decoding mediate inhibitory effects of the Leu-Pro CUC-CCG codon pair in Saccharomyces cerevisiae.
    Brandon S Bruno, Evan M Platten, Lisa Houston, Christina E Brule, Elizabeth J Grayhack.
      Translation elongation and efficiency are modulated by the genetic code, with reduced translation efficiency and slow translation caused by 17 inhibitory codon pairs in the yeast Saccharomyces cerevisiae. Nine of these inhibitory pairs are functionally important as they are disproportionately strongly conserved within orthologous genes in Saccharomyces sensu stricto. For three pairs, including CGA-CGA, inhibition is triggered by ribosome collisions followed by known quality control responses, but the mechanisms by which nine other pairs cause inhibition are unknown. Here, our examination of the molecular basis of inhibition by one such pair, the highly conserved Leu-Pro CUC-CCG codon pair yielded four findings. First, inhibition is mediated by tRNALeu(UAG), which decodes CUC by an U●C wobble interaction and effectively competes with the nonessential Watson-Crick base pairing tRNALeu(GAG). Second, despite nearly universal conservation of U33 in tRNAs, the C33 alteration in tRNALeu(GAG) does not significantly impair its function. Third, inhibition likely is mediated by ribosome collisions, as many suppressors bear mutations known or predicted to reduce ribosome concentration, and as local reduction in ribosome concentration suppresses inhibition. Thus, differences between CUC-CCG and CGA-CGA inhibition likely occur downstream of ribosome collisions. Fourth, we find a link between the metabolic state and CUC-CCG inhibition, as we find six suppressor mutations in SCH9, a downstream effector of TORC1 that mediates ribosome production. As Sch9 is inactive during starvation, causing reduced ribosome concentration, one biological function of inhibitory pairs may be to mediate a change in relative expression during starvation conditions.
    Keywords:  codons; inhibitory codon pairs; quality control; ribosome; translation
    DOI:  https://doi.org/10.1261/rna.081015.126
  34. Nat Cell Biol. 2026 Jun 15.
    Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
    Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.
      Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.
    DOI:  https://doi.org/10.1038/s41556-026-01991-z
  35. RNA. 2026 Jun 16. pii: rna.080881.125. [Epub ahead of print]
    Quantitative comparison of methodologies for translation site imaging in living cells.
    Agata D Misiaszek, Ester Griesbach, Egle Jaugaite, Aurelio Ortale, Jan Eglinger, Tobias Hochstoeger, Jeffrey A Chao.
      Single-molecule imaging of translation sites in living cells has enabled the dynamics of protein synthesis to be investigated with high spatial and temporal resolution. These methodologies utilize the interaction between a multimerized epitope tag and its cognate fluorescent single-chain variable fragment or nanobody to detect nascent polypeptides as they emerge from the ribosome. Here, we present a systematic comparison of current methodologies and determine that the ALFA-tag reduces perturbations of mRNA expression and increases the fluorescent signal of translation sites.
    Keywords:  single-molecule; translation
    DOI:  https://doi.org/10.1261/rna.080881.125
  36. iScience. 2026 Jun 19. 29(6): 116203
    Single-granule profiling reveals that RNP granule pH marks cellular translation.
    Yue Zhang, Shining Wu, Yifeng He, Xuhan Xia, Jinchao Wei, Shijia Wu, Ruijie Deng.
      Ribonucleoprotein (RNP) granules reshape RNA metabolism in eukaryotic cells, yet their biophysical properties remain poorly understood due to the lack of probes targeting these small, dynamic condensates. Herein, we developed RNP granule-pH (RNPg-pH), a ratiometric and targetable probe, to map the pH of processing bodies (P-bodies) and stress granules (SGs) at the single-granule level. This approach revealed a spatial pH heterogeneity within RNP granules, with a more alkaline periphery and a more acidic region near the nucleus. Stresses including oxidative stress, hyperosmotic stress, and translational inhibition induced granule acidification and reduced translation level, suggesting that RNPg-pH served as a sensitive marker of translation activity. Notably, compounds like myrtenol and oridonin reversed hydrogen peroxide (H2O2)-induced acidification, restored translation activity, and delayed cellular senescence, implying that RNPg-pH has the potential for screening anti-aging reagents. Our work provides an approach for monitoring RNP granules, shedding light on their roles in RNA metabolism and cell functions.
    Keywords:  cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116203
  37. J Gerontol A Biol Sci Med Sci. 2026 Jun 19. pii: glag165. [Epub ahead of print]
    Cell-based screen identifies translation state modulators that extend lifespan in D. melanogaster and C. elegans.
    Binbin Wu, Li-Jie Wang, Adwait A Godbole, Ji Heon Han, Erin S Keebaugh, Gisselle Chavez, Christine A Sedore, Anna L Coleman-Hulbert, Erik Johnson, Patrick C Phillips, Gordon J Lithgow, Monica Driscoll, Matthew S Gill, William W Ja.
