bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–09–13
sixty-four papers selected by
Cédric Chaveroux, CNRS
  1. eIF5A and polyamines restrict mRNA levels in response to ribosome stalls.
  2. Ribosome stalling position, spacing, and A-site occupancy impact translation and cotranslational mRNA decay in plants.
  3. Proteostasis in the regulation of pancreatic islet cell plasticity.
  4. m6A modification in immune-cell inflammatory fate: from RNA fate regulation to therapeutic translation in inflammatory diseases.
  5. Protein Synthesis Dysregulation in Neurodegeneration: Mechanisms, Consequences, and Therapeutic Modulation.
  6. m6A RNA methylation in mammalian oocytes and preimplantation embryos: implications for developmental competence.
  7. Quantitative RNA modification mapping by mass spectrometry with isobaric tags and nucleobase fragment analysis.
  8. The collaborative epitranscriptome: bidirectional crosstalk between m6A methylation and noncoding RNAs in cancer pathogenesis and precision therapy.
  9. The alarmone pGpp inhibits translation through GTP depletion.
  10. Ribosome engineering enhances genetic code expansion in Saccharomyces cerevisiae.
  11. Protein-RNA control networks at the plant-pathogen interface.
  12. Long-range mRNA folding shapes expression and sequence of bacterial genes.
  13. Experimental and Computational Tools for Mapping Circular RNA Modifications.
  14. African swine fever virus pMGF110-9L plays a critical role in the integrated stress response and viral pathogenesis.
  15. Heme as a Versatile Signaling Molecule: Coordinating Mitochondrial Metabolism with Global Cellular Responses.
  16. IGF2BP3 enhances paclitaxel resistance in bladder urothelial carcinoma by recognizing m6A-modified CENPA mRNA.
  17. Chemistry and biology of oxidatively damaged RNA nucleotides.
  18. Proximity labeling puts ZFP36L1 as central hub for posttranscriptional regulation networks in T cells.
  19. Localized ribosome access and distal tuning via the Listeria prfA RNA thermometer.
  20. Ribosome dynamics at the conserved PGP motif governs 2A peptide-bond-skipping efficiency.
  21. 18S rRNA 3' end cleavage by the phosphorylated endoribonuclease NOB1 is interconnected with early small subunit biogenesis.
  22. Cancer-associated synonymous mutations target mRNA structures and protein activity.
  23. Nucleolar dynamics are determined by the ordered assembly of the ribosome.
  24. The RNA helicase domain of NAT10 promotes the biogenesis of hypomodified ribosomes to enhance cancer cell proliferation.
  25. Gradient-based Optimization for mRNA Sequence Design.
  26. Advances in phytochemical modulation of protein aggregation in neurodegenerative diseases.
  27. GnRH Promotes Gonadotropin Synthesis and Secretion in the Bovine Anterior Pituitary by Inhibiting METTL1-Mediated m7G Modification of FOXO1 mRNA.
  28. Bardoxolone methyl induces mitochondrial dysfunction, activation of the cytosolic stress response, and increased chaperone capacity in SH-SY5Y cells. Focus on mitochondrial protease LONP1.
  29. Circular-pre-rRNA-dependent and -independent rRNA maturation pathways in Archaea.
  30. Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.
  31. Protein aggregation as a bistable switch in bacterial cell fate: from adaptive dormancy to cytotoxic death.
  32. Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
  33. Striatal small RNA remodeling in MPTP-induced Parkinson's disease highlights coordinated downregulation of mitochondrial tsRNAs.
  34. Integrated stress response inhibition decouples cardiotoxicity from anthracycline chemotherapy while enhancing antitumor efficacy.
  35. Mitochondrial resilience: a convergent framework for pathogenesis and neuroprotection in Parkinson's disease.
  36. TDP-43 controls RNA structure through high affinity lattice interactions.
  37. Single-Nucleus RNA Sequencing Highlights Endothelial and Müller Cell ER Stress During Retinal Neovascularization in Vldlr-/- Mouse.
  38. Transcriptomic characterization of the intestine in Stichopus monotuberculatus under gradient temperature stress and HSP gene family-mediated molecular adaptation.
  39. YBX1 as an adaptive RNA hub in cancer: linking state-dependent RNA regulation to tumor immunity, metabolic reprogramming, and therapy resistance.
  40. Complementation of a human disease phenotype by intercellular mRNA transfer.
  41. Global structure and determinants of transcriptomic adaptation in CHO cells.
  42. Post-translational control of MAVS signaling: linking mitochondrial antiviral immunity to metabolic and cellular stress contexts.
  43. Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.
  44. Transcriptomic Responses of Kveik Yeasts to Heat and Ethanol Stress.
  45. Arabidopsis EMB2788/Npa1L1 is critical for pre-rRNA processing, ribosome biogenesis, and embryo development.
  46. uORF-mediated translational control of CAK and Cdk activation in response to low nutrients in yeast.
  47. Peroxiredoxin 1 safeguards the nucleolar genome from oxidative damage.
  48. Impact of renal lipid droplet dynamics on tubular health.
  49. Conditional eIF2A Deletion Suggests Extra-Adipose Mechanisms Underlying Metabolic Syndrome in Total-Body eIF2A Knockout Mice.
  50. Chaperone-mediated autophagy as a regulator of hallmarks of cancer.
  51. Programmable in vivo mRNA circularization for enhanced gene expression in bacteria.
  52. Spatiotemporal control of mitoribosome-mediated metabolic reprogramming in cancer: implications for heterogeneity and therapeutic targeting.
  53. D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.
  54. Melatonin Inhibits Metastasis of Sunitinib-Resistant Renal Cell Carcinoma Cells Via the GRP78/p38/CTSD Expression.
  55. The VHL tumor suppressor at the crossroad of protein folding, aggregation, and cancer.
  56. TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses.
  57. PARP16 is a Druggable Regulator of Ribosome MARylation and Protein Homeostasis in Ovarian Cancer Cells.
  58. Dual regulation of transcription factor binding by tup11/12-mediated destabilization and DNA loop-mediated stabilization ensures stress-specific gene activation in fission yeast.
  59. Nsp1 from divergent coronaviruses has conserved endonuclease activity.
  60. Circular RNAs orchestrate integrated post-transcriptional responses to combined heat and drought stress in rice.
  61. Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.
  62. Amino acid reprogramming and biofilm-specific tricarboxylate transporters in PET-degrading Piscinibacter sakaiensis.
  63. Identification of Integrated Stress Response-Related Biomarkers in Sepsis-Induced Acute Respiratory Distress Syndrome.
  64. FTSJ3-Mediated 2'-O-Methylation of HSPA5 mRNA Stabilizes BOP1 via SUMOylation to Drive DRP1-Dependent Mitochondrial Fission and Fatty Acid Oxidation in Lung Squamous Cell Carcinoma.
  1. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2533876123
    eIF5A and polyamines restrict mRNA levels in response to ribosome stalls.
    Chloe M Wohlenberg, Parissa C Monem, Natalia Barbosa, Judith Frydman, Joshua A Arribere.
      Obstacles to translation elongation stall ribosomes and allow deleterious proteins to accumulate, which threatens cellular health. Cells recognize and clear stalled ribosomes via several interrelated pathways, although the mechanisms by which cells distinguish stalled from normally elongating ribosomes and mount an appropriate response are incompletely understood. While recent work highlights how ribosome collisions help cells to recognize stalled ribosomes, how other factors contribute to detection remains unclear. Here, we report a requirement for the translational factor eIF5A in the mRNA decay response to ribosomal stalling, i.e., No-Go mRNA Decay (NGD). We identified the Caenorhabditis elegans polyamine transporter, catp-6, via a forward genetic screen as a factor required for NGD. During our mechanistic dissection of the catp-6 phenotype, we uncovered a role for cellular polyamines and the translation elongation factor eIF5A in NGD, and we show this requirement is conserved from C. elegans to Saccharomyces cerevisiae. Our analyses support the idea that cells use eIF5A to identify ribosomal stalls and execute NGD and uncover a molecular function for a core protein synthesis factor in limiting expression from stall-inducing mRNAs. Our work offers insight into how cells identify and remove problematic mRNAs from the translational pool. Our work also raises the possibility that dysregulated mRNA decay is an unrecognized pathophysiology associated with polyaminopathies and eIF5A disorders, of relevance to varied neurodegenerative and aging phenotypes and efforts to pharmacologically inhibit eIF5A.