      Aging is associated with declining mitochondrial function and translational regulation-processes modulated by interventions such as dietary restriction (DR) and cold-induced longevity (CHIL). Both DR and CHIL inhibit global protein synthesis but selectively enhance translation of proteins that support mitochondrial efficiency, stress resistance, and lifespan extension. These translational shifts are mediated, at least in part, by the 4E-BP/eIF4E pathway, which regulates translation according to mRNA 5'-untranslated region (5'-UTR) length and structure. To identify compounds that mimic the beneficial effects of DR/CHIL, we developed a cell-based phenotypic screen that reports on mRNA translation as a function of 5'-UTR length. A pilot screen identified compounds that preferentially increased the expression of mRNAs with short 5'-UTRs relative to those with long 5'-UTRs, and these hits were enriched for known lifespan-extending agents, such as curcumin and rapamycin. Among the novel candidates, fluspirilene significantly extended life in both Drosophila melanogaster and Caenorhabditis elegans, and mitigated age-related locomotor decline in female flies. Fluspirilene-mediated longevity in C. elegans required the DAF-16/FOXO and HLH-30/TFEB transcription factors and the autophagy gene, atg-18. Fluspirilene failed to extend lifespan in two other Caenorhabditis species, as well as in flies maintained on a high-yeast diet, indicating that its pro-longevity effects are constrained by evolutionary divergence and nutrient status. Together, our findings identify fluspirilene as a novel modulator of translation that extends life and preserves healthspan via an autophagy-dependent mechanism and support the promise of drug discovery efforts that modulate translation state as a therapeutic strategy for healthy aging.
    Keywords:  CITP; Cell-based assay; Fluspirilene; Phenotypic screen; Translational regulation
    DOI:  https://doi.org/10.1093/gerona/glag165
  38. MedComm (2020). 2026 Jun;7(6): e70809
    Stearoyl-CoA Desaturase-1 Drives Tumor Growth by Interacting With Histone Deacetylase-2 and Deacetylating Nucleophosmin-1.
    Coline Wery, Laetitia Montero-Ruiz, Eric Bonneil, Mohammad Farran, Robin Jehay, Quentin Herrara Garfia, Gregory Fettweis, Silvia Blacher, Charles Pottier, Gael Cobraiville, Yasmine Boumahd, Olivier Peulen, Agnès Noël, Franck Dequiedt, Marianne Fillet, Nor Eddine Sounni.
      The adaptation of lipid metabolism in cancer cells, driven by changes in the tumor microenvironment, presents major challenges for cancer therapy. Here, we addressed the problem of altered lipid metabolism and its role in cancer progression and therapeutic resistance. We demonstrate that hypoxia upregulates the key desaturase, stearoyl-CoA desaturase-1 (SCD1), and the lipid droplet (LD) protein PLIN2, thus promoting lipid metabolic adaptation, cell proliferation, migration, and tumor growth. We found that SCD1 and PLIN2 are essential and interdependent for LD formation. PLIN2 supports cell survival under hypoxic and metabolic stress, whereas SCD1 sustains cancer cell proliferation upon reoxygenation. In addition, we found that SCD1 expression in cancer cells affects nonhistone protein deacetylation, whereas PLIN2 expression enhances protein acetylation. Among these proteins, nucleophosmin(NPM1), a tumor suppressor and regulator of p53, was destabilized through SCD1-dependent deacetylation. In addition, SCD1 interacts with NPM1, influences its cellular localization, and recruits histone deacetylase-2 (HDAC2) to the complex. Notably, we observed that knockdown of SCD1 in vitro or its pharmacological inhibition in vivo enhances cancer cell sensitivity to HDAC inhibitors. Our findings underscore the role of SCD1 in reshaping the cellular acetylome and suggest that targeting SCD1 could sensitize cancer cells to HDAC inhibitors, highlighting a promising therapeutic strategy.
    Keywords:  HDACs; NPM1; SCD1; cancer drug resistance; lipid droplets; nonhistone protein deacetylation
    DOI:  https://doi.org/10.1002/mco2.70809
  39. Adv Sci (Weinh). 2026 Jun 16. e19359
    PRC2.1 Coordinates Peri-Nucleolar H3K27me3-Enriched Heterochromatin Organization and NPM1 Pentamerization to Maintain Nucleolar Integrity.
    Lina Zhu, Wenqin Wang, Shuyun Chen, Gangyi Zhu, Zhen Wu, Yue Gu, Jingwen Xiong, Xu Zhang, Heng Liu, Kyoichi Isono, Youming Zhang, Jingjing Cao, Xiangzhi Li.
      The nucleolus, a membrane-less organelle within the nucleus, plays a fundamental role in ribosome biogenesis with cellular functions across diverse physiological and pathological states. While its multilayered, liquid-like architecture is formed by complex interactions between nucleolar proteins and nucleic acids, the regulatory mechanism of nucleoplasmic components on nucleolus remains poorly understood, particularly heterochromatin and its associated proteins. In this study, we revealed that Polycomb repressive complex 2.1 (composed of PRC2 core subunits plus Polycomb-like (PCL) homolog), associating with H3K27me3-enriched heterochromatin, accumulates surrounding the nucleolus to form a ring-like structure. Notably, as a key PRC2.1 component, PCL2 undergoes phase separation, while the intrinsically disordered region (IDR) in PCL2 regulates both the fluidity of the condensates and its interaction with nucleolar protein nucleophosmin (NPM1). PCL2 is a key regulator to facilitate NPM1 pentamerization and interaction among nucleolar components, ensuring the efficient progression of rRNA and protein synthesis. Taken together, our findings reveal that PRC2.1(PCL2) plays a crucial role in maintaining nucleolar integrity and rRNA synthesis, highlighting that PRC2.1(PCL2) is required for cell proliferation.
    Keywords:  H3K27me3‐enriched heterochromatin; NPM1 pentamerization; PRC2.1 (PCL2); nucleolus; phase separation
    DOI:  https://doi.org/10.1002/advs.202519359
  40. Biotechnol Adv. 2026 Jun 14. pii: S0734-9750(26)00156-4. [Epub ahead of print]91 108950
    Programming the translational landscape for predictable gene expression.
    Wenxing Yan, Guipeng Hu, Kaifang Liu, Guangjie Liang, Cong Gao, Xiaomin Li, Jing Wu.
      Precision engineering of biological systems requires multi-layered control of gene expression, where translational regulation serves as a critical intermediary balancing response speed and metabolic cost. This review explores the multi-faceted landscape of translation engineering across its initiation, elongation, and termination phases. We evaluate how the architecture of the 5'-UTR and mRNA folding dictate initiation rates, how synonymous codon optimization and ribosome-stalling kinetics influence elongation speed, and how termination-level interventions, such as stop-codon readthrough and mRNA decay, modulate final protein yields. This review underscores the transition from trial-and-error tuning to the rational design of translational landscapes, offering a roadmap for developing sophisticated synthetic biological systems tailored for smart biomanufacturing and precision medicine.
    Keywords:  Gene expression; Metabolic regulation; Synthetic biology; Translation level regulation
    DOI:  https://doi.org/10.1016/j.biotechadv.2026.108950
  41. Acta Biochim Biophys Sin (Shanghai). 2026 Jun 25. 58(6): 1187-1212
    The tRNA landscape in cancer: from pathogenesis to therapeutic interventions.
    Ni Jian, Han Ren, Yingqi Huang, Lijuan Ma, Yingchen Zhou, Libo Yu, Weiren Huang.
      Transfer RNA (tRNA) acts not only as an indispensable adaptor in protein synthesis but also as a key contributor to tumorigenesis when its regulation is disrupted. This review systematically summarizes aberrant tRNA-related mechanisms in cancer, including altered tRNA expression profiles, abnormal post-transcriptional modifications, dysregulated aminoacylation, production of tRNA-derived small RNAs (tdRs), and defects in tRNA trafficking and translational fidelity. Notably, the metabolically abnormal tumor microenvironment actively shapes tRNA reprogramming to facilitate adaptive survival, while dysregulated tRNA elements, such as specific modifications and tdRs, further drive cancer stem cell properties and therapeutic resistance. Collectively, these alterations reprogram the oncoproteome and signaling networks, thereby promoting tumor cell proliferation, metastasis, immune evasion, and drug resistance. Targeting these mechanisms represents a promising strategy for developing novel cancer therapies. Potential approaches include the use of suppressor tRNAs to restore tumor suppressor gene function, the employment of tdRs to modulate oncogenic signaling pathways, or direct inhibition of enzymes involved in tRNA biogenesis. These strategies aim to remodel the dysfunctional tRNA network in cancer and offer new avenues for innovative treatments.
    Keywords:  aminoacyl-tRNA synthetases; cancer; misreading tRNAs; sup-tRNAs; tRNA; tRNA modifications; tdRs
    DOI:  https://doi.org/10.3724/abbs.2026093
  42. Cell Stress Chaperones. 2026 Jun 18. pii: S1355-8145(26)00049-0. [Epub ahead of print] 100193
    Evolution of Hsp90 Targeting: From Stress Biology to Clinical Translation.
    Ilham Zarguan, Lamiae Belayachi, Abdelaziz Benjouad, Ahmed Chadli.