    Keywords:  NGD; PARK9; eIF5A; polyamine; ribosome
    DOI:  https://doi.org/10.1073/pnas.2533876123
  2. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2617633123
    Ribosome stalling position, spacing, and A-site occupancy impact translation and cotranslational mRNA decay in plants.
    Sjors van der Horst, Joseph L Gage, Julia Bailey-Serres.
      Ribosomes can pause during mRNA translation, but what causes pausing, how pauses affect protein production, and whether they trigger cotranslational mRNA decay are poorly understood in plants. Here, we investigate the causes and consequences of ribosome pausing in Arabidopsis and maize. This is accomplished by sizing, mapping, and quantifying footprints of individual ribosomes (monosomes) and closely spaced ribosome pairs (disomes) at single-codon resolution on open reading frames (ORFs). Ribosome footprinting was combined with 5'P-degradome-seq to examine the coincidence of pausing with cotranslational decay under control conditions and brief hypoxia in Arabidopsis. The data resolve two monosome conformations and three disome configurations. These include monosomes with a vacant or occupied A-site and disomes that have collided or are separated by one or two codons. Pausing is prevalent at initiation, termination, and di-Proline codons. Di-Proline pauses do not trigger cotranslational decay but appear important in cotranslational protein processing. Brief hypoxia induces stalling of A-site vacant ribosomes at Aspartate codons, often coinciding with 5'P peaks, indicating that rate-limiting decoding can trigger cotranslational mRNA decay. Notably, actively transcribed and translated hypoxia-response mRNAs accumulate 1- to 2-codon-separated disomes and are actively degraded. Comparative analysis of footprints in the two species reveals ribosome conformations and codon-specific pausing can be conserved or lineage-specific, as exemplified by pausing at di-Prolines and on Conserved Peptide upstream ORFs. In sum, the stalling of ribosomes at specific codons, coupled with ribosome A-site occupancy and disome spacing, modulates protein production and cotranslational mRNA decay in plants.
    Keywords:  cotranslational mRNA turnover; ribosome collision; ribosome pausing; uORF
    DOI:  https://doi.org/10.1073/pnas.2617633123
  3. J Diabetes Investig. 2026 Sep 11.
    Proteostasis in the regulation of pancreatic islet cell plasticity.
    Jun Shirakawa.
      Pancreatic islet cells continuously synthesize and secrete large quantities of peptide hormones, making them uniquely dependent on robust proteostasis networks to maintain cellular function. Traditionally, the unfolded protein response (UPR) is considered a stress-responsive pathway that protects cells from endoplasmic reticulum (ER) dysfunction or triggers apoptosis when ER stress is excessive. Here, we propose that proteostasis functions as an active physiological signaling network that governs islet cell adaptation, plasticity, and long-term homeostasis, extending beyond its conventional role in the response to cellular damage. In pancreatic β cells, glucose signaling suppresses the expression of the proapoptotic factor CHOP through both IRS2-dependent and IRS2-independent pathways, indicating that metabolic signaling directly remodels the ER stress response. In contrast, the CHOP-GADD34-eIF2α dephosphorylation axis constitutes a negative feedback mechanism that fine-tunes translational recovery and determines the balance between adaptation and cell death. Moreover, 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling alleviate proteotoxic stress and promote β-cell survival under conditions of increased secretory demand. In addition to translational control, IGF2 receptor-mediated signaling has recently been implicated in the regulation of autophagy, further linking lysosomal quality control to β-cell proteostasis. Importantly, proteostasis also affects α-cell biology, where UPR signaling regulates glucagon secretion and contributes to α-to-β cell transdifferentiation, highlighting a previously unrecognized role of ER homeostasis in endocrine cell identity. Finally, recent findings indicate that progressive impairment of proteostasis is a hallmark of islet aging, integrating defects in protein folding, translation, autophagy, and stress adaptation into the pathogenesis of diabetes.
    Keywords:  ER stress; alpha cell; beta cell; islet cell; proteostasis
    DOI:  https://doi.org/10.1111/jdi.70438
  4. Front Immunol. 2026 ;17 1918662
    m6A modification in immune-cell inflammatory fate: from RNA fate regulation to therapeutic translation in inflammatory diseases.
    Yizhang Zhu, Shiye Yang, Lei Qin, Dongyang Ding, Xiaojie Gan.
      Inflammatory disease is sustained not only by immune activation but also by the failure of activated cells to terminate effector programs and return tissues to homeostasis. This review evaluates N6-methyladenosine (m6A) as a post-transcriptional regulator of that persistence. Rather than cataloguing diseases or classifying individual m6A regulators as pro- or anti-inflammatory, we organize the evidence around a causal chain linking a regulator and target RNA to a site- or reader-dependent change in RNA fate, an immune-cell phenotype, and a disease outcome. Mechanistically developed evidence is concentrated in macrophages and T cells, including STAT1 stability and decay, SOCS turnover, SLC37A2 translation, and lineage-specific T-cell programs. Mechanisms in other innate and adaptive immune populations are emerging, but cell-subset resolution and disease-stage validation remain uneven. Across inflammatory signaling, immunometabolic, and cell-death pathways, the same m6A regulator can produce opposing outcomes through different target transcripts or readers. We therefore distinguish mechanistically resolved, functional/intermediate, and associative evidence while highlighting the limitations of global m6A assays, bulk-tissue profiling, and pathway-level inference. The translational value of m6A is likely to depend on target-RNA selection, cell-specific delivery, disease-stage timing, and preservation of protective immunity and tissue repair. An evidence-aware, transcript-centered framework may help move m6A research from descriptive association toward causal immune-state biology and clinically testable interventions.
    Keywords:  RNA fate; immune cells; immunometabolism; inflammation resolution; inflammatory diseases; m6A
    DOI:  https://doi.org/10.3389/fimmu.2026.1918662
  5. Annu Rev Pharmacol Toxicol. 2026 Sep 08.
    Protein Synthesis Dysregulation in Neurodegeneration: Mechanisms, Consequences, and Therapeutic Modulation.
    Karinder K Brar, Adrian J Butcher, Giovanna R Mallucci.
      Protein synthesis in neurons is essential for shaping and maintaining the proteome, which underpins synaptic function, learning, memory, and neuronal resilience. Dysregulated mRNA translation control, particularly at the level of initiation, results in reduced global protein synthesis and is a common pathological feature of many neurodegenerative disorders. In mouse models of these diseases, sustained global translational repression drives synaptic dysfunction and loss, ultimately leading to neurodegeneration. Crucially, interventions alleviating this repression restore the proteome, rescue synaptic dysfunction, and promote neuronal survival, leading to their therapeutic potential being assessed in clinical trials. Recently, alternative nodes of regulation have emerged, not only of global mRNA translation-including elongation control-but also of mechanisms fine-tuning subcellular translation in different cellular compartments, notably at synapses and mitochondria. These translation regulatory mechanisms bring a more nuanced understanding of the role of local protein synthesis in neuronal health and disease and the opportunity for novel therapies.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-080125-105017
  6. Front Vet Sci. 2026 ;13 1883063
    m6A RNA methylation in mammalian oocytes and preimplantation embryos: implications for developmental competence.