      Hsp90 inhibitors represent a decades-long experimental framework that has progressively uncovered how molecular chaperone systems are organized, regulated, and rewired in disease. Early natural products established that pharmacologic engagement of Hsp90 simultaneously destabilizes broad client networks and exposes a central layer of proteostasis control. Subsequent structural, biochemical, and translational studies revealed the mechanistic importance of nucleotide-driven conformational cycling, cochaperone exchange, paralog specialization, and subcellular compartmentalization, as well as the emergence of disease-specific chaperone assemblies such as the epichaperome. In parallel, adaptive responses to Hsp90 inhibition, including heat-shock factor 1 activation, unfolded-protein-response signaling, autophagy induction, and oncogenic network rewiring, illuminated the resilience built into proteostasis architecture and the conditions under which it can be overcome. Later inhibitor classes, encompassing C-terminal allosteric ligands, middle-domain modulators, isoform-selective agents, epichaperome-directed compounds, and targeted degraders, extended the field from pan-inhibition toward increasingly precise intervention in specific chaperone states. The first regulatory approval of an Hsp90 inhibitor, Pimitespib, for refractory gastrointestinal stromal tumor, marks a translational milestone that validates this framework clinically. Combination studies have further mapped where Hsp90 inhibition is most informative and most effective, demonstrating that benefit is strongest when deployment is guided by defined client dependency, proteostasis burden, immune context, or biomarker selection. Together, these advances position Hsp90 inhibitor research as a major source of mechanistic insight into molecular chaperones and as a foundation for biomarker-guided, context-aware targeting of proteostasis in oncology and beyond.
    Keywords:  Cancer, Stress Response; Chaperones; Hsp90; Inhibitors
    DOI:  https://doi.org/10.1016/j.cstres.2026.100193
  43. Dev Cell. 2026 Jun 16. pii: S1534-5807(26)00195-4. [Epub ahead of print]
    P5CS represses tumor progression via inhibiting assembly of 48S pre-translation initiation complex.
    Qingqing Zhang, Shuwen Cheng, Yinmin Gu, Yongbo Pan, Xiaofeng Zhu, Jinghan Sun, Ya Wen, Shan Gao.
      Δ1-Pyrroline-5-carboxylate synthase (P5CS), therate-limiting enzyme in the proline biosynthesis, has been implicated in diverse physiology and pathology, including cancer. However, whether P5CS exerts functions beyond its enzymatic activity has remained unclear. Here, we identify P5CS as a non-canonical RNA-binding protein that inhibits cancer cell growth and metastasis by inhibiting translation initiation in an enzyme-activity-independent manner in human cancer cells and cell-derived xenograft mouse models. Mechanistically, P5CS binds to the 5' untranslated region (UTR) of oncogenic mRNAs and disrupts the recruitment of eukaryotic translation initiation factor (eIF) 3a/3d-containing 43S preinitiation complex to cap-binding complex eIF4F, thereby blocking 48S assembly and subsequent global protein synthesis. Loss of P5CS accelerates the translational efficiency of IGF1R and promotes tumor progression. Collectively, our study highlights a non-canonical function of P5CS in translational regulation and the emerging non-metabolic functions of metabolic enzymes in tumorigenesis.
    Keywords:  43/48S; P5CS; RNA-binding protein; eIF3a/3d; translation regulation
    DOI:  https://doi.org/10.1016/j.devcel.2026.05.011
  44. Front Neurol. 2026 ;17 1778877
    Anticodon-engineered tRNAs restore full-length MeCP2 expression and function in Rett syndrome nonsense mutations.
    Elena Fara, Stefano Pezzini, Ginevra Arpaia, Angelisa Frasca, Joseph J Porter, John D Lueck, Nicoletta Landsberger.
      
    Keywords:  ACE-tRNAs; MeCP2; Rett syndrome; nonsense mutations; readthrough
    DOI:  https://doi.org/10.3389/fneur.2026.1778877
  45. mBio. 2026 Jun 18. e0113726
    Alternative ribosomal protein RpmE2 is produced under zinc limitation in Neisseria gonorrhoeae and slows translation and bacterial growth.
    Amy L Forehand, Kinga Malezyna, Keena S Thomas, Ian J Glomski, Cynthia Nau Cornelissen, Ahmad Jomaa, Alison K Criss.