    Chiara Cosseddu, Sara Succu, Francesca Mossa, Adele Frau, Maria Grazia Palmerini, Sergio Ledda, Daniela Bebbere.
      Chemical modifications of RNA molecules, collectively referred to as epitranscriptomics, have emerged as a critical layer of post-transcriptional gene regulation. Among these modifications, N6-methyladenosine (m6A) plays a key role in modulating RNA stability, localization, and translational efficiency without altering the underlying nucleotide sequence. In recent years, epitranscriptomics has been increasingly recognized for its involvement in mammalian reproductive processes. In mammalian oocytes, which undergo an extended period of transcriptional quiescence and rely predominantly on post-transcriptional regulation of maternally stored transcripts, RNA modifications are essential for proper gene expression control. During oocyte maturation and early pre-implantation embryo development, epitranscriptomic mechanisms ensure the timely turnover and translational regulation of maternal mRNAs, thereby supporting the correct execution of the maternal-to-zygotic transition. The proper accomplishment of these processes is crucial for the acquisition of developmental competence. Reversible RNA modifications therefore add an additional layer of complexity to the regulation of gene expression in oocytes and early embryos. This mini-review summarizes current knowledge on the role of m6A RNA methylation in mammalian oocyte developmental competence and early embryogenesis, highlighting recent experimental evidence and discussing potential implications for fertility and assisted reproductive technologies.
    Keywords:  embryo; epitranscriptomics; gene regulation; m6A RNA methylation; oocyte developmental competence
    DOI:  https://doi.org/10.3389/fvets.2026.1883063
  7. Nat Commun. 2026 Aug 08. pii: 9538. [Epub ahead of print]17(1):
    Quantitative RNA modification mapping by mass spectrometry with isobaric tags and nucleobase fragment analysis.
    Junzhou Wu, Jingjing Sun, Yifeng Yuan, Shiuan Nee Goh, Hazel Chay, Dwijapriya, Valérie de Crécy-Lagard, Peter C Dedon.
      RNA modifications regulate RNA stability, translation, stress responses, and disease processes, yet their function remains poorly understood due to technical limitations in sequence analysis. Here, we present an RNA-specific isobaric tandem mass tagging (RMT) platform for omic-scale quantitative mapping of RNA modifications. The platform combines RNA-specific tags adapted from proteomics with an end-to-end workflow spanning sample preparation through data processing. Validation using synthetic oligonucleotides and total tRNA from Pseudomonas aeruginosa yielded reproducible quantification, with coefficients of variation below 5%. Together with nucleobase fragment analysis, we identified and quantified 24 RNA modifications in PA14 tRNAs, including previously undescribed m2A38 and Gm/Cm39, and assigned their corresponding writer enzymes. Further analyses of tRNAs from writer knockout strains and stressed cells revealed dynamic modification patterns, modification interdependencies, and their potential roles in stress adaptation. This method provides a robust, cost-effective platform for quantitative RNA modification mapping, enabling deeper biological insights.
    DOI:  https://doi.org/10.1038/s41467-026-76537-w
  8. Int Immunopharmacol. 2026 Sep 11. pii: S1567-5769(26)01199-9. [Epub ahead of print]189 117352
    The collaborative epitranscriptome: bidirectional crosstalk between m6A methylation and noncoding RNAs in cancer pathogenesis and precision therapy.
    Nan Li, Jiaxue Lu, Wenling Zhang.
      Altered post-transcriptional regulation contributes to cancer development and treatment resistance. N6-methyladenosine (m6A) modification and noncoding RNAs are closely connected within this process and can regulate one another in both directions. This review summarizes the m6A regulatory system, the biological characteristics of major ncRNA classes, and the mechanisms through which m6A and ncRNAs interact in cancer. m6A can affect ncRNA biogenesis, stability, localization, protein binding, and translation, whereas ncRNAs can alter the expression or activity of m6A writers, erasers, and readers and influence their interactions with specific RNA targets. The effects of these pathways vary with the RNA involved, the modified site, the associated proteins, and the cellular context, which helps explain why similar changes in the m6A machinery can produce different outcomes in different tumors. m6A-ncRNA interactions have been associated with tumor progression, metabolic adaptation, regulated cell death, immune regulation, and response to anticancer treatment. Several ncRNAs involved in these pathways have also been linked to prognosis, recurrence, or treatment response in patient cohorts. Experimental studies have begun to examine therapeutic strategies based on ncRNA inhibition or restoration and, in a smaller number of cases, direct manipulation of defined m6A events. The review also considers the clinical evidence for these pathways and the practical challenges that need to be addressed before they can be more widely explored as biomarkers or therapeutic targets.
    Keywords:  Antitumor immunity; Ferroptosis; Metabolic adaptation; Posttranscriptional regulation; Transcript stability; Treatment resistance
    DOI:  https://doi.org/10.1016/j.intimp.2026.117352
  9. Nucleic Acids Res. 2026 Sep 07. pii: gkag858. [Epub ahead of print]54(17):
    The alarmone pGpp inhibits translation through GTP depletion.
    Kevin A England, Aude Trinquier, Leah K McKinney, Jue D Wang, Heather A Feaga.
      Bacteria produce the alarmone nucleotides ppGpp and pppGpp during stress to affect replication, transcription, and metabolism. ppGpp and pppGpp also attenuate translation by competitively binding translational GTPases to conserve resources during stress. Recently, pGpp was identified as a third alarmone, and important pathogens like Clostridioides difficile exclusively produce pGpp in response to stress. Despite its abundance as an alarmone, the precise role of pGpp in mediating stress responses is poorly understood. Here, we show that, while pGpp is a weaker inhibitor of protein synthesis than ppGpp and pppGpp in vitro, pGpp production in the model Gram-positive bacterium Bacillus subtilis leads to faster translation inhibition in vivo. pGpp production leads to fewer ribosomes engaged in translation and more hibernating ribosome dimers than (p)ppGpp production, suggesting that translation initiation is strongly inhibited. Additionally, pGpp production depletes cellular GTP more rapidly than (p)ppGpp production, which we show is sufficient for translation inhibition. Faster GTP depletion during pGpp production is also accompanied by more robust transcriptome remodeling. This work expands the model by which alarmones inhibit translation to include GTP depletion and demonstrates how different alarmone species exert varying effects on physiology.
    DOI:  https://doi.org/10.1093/nar/gkag858
  10. Synth Syst Biotechnol. 2027 Apr;18 76-84
    Ribosome engineering enhances genetic code expansion in Saccharomyces cerevisiae.
    Xiaoxu Chen, Wenlu Shen, Xianqing Chen, Fangfang Zhang, Bo Yang, Zhiyong Yue, Guanghou Zhao.
      Genetic code expansion enables the site-specific installation of noncanonical amino acids (ncAAs) into proteins, but its limited efficiency in eukaryotes remains a major barrier to broader application. Here we establish a visual, plug-and-play screening platform to evolve 18S ribosomal DNA in Saccharomyces cerevisiae and identify ribosomal variants that improve ncAA incorporation. The best-performing strain, designated ribo-hyper, increased ncAA-dependent GFP production by 2.9-fold relative to the wild-type rDNA strain and enhanced incorporation across distinct orthogonal aminoacyl-tRNA synthetase/tRNA pairs. Characterization of ribo-hyper showed that global translation activity and cellular growth were moderately reduced. Proteomic analysis further revealed changes in amino acid biosynthesis, translation-related proteins and stress-response pathways, indicating that the engineered ribosome reshapes cellular translation homeostasis. Perturbation of translation quality-control pathways, including the ribosome-rescue factors Dom34 and Hbs1 and the core mRNA exosome component Ski6, reduced ncAA-containing protein output, whereas disruption of ribosome quality-control factor Rqc2 had little effect. These findings support a role for ribosome rescue and associated mRNA turnover in efficient ncAA incorporation in the ribo-hyper strain. Together, our results establish eukaryotic ribosome engineering as a viable strategy for improving genetic code expansion in yeast.