      To enhance its pathogenic potential, Neisseria gonorrhoeae (Gc) pirates zinc from human metal sequestration proteins using TonB-dependent outer membrane transport systems. However, cytoplasmic mechanisms by which Gc adapts to zinc limitation are still uncharacterized. rpmE2 and rpmJ2 transcripts, encoding alternative L31 and L36 ribosomal proteins, respectively, which are not predicted to bind zinc, are significantly more abundant in zinc-limited Gc. In other bacterial species, alternative ribosomal proteins replace canonical zinc-binding ribosomal proteins when zinc availability is low, enabling growth under metal limitation. We found that Gc rpmE2 and rpmJ2 are in an operon and transcriptionally induced under zinc limitation by derepression via the zinc uptake regulator Zur, while genes encoding canonical proteins rpmE and rpmJ are not zinc-regulated. In contrast to other bacteria, ribosomes in zinc-limited Gc contained both RpmE2 and RpmE. Furthermore, Gc deleted for RpmE2 and RpmJ2 grew better than the wild-type parent under zinc limitation. Gc engineered to produce only RpmE2 exhibited a growth defect relative to RpmE-only Gc, regardless of zinc availability. Moreover, ribosomes from RpmE2-only Gc had reduced translation in vitro. Thus, unlike other bacteria, the alternative L31 protein RpmE2 is not functionally equivalent to the canonical RpmE in Gc. Instead, the ribosomes of zinc-limited Gc are heterogeneous, containing either alternative or canonical ribosomal proteins. We propose that L31 ribosomal protein alternation allows Gc to withstand zinc limitation by reducing translation and slowing growth, to prolong its survival when encountering host-imposed nutritional immunity.
    IMPORTANCE: Zinc acquisition is crucial for growth and infectivity of Neisseria gonorrhoeae (Gc). However, research on Gc adaptation to zinc limitation has primarily focused on outer and inner membrane zinc transporters. Here, we implicate ribosomal protein alternation in the Gc response to zinc limitation. Ribosomes containing the non-zinc-binding, alternative ribosomal protein RpmE2 are less translationally active, and RpmE2-producing bacteria grow more slowly. This contrasts with reports from other bacteria, where ribosomal protein alternation facilitates growth in zinc-limited conditions. This work uncovers a new way in which ribosomal protein alternation enables bacterial resistance to nutritional immunity.
    Keywords:  Neisseria gonorrhoeae; nutritional immunity; ribosome; translation; zinc
    DOI:  https://doi.org/10.1128/mbio.01137-26
  46. ACS Synth Biol. 2026 Jun 14.
    Nucleotide-Level Chemical Reaction Network Modeling Enables Quantitative Prediction of Reconstituted Cell-Free Expression Systems.
    Zoila Jurado, Ayush Pandey, Richard M Murray.
      Cell-free expression systems offer a method for the rapid prototyping of DNA circuits and functional protein synthesis. While crude extracts remain a black box with many components carrying out unknown reactions, PURE contains only the required transcription and translation components for protein production. All proteins and small molecules are at known concentrations, enabling detailed modeling of reliable computational predictions. However, there are few experimental data supporting the expression of target proteins for PURE-based models. In this work, we generalized the PURE detailed translation model for proteins with arbitrary amino acid compositions and lengths. We then built a chemical reaction network (CRN) for transcription in PURE, validating the transcription models using DNA expression for the malachite-green aptamer (MGapt) to measure RNA production. Lastly, we coupled the transcription and the generalized translation models to create a PURE protein synthesis model built purely of mass-action reactions. We used the combined model to capture the kinetics of MGapt and deGFP expressed from plasmids at various concentrations.
    Keywords:  PURE system; cell-free transcription/translation; chemical reaction networks; synthetic biology
    DOI:  https://doi.org/10.1021/acssynbio.6c00163
  47. Mol Cell. 2026 Jun 18. pii: S1097-2765(26)00343-6. [Epub ahead of print]86(12): 2240-2242
    Stress granules go viral.
    Lei Wang, Wen Zhou.
      Stress granules are antiviral RNA condensates, but their core scaffold can be turned against the host. In this issue, Liu et al.1 show that alphavirus nsP3 redirects G3BP into proviral condensates that shelter viral RNA and promote its translation.
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.019
  48. Genome Biol Evol. 2026 Jun 17. pii: evag147. [Epub ahead of print]
    The effects of rapid mitochondrial gene loss on organellar proteomes.
    Jessica M Warren, Amanda K Broz, Ryan Stikeleather, Daniel B Sloan.
      Mitochondrial genomes retain only a tiny number of genes from their bacterial progenitors, including key components of protein translation machinery. The set of mitochondrially encoded tRNAs and ribosomal subunits is highly variable across angiosperms, with many examples of mitochondrial gene loss, replacement, and/or transfer to the nucleus. This dynamic history suggests large-scale remodeling of mitochondrial translation machinery in some lineages, but such conclusions are largely inferred from genomic sequence and protein targeting predictions. Here, we use proteomic (LC-MS/MS) analysis of purified mitochondria and chloroplasts from angiosperm species with major differences in mitochondrial gene content (Arabidopsis thaliana and Silene conica). Our analysis largely confirms the current understanding of subcellular localization for nuclear-encoded proteins involved in tRNA metabolism and ribosome function in A. thaliana, although some aminoacyl-tRNA synthetases (aaRSs) may have more specialized subcellular roles than previously thought. In contrast, S. conica has undergone extensive mitochondrial gene loss and numerous associated changes in the composition of its mitochondrial proteome, including apparent retargeting of aaRSs, replacement of ribosomal subunits, and loss of the glutamine amidotransferase (GatCAB) complex. Overall, this analysis illustrates how the complex network of molecular interactions necessary for mitochondrial translation are perturbed by gene loss, transfer, and replacement.