    Keywords:  Genetic code expansion; Noncanonical amino acid; Ribosome engineering; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1016/j.synbio.2026.08.009
  11. Planta. 2026 Sep 07. pii: 119. [Epub ahead of print]264(4):
    Protein-RNA control networks at the plant-pathogen interface.
    Wajid Zaman, Asma Ayaz.
       MAIN CONCLUSION: Plant immunity depends on coordinated control of signaling gain, molecular persistence, RNA fate, interorganismal exchange and timely attenuation, defining testable routes to durable disease control. Plant immunity is often reviewed as a sequence of receptor activation, transcriptional reprogramming, and antimicrobial output. That organization is useful, but it obscures a central mechanistic problem: immune performance depends on coupled control of protein abundance, RNA fate, interorganismal exchange and response termination. Here, we develop an evidence-weighted protein-RNA control-loop framework that is explicitly differentiated from receptor-, proteostasis-, RNA-silencing- and extracellular-vesicle-centered reviews. The framework organizes plant-pathogen interactions around five experimentally tractable control variables: signaling gain, molecular persistence, RNA routing, interorganismal exchange and memory versus cost. We evaluate how pattern-recognition receptors and nucleotide-binding leucine-rich-repeat receptors set signaling gain; ubiquitination, SUMOylation, proteasomal turnover and autophagy determine persistence; RNA-binding proteins, alternative splicing, N6-methyladenosine (m6A), translation and decay route immune messages; and vesicular or non-vesicular ribonucleoprotein carriers mediate cross-kingdom RNA exchange. For each layer, we distinguish association from physical mechanism, causal perturbation, and crop-level validation. Receptor synergy, resistosome signaling, selected proteolytic circuits and several cross-kingdom RNA interference mechanisms are strongly supported, whereas generalized roles for immune m6A, stress-granule routing, vesicle-exclusive RNA transport and durable epigenetic memory remain incompletely demonstrated. The framework yields testable predictions and a stage-gated roadmap for engineered receptors, host- and spray-induced gene silencing, proteostasis or RNA-binding-protein engineering, and multi-omics breeding. Durable resistance should therefore be judged not by maximal defense activation, but by sufficient gain, correct routing, appropriate persistence and timely attenuation with acceptable yield and environmental costs.
    Keywords:  Crop disease management; Cross-kingdom silencing; Extracellular vesicles; Post-transcriptional regulation; Proteostasis; Resistosomes
    DOI:  https://doi.org/10.1007/s00425-026-05144-2
  12. Mol Cell. 2026 Sep 08. pii: S1097-2765(26)00561-7. [Epub ahead of print]
    Long-range mRNA folding shapes expression and sequence of bacterial genes.
    Manraj S Gill, Isabelle A Kim, James R Xue, Yashna Thappeta, James C Taggart, Gene-Wei Li.
      Bacterial gene expression is strongly influenced by local mRNA secondary structure, yet the impact of long-range folding remains poorly understood. Here, we show that sequences hundreds of nucleotides from the mRNA 5' end can act as potent repressors of gene expression through long-range base pairing to the ribosome binding site (RBS), subjecting anti-RBS sequences to negative selection. Using massively parallel reporter assays in Bacillus subtilis, we identify anti-RBS sequences as among the strongest determinants of reduced mRNA abundance across the transcript body. We demonstrate that distal anti-RBS elements engage in long-range folding with the Shine-Dalgarno sequence, blocking ribosome entry and promoting mRNA decay. Consistent with these repressive effects, anti-RBS-like sequences are depleted throughout diverse bacterial coding sequences but not from leaderless transcripts, and introducing distal anti-RBS to native genes reduces expression. Our findings establish that long-range mRNA folding is a conserved force shaping gene expression and constrains coding sequence evolution.
    Keywords:  RNA structure; bacterial coding sequence; bacterial mRNA; mRNA degradation; mRNA folding; mRNA stability; mRNA translation; ribosome binding site; sequence evolution; translation efficiency
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.014
  13. Wiley Interdiscip Rev RNA. 2026 Sep-Oct;17(5):17(5): e70055
    Experimental and Computational Tools for Mapping Circular RNA Modifications.
    Gaurahari Sahoo, Dishanee Santra, Amaresh Chandra Panda.
      Posttranscriptional RNA modifications and their impact on the structure and function have been extensively studied on linear RNAs. As RNA modifications affect RNA structure, stability, localization, and translation, several methods have been developed to study modifications on linear RNAs. These modifications on RNAs ultimately regulate gene expression. One of the poorly characterized classes of RNA critical for gene expression is circular RNAs (circRNAs), which are ubiquitously expressed and are covalently closed RNA molecules. Although advances in sequencing technologies have greatly enhanced the identification of RNA modifications and their importance in gene regulation, the effects of these modifications on circRNA structure and function are only now emerging. Only a few modifications, like N6-methyladenosine (m6A), 5-methylcytosine (m5C), adenosine-to-inosine (A-to-I), and to a lesser extent N1-methyladenosine (m1A), have been reported so far for circRNAs. In this article, we discuss the importance of these modifications and their implications in circRNA function. Moreover, we will discuss molecular and computational methods for detecting circRNA modifications, to help researchers studying circRNAs select the most effective methods for investigating modifications in this novel class of circRNAs.
    DOI:  https://doi.org/10.1002/wrna.70055
  14. J Virol. 2026 Sep 08. e0108026
    African swine fever virus pMGF110-9L plays a critical role in the integrated stress response and viral pathogenesis.
    Shuai Fan, Han Zhong, Dan Li, Jing Zhang, Yuhang Zhang, Man Hu, Wenrui He, Bo Wan, Zixiang Zhu, Shichong Han, Haixue Zheng, Gaiping Zhang.
      African swine fever virus (ASFV) is the causative agent of ASF, a highly contagious and frequently fatal hemorrhagic disease in domestic swine and wild boars, posing a significant threat to the global pig industry. To ensure successful replication, ASFV may modulate cellular stress mechanisms to hijack the host translation machinery and promote viral factory formation to favor viral protein synthesis and counteract host defenses. However, the interplay between ASFV replication and cellular stress responses has not yet been elucidated, hindering the development of vaccines or therapeutic options. In this study, we dissected how ASFV manipulates the integrated stress response (ISR) to facilitate viral replication and identified the virulence-related factor pMGF110-9L as the strongest activator of ATF4 expression, a key factor downstream of eIF2α phosphorylation during ISR activation. We characterized pMGF110-9L as an endoplasmic reticulum (ER)-localized membrane protein, the expression of which profoundly reorganized the cellular compartments, leading to ER swelling and aggregation. Further proteomic analyses and biochemical experiments revealed that pMGF110-9L is crucial for ASFV-induced ER stress and promotes the activation of the PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 branches of the unfolded protein response. Specifically, we demonstrated that pMGF110-9L activates the ISR through the PERK/PKR-eIF2α pathway, leading to viral takeover of the protein synthesis machinery, accompanied by global protein synthesis shutdown and stress granule formation. Furthermore, the transmembrane domain of pMGF110-9L is indispensable for targeting the ER and subsequent stress responses. Overall, these findings inform novel insights into ASFV-host interactions and define a previously uncharacterized role for pMGF110-9L in ASFV pathogenesis.IMPORTANCEAfrican swine fever (ASF), caused by African swine fever virus (ASFV), poses a catastrophic threat to global pork production. The complex pathogenesis and immunoevasion strategies of ASFV have not been clearly elucidated, raising safety concerns regarding modified live virus (MLV) vaccines. Therefore, a better understanding of how ASFV manipulates host responses to establish intracellular conditions favorable for viral replication could provide essential insights into ASFV-host interactions and enable the development of safer and more effective MLV vaccines. In this study, we comprehensively elucidated the relationship between ASFV-encoded proteins and the activation of the integrated stress response. We identified pMGF110-9L as a prominent virulence factor involved in viral takeover of the protein synthesis machinery, accompanied by endoplasmic reticulum (ER) stress, ER-associated aggresome formation, halted host protein translation, and stress granule formation. Importantly, the transmembrane domain of pMGF110-9L was critical for triggering cellular stress mechanisms. This study advances our understanding of ASFV pathogenesis and highlights pMGF110-9L as a potential target for MLV vaccine development.