    Keywords:  mass spectrometry; mitochondrial genome; plastids; proteomics; translation
    DOI:  https://doi.org/10.1093/gbe/evag147
  49. EMBO Rep. 2026 Jun 15.
    The E3 ligase MKRN2 prevents DRiP accumulation in stress granules and maintains granulostasis.
    Emmanuel Amzallag, Yehuda M Danino, Valentina Secco, Serena Carra, Eran Hornstein.
      Stress granules (SGs) are transient cytoplasmic biomolecular condensates that play a role in the cellular response to proteotoxic stress. It has been previously shown that ubiquitination regulates SG dynamics; however, the specific mechanisms by which ubiquitin affects SGs are not fully understood. Here, using proximity proteomics, we discover that the recruitment of several E3 ubiquitin ligases, VCP cofactors and HSP70 to SGs is dependent on the activity of the E1 ubiquitin ligase UBA1. The RNA-binding E3 ubiquitin-protein ligase Makorin 2 (MKRN2) is strongly depleted from SGs in the absence of UBA1 function. MKRN2 promotes both the proper formation of SGs and their disassembly following stress recovery, by preventing the accumulation of misfolding-prone defective ribosomal products (DRiPs) within SGs. Therefore, MKRN2 is a novel regulator of SGs that mediates the maintenance of granulostasis.
    DOI:  https://doi.org/10.1038/s44319-026-00832-2
  50. Trends Biochem Sci. 2026 Jun 17. pii: S0968-0004(26)00172-6. [Epub ahead of print]
    Cap in hand: giant viruses, stolen translation, and a road to endosymbiosis?
    Nicholas W Hubbard, Nels C Elde.
      Fels et al. (2026) report that the giant DNA virus mimivirus encodes a complete, functional translation initiation complex, termed vIF4F, which replaces the host's own initiation machinery during infection, sustains viral protein synthesis under cellular stress, and points to a blurring of boundaries between viral and cellular life.
    Keywords:  endosymbiosis; protein translation; virus evolution
    DOI:  https://doi.org/10.1016/j.tibs.2026.05.010
  51. Nucleic Acids Res. 2026 Jun 08. pii: gkag598. [Epub ahead of print]54(11):
    rRNA intermediates associate with nucleolar reshaping in C. elegans.
    Jiewei Cheng, Liang Liu, Demin Xu, Yuxia Chen, Yan Kuang, Ao Zheng, Minjie Hong, Xiaona Huang, Xiaotian Zhou, Wanjing Niu, Ji Zhao, Xinya Huang, Chengming Zhu, Xiangyang Chen, Xuezhu Feng, Shouhong Guang.
      The nucleolus is a multilayered organelle essential for ribosome biogenesis, yet how ribosomal RNA (rRNA) events coordinate its organization remains unclear. We previously reported that the accumulation of 27SA2 pre-rRNA upon class I RPLs (large subunit ribosomal proteins) depletion accompanies the formation of nucleolar rings and vacuoles in Caenorhabditis elegans. Here, we systematically investigated the effects of pre-18S rRNA processing and rRNA transcription on nucleolar structure and reported that defects in these molecular events result in reorganization of the nucleolar architecture. Depleting class I RPSs (small subunit ribosomal proteins) induced a concentric three-layered nucleolar architecture, while inhibiting rRNA transcription induced another three-layered sandwich-like nucleolus. During nucleolar reshaping, nucleolar proteins redistributed into distinct subnucleolar compartments. Tracking the subcellular localization of ribosomal DNA (rDNA) via a lacI::tagRFP/lacO system revealed that rDNA also redistributed upon nucleolar reorganization. We identified Ce.22SB pre-rRNA accumulation upon class I RPSs depletion as a key intermediate associated with concentric-spherical nucleoli. Moreover, the conserved nucleolar protein NUCL-1/nucleolin, FIB-1/fibrillarin, and LPD-6/PPAN are essential for nucleolar architecture reorganization and regulates the development of nematodes during impaired rRNA production. Together, these findings demonstrate that nucleolar architecture is associated with the status of rRNA biogenesis and that the accumulation of specific rRNA intermediates correlates with the emergence of distinct nucleolar architectures.
    DOI:  https://doi.org/10.1093/nar/gkag598
  52. Front Plant Sci. 2026 ;17 1818877
    Decoding polyamine-ethylene dynamics: synergies at synthesis and signalling levels during osmotic stress and ripening.