    Keywords:  African swine fever virus; ER stress; eIF2α phosphorylation; integrated stress response; pMGF110-9L; stress granules; translational shutdown
    DOI:  https://doi.org/10.1128/jvi.01080-26
  15. J Biol Chem. 2026 Sep 07. pii: S0021-9258(26)02390-2. [Epub ahead of print] 113518
    Heme as a Versatile Signaling Molecule: Coordinating Mitochondrial Metabolism with Global Cellular Responses.
    Iva Chitrakar, Breann L Brown.
      Heme is an essential iron-containing cofactor that supports diverse biological processes, including oxygen transport, mitochondrial respiration, and xenobiotic metabolism. Beyond these canonical functions, accumulating evidence has established heme as a dynamic signaling molecule that couples mitochondrial metabolic state to cellular stress responses, gene expression, and metabolic adaptation. Heme biosynthesis is compartmentalized between mitochondria and the cytosol, requiring tightly coordinated synthesis, trafficking, sensing, and degradation to maintain cellular homeostasis and prevent heme toxicity. In this review, we examine mechanisms by which heme regulates mitochondrial protein quality control, respiratory chain assembly, and metabolic feedback to coordinate organellar function with cellular energy demands. We further discuss how heme is trafficked to extramitochondrial compartments, where it modulates cytoplasmic stress signaling, iron homeostasis, transcriptional networks, and metabolic programs through interactions with proteins, including the BACH1 transcription factor, REV-ERB nuclear receptors, and the glycolytic enzyme GAPDH. We also highlight ongoing debates surrounding mitochondrial heme trafficking and identify critical unanswered questions regarding the identity of intracellular heme chaperones and mitochondrial heme sensors. Finally, we discuss how dysregulation of heme synthesis, trafficking, sensing, and degradation contributes to diverse pathologies. Collectively, recent advances establish heme as a central regulator of mitochondrial communication and cellular homeostasis, underscoring the therapeutic potential of targeting heme signaling pathways in human disease.
    Keywords:  heme; iron; mitochondria; oxidative stress; porphyrin; unfolded protein response
    DOI:  https://doi.org/10.1016/j.jbc.2026.113518
  16. Med Oncol. 2026 Sep 10. pii: 278. [Epub ahead of print]43(10):
    IGF2BP3 enhances paclitaxel resistance in bladder urothelial carcinoma by recognizing m6A-modified CENPA mRNA.
    HanJie Yi, YongQing Han, Xia Wang, Qing Li, Le Xiong, ShanFeng Li.
      Bladder urothelial carcinoma (BUC) is associated with poor prognosis and chemoresistance. The RNA-binding protein IGF2BP3 has been implicated in the progression and drug resistance of various cancers, but its role in UC remains underexplored. This study aimed to investigate the role of IGF2BP3 in regulating CENPA mRNA stability and its contribution to UC malignancy and paclitaxel (PTX) resistance. We analyzed human BUC cell lines (UMUC3, T24) and their paclitaxel-resistant counterpart (T24/R). The interaction between IGF2BP3 and CENPA mRNA was assessed using RNA immunoprecipitation (RIP), MeRIP-qPCR, and dual-luciferase reporter assays. RNA stability was measured with actinomycin D treatment. Cell migration, invasion, and clonogenic assays were performed to evaluate the impact of IGF2BP3 and CENPA modulation on tumor behavior. In vivo tumorigenicity and paclitaxel response were evaluated using xenograft mouse models. IGF2BP3 directly binds to m6A-modified CENPA mRNA and enhances its stability, thereby sustaining its expression in BUC. IGF2BP3 knockdown markedly decreased CENPA mRNA and protein levels and increased paclitaxel sensitivity. CENPA overexpression restored the migratory, invasive, and clonogenic capacities of IGF2BP3-silenced cells under paclitaxel treatment, whereas mutation of the m6A site abolished this rescue effect, indicating m6A dependency. In vivo, IGF2BP3 silencing suppressed tumor growth and enhanced paclitaxel sensitivity in T24/R-derived xenografts, which was partially reversed by CENPA overexpression. IGF2BP3 promotes malignant phenotype and paclitaxel resistance in BUC by stabilizing CENPA mRNA. Targeting the IGF2BP3-CENPA axis may provide a novel therapeutic strategy to overcome chemoresistance in BUC.
    Keywords:  Bladder urothelial carcinoma; CENPA; Drug resistance; IGF2BP3; m6A modification; mRNA stability
    DOI:  https://doi.org/10.1007/s12032-026-03383-7
  17. RSC Chem Biol. 2026 Sep 01.
    Chemistry and biology of oxidatively damaged RNA nucleotides.
    Kasturi Raorane, Marlies Weber, Virginie Marchand, Mark Helm, Yuri Motorin.
      Nucleic acid damage under oxidative stress conditions is a well-established phenomenon relevant to evolution of all living organisms. While well investigated for DNA, cellular RNAs are also a subject of extensive damage, featuring similar reactivity towards reactive oxygen species generated by external factors and cellular metabolism. The chemistry of DNA and RNA oxidative damage is rather complex, involving a variety of concomitant chemical reactions which are further exacerbated by secondary reactions that increase the already overwhelming list of chemically damaged nucleotides. The damage is of random character, typically resulting in sub-stoichiometrically damaged sites. This substantially complicates the analysis of RNA oxidation. Modern analytical techniques include deep sequencing-based protocols allowing precise mapping of such damaged residues in cellular RNAs. Increasing experimental evidence suggests vast and widespread biological consequences and highlights the importance of the metabolism of oxidized RNA in a variety of cellular processes. The main effects are expected at the level of translation, since all key players of the translational machinery, mRNA, rRNA and tRNAs are prominent oxidation targets. In this review we present current achievements in the analysis of RNA oxidation/damage chemistry, traditional and modern methods allowing RNA oxidation analysis and current view on the biological consequences of RNA oxidation in the living cell.
    DOI:  https://doi.org/10.1039/d6cb00143b
  18. Life Sci Alliance. 2026 Nov;pii: e202603825. [Epub ahead of print]9(11):
    Proximity labeling puts ZFP36L1 as central hub for posttranscriptional regulation networks in T cells.
    Anouk P Jurgens, Branka Popović, Floris Pj van Alphen, Maxime Steinmetz, Leyma Wardak, Antonia Bradarić, Sander Engels, Carmen van der Zwaan, Maartje van den Biggelaar, Arie J Hoogendijk, Julien Béthune, Monika C Wolkers.