    Shalu Gupta, Krishan Kant, Navneet Kaur, Parnika Jindal, Magda Pál, M Naeem, Akbar Ali.
      Amid climate uncertainty, agriculture faces numerous challenges, including drought, salinity, hypoxia, heat, cold, osmotic, biotic stresses, and, in turn, oxidative stress, in its struggle to secure global food supplies. Plant development is influenced by numerous internal and external factors that collectively regulate the entire life cycle of a plant and, thus, yield. Ethylene (ETH) and polyamines (PAs) are multifunctional regulatory compounds. Their interaction plays a significant role under osmotic stress and fruit ripening, both synergistically and antagonistically. Although both of them are produced from the same precursor, S-adenosylmethionine (SAM), their signalling pathways differ and induce distinct physiological effects that are often antagonistic. Putrescine, spermidine, and spermine are the most abundant PAs that are typically linked to stress resilience, membrane stability, antioxidative responses, and cellular defence. ETH, on the other hand, exhibits two distinct characteristics: at moderate levels, it functions as a ripening hormone stress signal to initiate adaptive responses, but at higher or prolonged stress levels, it promotes senescence and inhibits growth. This review article discusses SAM as the common linking molecule between the overlapping ETH and PA biosynthesis, ETH-PA interaction under osmotic stress, as well as their signalling and regulatory crosstalk in ripening, and how ROS are generated and mitigated by ETH and PA application in a stressful environment. We discuss recent advances in this subject, highlight some unanswered questions, and provide a roadmap for increasing productivity and unleashing climate-smart farming.
    Keywords:  ROS; SAM (S-adenosylmethionine); ethylene; polyamines; regulation and sustainable agriculture
    DOI:  https://doi.org/10.3389/fpls.2026.1818877
  53. J Vis Exp. 2026 May 29.
    Visualization and Quantification of Intermolecular RNA Base Pairing in in vitro RNA Clusters Using Split Broccoli RNA Reporters.
    Siran Tian, Tatjana Trcek.
      RNA clustering, driven by multivalent intermolecular RNA-RNA interactions, can occur in vitro in the absence of proteins. While chemical probing and computational simulations have been used to predict these interactions, methods for directly assessing intermolecular base pairing in RNA clusters remain limited. This study presents a visual assay based on split Broccoli RNA reporters conjugated to fluorescently labeled RNAs of interest. The assay enables the detection and quantification of intermolecular base pairing in RNA clusters. The split Broccoli system contains complementary reporter sequences that dimerize to form the Broccoli RNA aptamer. The resulting dimerized RNA structure binds DFHBI-1T, a fluorophore that emits green fluorescence upon binding. Upon RNA clustering, the appearance of green fluorescence reports base pairing mediated by the complementary reporter sequences among the RNAs of interest. Measurement of DFHBI-1T fluorescence enables quantitative assessment of how in vitro RNA clustering conditions influence intermolecular base pairing between these reporter sequences.
    DOI:  https://doi.org/10.3791/70886
  54. Am J Physiol Regul Integr Comp Physiol. 2026 Jun 15.
    Prolonged heat stress induces autophagy in mouse skeletal muscle.
    Sau Qwan Yap, Melissa Roths, Swathy Krishna, Tori E Rudolph, Joshua T Selsby.
      Environment-induced heat stress (HS) is a significant and expanding threat to human health and efficient agricultural production. In this investigation, we aimed to determine the extent to which HS impacted skeletal muscle health. We hypothesized that HS would decrease autophagosome degradation and autophagic flux in mouse skeletal muscle. To test this hypothesis, female C57 mice were exposed to thermoneutral (TN; 30 °C) or heat stress (HS; 37.5 °C) conditions for 24 h, and the gastrocnemius, soleus, and diaphragm muscles were immediately collected. A subset of mice was treated with colchicine to assess autophagic flux. Environment-induced HS increased rectal and subcutaneous temperatures by ~2.0 °C and decreased feed intake by 75% and body mass by 14%, without a change in muscle mass. In all muscles, 24 h of HS increased phosphorylated HSP 27 by 1.47-fold to 4.5-fold compared to TN; however, HSPs 27, 60, 72, and 90 were similar between groups. We discovered HS increased autophagic flux in the gastrocnemius and diaphragm, but not soleus, without changes in most key autophagy regulatory proteins. Markers of mitophagy, regulators of mitochondrial architecture, and mitochondrial abundance were largely similar between groups for all muscles. Environment-induced HS increased ER stress regulators, BIP by 1.7-fold to 2.9-fold and p-IRE1α by 1.84-fold to 2.75-fold in all muscles, and p-eIF2α was increased 3.6-fold in soleus. Counter to our hypothesis, these data demonstrate that 24 h of HS did not decrease autophagosome degradation or flux across a range of muscles in a mouse HS model.