      Effective T cell responses against pathogens require a rapid yet tightly controlled remodeling of the proteome, and RNA binding proteins (RBPs) are key in this process. For instance, the RBP ZFP36L1 prevents excessive protein production and thereby limits immunopathology. ZFP36L1 is primarily known to mediate mRNA decay, but it can also regulate other processes. How its mode of action relates to its interaction partners is, however, not well-understood. Here, we mapped the ZFP36L1 interactome in primary human T cells. Using proximity labeling, we identified known and new interactors that regulate 3'UTR-mediated RNA degradation, deadenylation, stress granule/p-body formation, as well as 5'UTR-mediated translation repression and mRNA decapping. Snapshot analysis uncovered the ZFP36L1 interactome dynamics and RNA (in)dependency throughout T cell activation. Intriguingly, proximity labeling also uncovered regulators of ZFP36L1 protein expression. This included the helicase UPF1, which not only interacts with ZFP36L1 protein but that may also promote its protein expression. Altogether, this comprehensive interactome map underlines the versatility of interactions with ZFP36L1 and their possible role in cellular function.
    DOI:  https://doi.org/10.26508/lsa.202603825
  19. Biophys J. 2026 Sep 10. pii: S0006-3495(26)00610-7. [Epub ahead of print]
    Localized ribosome access and distal tuning via the Listeria prfA RNA thermometer.
    Martin R O'Steen, Jocelyn V Chen, David H Beier, Nils G Walter, Sarah C Keane.
      RNA thermometers (RNATs) are temperature-responsive structures in 5' untranslated regions (UTRs) of some bacterial messenger RNA (mRNA) that control translation by modulating ribosome access. The Listeria monocytogenes prfA RNAT represses translation of PrfA (positive regulatory factor A), the master virulence regulator, at ambient temperature and activates it near the human host temperature (∼37 °C) by modulating ribosome binding site (RBS) accessibility. However, the prfA RNAT shares no homology with known RNAT classes, and its unfolding mechanism remains unclear. Here, we used analytical ultracentrifugation and single-molecule kinetic analysis of RNA transient structure (SiM-KARTS) to map prfA RNAT unfolding. SiM-KARTS analysis demonstrates that thermal opening occurs predominantly at the RBS, while the upper helix of the RNAT hairpin remains largely folded at 37 °C. The RBS binding kinetics increases with temperature in parallel with translation output, establishing a quantitative link between structural unfolding and function. Mutations in the upper helix impair thermal regulation, indicating that this region tunes switching even as it stays structured at host temperature. Together, these data reveal a hierarchical unfolding pathway in which initial RBS opening triggers activation, whereas the upper helix remotely tunes temperature sensitivity.
    DOI:  https://doi.org/10.1016/j.bpj.2026.09.005
  20. Nucleic Acids Res. 2026 Sep 07. pii: gkag875. [Epub ahead of print]54(17):
    Ribosome dynamics at the conserved PGP motif governs 2A peptide-bond-skipping efficiency.
    Xincheng Wu, Saori Uematsu, Yan Wu, Shu-Bing Qian.
      Viral 2A oligopeptides drive an unusual ribosome recoding event in which peptide-bond formation fails at a conserved PG↓P motif, producing two discrete proteins without canonical termination. Despite decades of study, the molecular basis of 2A-mediated peptide-bond skipping remains poorly understood. Here, we combine quantitative 2A reporters with high-resolution ribosome profiling to interrogate ribosome dynamics at the core 2A sequences. We identify a pausing event at the terminal proline codon of the PGP motif that functions as a kinetic decision point: ribosome dwell time at this site inversely correlates with skipping efficiency. Increasing nascent chain flexibility by inserting linkers immediately upstream of the 2A sequence reduces ribosome occupancy at the terminal proline codon and enhances peptide-bond skipping. Strikingly, amino acid repeats positioned distally upstream also modulate 2A activity, indicating long-range coupling between nascent chain properties outside of the ribosome and the peptidyl transferase center inside the ribosome. In particular, hydrophobic residues potently suppress skipping, an effect that can be rescued by extending flexible segments within the peptide exit tunnel. Together, our findings support a model in which nascent chain features-beyond the core 2A motif-dynamically tune ribosomal recoding efficiency through co-translational feedback into the catalytic center.
    DOI:  https://doi.org/10.1093/nar/gkag875
  21. RNA. 2026 Sep 10. pii: rna.081089.126. [Epub ahead of print]
    18S rRNA 3' end cleavage by the phosphorylated endoribonuclease NOB1 is interconnected with early small subunit biogenesis.
    Katja I Bloch von Blottnitz, Mona Honemann-Capito, Philipp Hackert, Olexandr Dybkov, Christof Lenz, Markus T Bohnsack, Sonja Lorenz, Henning Urlaub, Claudia Schneider, Katherine E Bohnsack.
      Processing of the precursor ribosomal RNAs (pre-rRNAs) is a key aspect of ribosomal subunit assembly that is closely coordinated with other maturation events. The ribonucleases that mediate pre-rRNA cleavages require regulation to ensure that their activities are exerted in a timely manner. Post-translational modifications can influence protein functions, and although many human ribosome assembly factors are reported to be post-translationally modified, most of these sites remain unconfirmed and functional insights are lacking. Here, we show that NOB1, the PIN domain endoribonuclease responsible for cleavage of the 3' end of the 18S rRNA, is phosphorylated within an evolutionarily conserved acidic tract that can be modified by casein kinase II in vitro. Association of NOB1 with pre-ribosomes is independent of these phosphorylations, and lack of NOB1 phosphorylation only mildly perturbs the efficiency of SSU maturation events upstream of 3' end cleavage of the 18S rRNA. Interestingly, our analyses of pre-rRNA levels in cells depleted of NOB1 or lacking its catalytic activity revealed not only accumulation of the 18SE precursor of the 18S rRNA, but also altered levels of pre-rRNAs containing 5' external transcribed spacer (ETS) sequences (43S, 26S and 30S). This suggests that lack of NOB1-mediated pre-rRNA cleavage impairs recycling of assembly factors required during early biogenesis steps, leading to altered kinetics of 5' ETS processing. Taken together, these data provide new insights into the role of NOB1 during SSU biogenesis and the post-translational regulation of this ribonuclease.
    Keywords:  Endoribonuclease; Phosphorylation; PilT N-terminal (PIN) domain; Ribosomal RNA processing; Ribosome biogenesis
    DOI:  https://doi.org/10.1261/rna.081089.126
  22. Trends Cancer. 2026 Sep 07. pii: S2405-8033(26)00190-1. [Epub ahead of print]
    Cancer-associated synonymous mutations target mRNA structures and protein activity.
    Robin Fahraeus.
      The role of adaptive mRNA structures in regulating gene expression in mammalian cells remains poorly understood. Synonymous mutations have been linked to a range of diseases, including cancer, yet their impact on cell biology remains largely unexplored. This opinion focuses on how cancer-associated synonymous mutations (CASMs) in the TP53 mRNA disrupt signal-induced mRNA structures and alter the activity of the encoded protein. CASM203 induces conformational changes that recapitulate those driven by PERK during the unfolded protein response, promoting expression of the p53/p47 isoform. By contrast, CASM22 and CASM34 interfere with DNA damage-induced RNA structures and affect full-length p53 activity. Together, these examples illustrate an underappreciated regulatory axis in which dynamic mRNA structures interface between upstream signalling pathways and downstream effector functions, with direct implications for tumour biology.
    Keywords:  RNA structures; cancer-associated synonymous mutations; cell signalling
    DOI:  https://doi.org/10.1016/j.trecan.2026.08.005
  23. J Cell Biol. 2026 Nov 02. pii: e202605096. [Epub ahead of print]225(11):
    Nucleolar dynamics are determined by the ordered assembly of the ribosome.
    Jessica Sheu-Gruttadauria, Xiaowei Yan, Nico Stuurman, Riley O Ogrean, Sabrina Lin, Stephen N Floor, Ronald D Vale.
      Ribosome biogenesis occurs in the nucleolus, a biomolecular condensate whose material properties are thought to be important for function. However, the molecular basis of nucleolar dynamics and their relationship to ribosome assembly remain incompletely understood. We present a platform for high-throughput FRAP (HiT-FRAP) and use it to screen hundreds of genes for their impact on dynamics of the nucleolar scaffold nucleophosmin (NPM1). We find that NPM1 dynamics and nucleolar morphology are sensitive to ribosome assembly state: accumulation of early pre-ribosomal intermediates slows NPM1 dynamics and compacts the condensate, while accumulation of abortive late precursors accelerates dynamics and disrupts condensate integrity. These opposing biophysical states correlate with the strength of NPM1-pre-ribosome interactions. Importantly, mutations in the NPM1 intrinsically disordered region that alter pre-ribosome binding directly tune nucleolar dynamics. These results establish that ribosomal precursor assembly state determines nucleolar material properties through the strength of scaffold-pre-ribosome interactions and introduce HiT-FRAP as a platform for interrogating condensate dynamics broadly.
    DOI:  https://doi.org/10.1083/jcb.202605096
  24. Nat Commun. 2026 Aug 08. pii: 9529. [Epub ahead of print]17(1):
    The RNA helicase domain of NAT10 promotes the biogenesis of hypomodified ribosomes to enhance cancer cell proliferation.
    Mahmood H Dalhat, Sharath Narayan, Maria Eleftheriou, James Russell, James Heslop, Hannah Serio, Khulood A Alzahrani, Adam Suh, Ajay Edakkara, Sweta Raikundalia, Lea Landmann, Ryan Asby, Evangelia Stamou, Judith López, Yogeshkumar Malam, Demetrios Aspris, Emmely A Patrasso, Stephanie Mou, George Giotopoulos, Walid T Khaled, Brian J P Huntly, Fotios Sampaziotis, Konstantinos Tzelepis, Daniel Arango.
      N-acetyltransferase 10 (NAT10) is a multifunctional enzyme that harbors RNA acetyltransferase and RNA helicase domains and has emerged as a therapeutic vulnerability in solid and hematological malignancies. By coupling Proteolysis Targeting Chimera-mediated degradation of NAT10 with a deep mutational scanning assay, followed by validations in biochemical assays, human cell lines, and female mouse xenografts, we find that the RNA helicase domain of NAT10 enhances cancer cell proliferation and tumor growth. This proliferative function of NAT10 is independent of RNA acetylation but requires its RNA-binding activity. The RNA helicase domain of NAT10 is required for 18S rRNA binding, promoting biogenesis of the 40S ribosomal subunit, while simultaneously interfering with the deposition of the conserved 18S rRNA modification m¹acp³Ψ. Loss of m¹acp³Ψ in 18S rRNA enhances cancer cell proliferation, revealing that NAT10 promotes the biogenesis of hypomodified ribosomes to facilitate tumor growth. These findings uncover a mechanism by which NAT10 promotes cancer cell proliferation and establish its RNA helicase domain as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-76383-w
  25. Bioinformatics. 2026 Sep 10. pii: btag667. [Epub ahead of print]
    Gradient-based Optimization for mRNA Sequence Design.
    Hongmin Li, Goro Terai, Takumi Otagaki, Kiyoshi Asai.
       MOTIVATION: Designing mRNA coding sequences that simultaneously optimize RNA accessibility in the translation initiation region and codon adaptation while preserving the encoded protein requires navigating a vast discrete combinatorial space. The inherently discrete nature of codon choices prevents direct application of gradient-based optimization, despite the availability of accurate deep learning predictors such as DeepRaccess for RNA accessibility prediction.
    RESULTS: We present the Input Data Differentiable Designer (ID3), a unified framework for mRNA codon optimization. ID3 treats trained models as fixed differentiable functions and optimizes input data through continuous probability distributions while preserving the encoded amino acid sequence through three constraint mechanisms. The framework shows strong performance in both accessibility optimization and joint accessibility-CAI optimization across diverse protein targets. We also provide convergence analyses from the perspective of trained model input optimization.
    AVAILABILITY AND IMPLEMENTATION: Code, datasets, and reproduction scripts are available at https://github.com/Li-Hongmin/ID3.git and archived on Zenodo (DOI: 10.5281/zenodo.18917770).
    Keywords:  ID3; RNA sequence optimization; codon adaptation index; codon optimization; constraint mechanisms; deep learning integration; discrete-continuous optimization; gradient; mRNA accessibility; theoretical convergence
    DOI:  https://doi.org/10.1093/bioinformatics/btag667
  26. 3 Biotech. 2026 Oct;16(10): 416
    Advances in phytochemical modulation of protein aggregation in neurodegenerative diseases.
    Nitu Kumari, Santosh Anand.
      Protein aggregation and misfolding are central pathological events underlying major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and related proteinopathies. The aberrant aggregation of amyloid-β, tau, and α-synuclein generates toxic oligomeric and fibrillar species that disrupt proteostasis, impair synaptic function, promote oxidative stress and neuroinflammation, and ultimately drive progressive neuronal loss. This review critically summarizes recent advances in plant-derived secondary metabolites with anti-aggregation properties, emphasizing their structural diversity, molecular mechanisms, structure-activity relationships, and translational potential. Current findings demonstrate that polyphenols, flavonoids, terpenoids, alkaloids, curcuminoids, and secoiridoids inhibit protein aggregation through multiple complementary mechanisms, including direct modulation of amyloidogenic proteins and restoration of proteostasis via molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, mitochondrial protection, and suppression of neuroinflammatory signaling. Emerging evidence further demonstrates that rational structural optimization, hybrid molecule design, and nanotechnology-based delivery systems can substantially improve the pharmacokinetic limitations of these compounds. Overall, the accumulated evidence indicates that phytochemicals possess multitarget therapeutic potential by simultaneously reducing protein aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation, thereby offering broader neuroprotection than single-target approaches. Nevertheless, limited bioavailability, poor blood-brain barrier penetration, interspecies variability, and insufficient clinical validation continue to impede translation. By integrating mechanistic evidence with recent advances in medicinal chemistry and drug delivery, this review highlights promising strategies to accelerate the development of phytochemical-based therapeutics for protein aggregation-associated neurodegenerative diseases. Unlike previous studies that primarily summarize anti-amyloid phytochemicals, this review integrates recent mechanistic insights into protein aggregation, proteostasis regulation, medicinal chemistry optimization, structural biology, and translational challenges across multiple neurodegenerative proteinopathies.
    Keywords:  Amyloid-β; Neurodegeneration; Phytochemicals; Polyphenols; Protein aggregation; α-Synuclein
    DOI:  https://doi.org/10.1007/s13205-026-05046-w
  27. FASEB J. 2026 Sep 15. 40(17): e72279
    GnRH Promotes Gonadotropin Synthesis and Secretion in the Bovine Anterior Pituitary by Inhibiting METTL1-Mediated m7G Modification of FOXO1 mRNA.
    Yu Xiao, Bing-Bing Wang, Hai-Xiang Guo, Yu-Xin Zhang, Hao Zhang, Cheng-Zhen Chen, Hao Jiang, Zhe Zhang, Yi Zheng, Bao Yuan.
      The pituitary gland is a key regulator of mammalian reproduction. By secreting the gonadotropins-follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-the anterior pituitary precisely coordinates reproductive function. The hypothalamus releases gonadotropin-releasing hormone (GnRH), which in turn regulates the synthesis and secretion of gonadotropins by the anterior pituitary gland. Although GnRH-dependent regulation of pituitary gonadotropins has been extensively studied in rodents, the mechanisms by which GnRH regulates gonadotropins in the bovine anterior pituitary gland remain unclear. In this research, we primarily used primary bovine anterior pituitary cells (PCs) for the experiments, and employed the mouse gonadotropin cell line LβT2 to further validate the regulatory effect of GnRH on pituitary gonadotropin-secreting cells. We first demonstrated that GnRH promotes bovine gonadotropin synthesis and secretion and concomitantly reduces global cellular m7G methylation. Further experiments demonstrated that METTL1, a key methyltransferase responsible for m7G modification, is downregulated after GnRH treatment and functions as a negative regulator of gonadotropin synthesis and secretion. Mechanistically, experiments such as MeRIP-qPCR and RNA stability analyses showed that METTL1 mediates m7G methylation of bovine FOXO1 mRNA, thereby modulating FOXO1 stability and protein expression, and regulating gonadotropin synthesis and secretion. Collectively, these findings demonstrate that GnRH regulates gonadotropin synthesis and secretion in the bovine anterior pituitary, and reveal an important role for RNA epigenetic modification in this process.