    Keywords:  Colchicine; Heat Stroke; Heat shock proteins; Hyperthermia; Unfolded protein response
    DOI:  https://doi.org/10.1152/ajpregu.00190.2025
  55. Genes Genet Syst. 2026 Jun 17.
    Regulation of Fhl1 function through interactions with Hmo1 and Fpr1 at ribosomal protein gene promoters in Saccharomyces cerevisiae.
    Naoki Shimamura, Koji Kasahara.
      In budding yeast Saccharomyces cerevisiae, interacts with fork head 1 (Ifh1) is a transcriptional co-activator essential for growth and is recruited to ribosomal protein gene (RPG) promoters through interaction with the forkhead-associated (FHA) domain of fork head-like 1 (Fhl1). However, the lethality of the ifh1Δ cells is rescued by deletion of FHL1 or its FHA domain, suggesting that the essential function of Ifh1 is suppressing FHA domain-mediated growth inhibition. In our recent study, we found that deletion of the previously uncharacterized C-terminal regions, as well as the FHA domain, of Fhl1 rescues the lethality of the ifh1Δ cells. Chromatin immunoprecipitation analysis of Fhl1 deletion mutants showed that deletion of the 754-844 aa region significantly decreased binding to category 1 RPG promoters, which are enriched for high mobility group 1 (Hmo1) binding, whereas deletion of the 572-662 aa region markedly reduced binding to all RPG promoters examined. These results suggest that reduced Fhl1 binding to RPG promoters enables growth of the ifh1Δ cells. Because Fhl1 binding is regulated by Hmo1 and/or FK506-sensitive proline rotamase 1 (Fpr1), we examined the effect of HMO1 deletion and found that the hmo1Δifh1Δ double mutant became viable. Yeast two-hybrid analysis revealed that the 754-844 aa region of Fhl1 interacts with Hmo1, particularly its box B domain, suggesting that this interaction contributes to the recruitment of Fhl1 to category 1 RPG promoters. Furthermore, we observed a weak interaction between Fpr1 and the 540-662 aa region of Fhl1. Genetic analysis showed that the fhl1Δfpr1Δ double mutants exhibited much more severe growth defects than either single mutant, indicating that both proteins cooperatively play important roles in yeast growth, although the underlying mechanism remains unclear. Collectively, these results suggest that Hmo1 and Fpr1 regulate Fhl1 function, which exerts both negative and positive effects on yeast growth.
    Keywords:  Fhl1; Fpr1; Hmo1; Saccharomyces cerevisiae; ribosomal protein gene
    DOI:  https://doi.org/10.1266/ggs.26-00060
  56. Nat Commun. 2026 Jun 19.
    PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1.
    Céline Philippe, Shoshana Burke, Arantxa Carrasco-Leon, Andrea Martisova, Pedro Casado, Eleni Maniati, Jimena Castorena, Pantelitsa Protopapa, Alyssa Fronk, Ru-Pin Alicia Chi, Rachel Boniface, Vinothini Rajeeve, Martin Dodel, Beatriz Galvão, Marc Aubry, Kaliya Svetlinova Georgieva, Doriana Di Bella, Brian N Papas, Taylor Floyd, Kendall Anderson, Martin Akerman, Jun Wang, Lovorka Stojic, Faraz Mardakheh, Marcos Morgan, Eric Chevet, Christian Touriol, Pedro R Cutillas, Kevin Rouault-Pierre.
      The unfolded protein response (UPR) is a critical adaptive program triggered upon cellular stresses that profoundly reshapes the transcriptome and translatome. In the very first minutes of cellular stress, translation blockage, RNA decay and RNA granules formation prompt the synthesis of proteins essential to the stress response. Due to the dynamic nature of these processes, investigating translation upon stress has proven to be challenging; therefore, our understanding of these mechanisms and translatome rewiring upon stress remains limited. Here, we exploit O-Propargyl-puromycin (OPP) labelling of de novo peptides followed by LC-MS/MS to identify de novo proteins translated upon endoplasmic reticulum (ER) stress. Combined with transcriptomic analyses, our approach reveals that ER stress profoundly impacts the synthesis of core splicing factor proteins leading to a significant reshaping of the splicing landscape. We identify a signature of seven splicing events consistently occurring in mammalian cells exposed to ER stress. Using pharmacological, genetic, phosphoproteomic and sequencing approaches, we demonstrate that this specific signature is driven by PERK activation and is dependent on the axis CLK1/SRSF1. Our findings identify PERK/CLK1/SRSF1 -mediated splicing regulation as a new facet of ER stress, defining an ERi-splice signature spanning healthy and malignant tissues.
    DOI:  https://doi.org/10.1038/s41467-026-74397-y
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