    Keywords:  FOXO1; GnRH; bovine pituitary; gonadotropins; m7G methylation
    DOI:  https://doi.org/10.1096/fj.202602504RR
  28. Gen Physiol Biophys. 2026 Sep;45(5): 455-466
    Bardoxolone methyl induces mitochondrial dysfunction, activation of the cytosolic stress response, and increased chaperone capacity in SH-SY5Y cells. Focus on mitochondrial protease LONP1.
    Lubos Hudak, Andrea Evinova, Monika Liskova, Jaroslava Guzikova, Michal Pokusa, Zuzana Tatarkova, Maria Brodnanova, Magdalena Kurekova, Patrik Jambrich, Peter Racay.
      Our work aimed to study the impact of bardoxolone methyl, 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me), on mitochondrial function and morphology in SH-SY5Y cells, molecular responses, with a focus on the expression of proteins of mitochondriaspecific unfolded protein response (mtUPR), the endoplasmic reticulum-specific UPR (UPRER), and the cytosolic stress response. Treatment of SH-SY5Y cells with CDDO-Me is associated with decreased relative cell survival associated with gasdermin E cleavage, compatible with pyroptotic cell death features. Treatment of SH-SY5Y cells with CDDO-Me results in decreased ROUTINE respiration, maximal respiration, succinate-driven maximal respiration, ATP-coupled respiration, and spare respiratory capacity. We have not observed significant changes in the expression of proteins that play important roles in both mtUPR (LONP1) and UPRER (HRD1 and SEL1L), whereas expression of cytosolic chaperone HSP70 was significantly increased in response to CDDO-Me. In addition, we have observed increased expression of mitochondrial chaperones HSP60 and GRP75 as well as ER chaperone GRP78. Finally, we have observed the formation of donut-like mitochondria induced by CDDO-Me. Our results, together with previously published data, indicate that mitochondrial dysfunction, activation of cytosolic stress response, and an increase in chaperone capacity elicited by CDDO-Me could be attributed to CDDO-Me's ability to inhibit LONP1 protease.
    DOI:  https://doi.org/10.4149/gpb_2026019
  29. RNA. 2026 Sep 09. pii: rna.081051.126. [Epub ahead of print]
    Circular-pre-rRNA-dependent and -independent rRNA maturation pathways in Archaea.
    Daniela Strauß, Maximilian Liebl, Pranav Sharma, Michael Jüttner, Robert Reichelt, Aurore Gorlas, Sarah J Berkemer, Sébastien Ferreira-Cerca.
      Ribosome biogenesis in archaea is uniquely characterized by the formation of circular pre-rRNA intermediates, a process dependent on bulge-helix-bulge (bhb) motifs-structured RNA elements located in the processing stems flanking the rRNA and critical for cleavage and ligation by the tRNA splicing machinery. In this study, we confirm the existence of circular-dependent rRNA maturation pathways across diverse archaeal species. In addition, we also reveal the presence of circular-independent rRNA maturation pathways. Using a pan-archaeal assay, we detected circular pre-16S rRNA in most analysed species, but notably, Thermoplasma acidophilum lacks both circular pre-16S intermediate and a bhb motif in the 16S processing stem, indicating a novel, bhb- and circular-independent pre-16S maturation mechanism. In Haloarcula marismortui, we identified hybrid pathways, where different operons utilize either circular-dependent or -independent maturation routes. Additionally, we uncovered unprecedented diversity in bhb motifs, with central helix lengths ranging from 3 to 6 nucleotides, contrasting with the canonical 4-nucleotide helix typically observed in the context of tRNA splicing. These findings expand our understanding of rRNA maturation in archaea, demonstrating that circular pre-16S rRNA formation in archaea is not a universal requirement and highlighting the adaptability of archaeal ribosome biogenesis.
    Keywords:  Archaea; bulge-helix-bulge; circular-RNA; rRNA maturation
    DOI:  https://doi.org/10.1261/rna.081051.126
  30. Biochim Biophys Acta Mol Cell Res. 2026 Sep 06. pii: S0167-4889(26)00119-9. [Epub ahead of print]1873(8): 120220
    Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.
    Tânia Catarina Medeiros, Gaetano Calabrese.
      Mitochondria are central hubs of cellular metabolism that harbor their own genome (mtDNA), whose maintenance is essential for both cellular and organismal homeostasis. Unlike nuclear DNA, mtDNA replicates continuously throughout the cell cycle, rendering it particularly sensitive to changes in metabolic state. Emerging evidence indicates that mtDNA homeostasis is not governed solely by dedicated replication factors but is tightly coupled to cellular metabolism. In this review, we discuss how metabolic networks shape mtDNA maintenance through three interconnected layers: mitochondrial nucleotide pools, metabolic control of the replication machinery, and stress-response pathways. This conceptual framework underscores the direct role of metabolic state in governing mtDNA replication, stability, and quality control, with significant implications for mitochondrial disease and therapeutic strategies.
    Keywords:  Integrated stress response (ISR); Metabolism; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Nucleotides; Replication machinery
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120220
  31. Front Microbiol. 2026 ;17 1929318
    Protein aggregation as a bistable switch in bacterial cell fate: from adaptive dormancy to cytotoxic death.
    Yuejuan Nong, Weijie Wang, Weiwei Zhu.
      Protein aggregation has traditionally been considered a hallmark of proteostasis disruption and cellular dysfunction. However, recent studies have revealed that bacterial protein aggregation is not merely a passive consequence of stress-induced damage but may represent a dynamic component of cellular adaptation. Under adverse conditions, reversible protein condensation and aggregation have been associated with bacterial dormancy, persistence, and the viable but non-culturable (VBNC) state, whereas excessive and irreversible aggregation may contribute to loss of cellular function and bacterial death. Nevertheless, whether protein aggregation serves as a primary determinant of bacterial cell fate or reflects a consequence of broader physiological changes remains an important unresolved question. In this review, we summarize current advances in understanding bacterial protein aggregation, including the roles of liquid-liquid phase separation (LLPS), protein quality control systems, ATP-dependent proteostasis regulation, and aggregate maturation. We discuss how stress-induced alterations in proteostasis networks influence bacterial survival, aging, persistence, and antibiotic tolerance. Available evidence supports a working model whereby the physicochemical properties of protein aggregates may dictate ultimate bacterial cell fate. Nevertheless, the causal link between condensate phase behavior, aggregate material characteristics, and cell fate decisions remains to be thoroughly validated, even though emerging technologies including live single-molecule cell imaging and quantitative analytical tools have greatly advanced our mechanistic understanding of the dynamic progression of bacterial protein aggregation. Finally, we discuss the therapeutic potential and challenges of targeting bacterial proteostasis and aggregation pathways to combat persistent and multidrug-resistant pathogens. A deeper mechanistic understanding of how protein aggregation balances adaptation and toxicity may reveal new vulnerabilities within bacterial survival strategies.
    Keywords:  bacterial aging; bacterial dormancy; bacterial proteostasis; cell death; protein aggregation; stress response
    DOI:  https://doi.org/10.3389/fmicb.2026.1929318
  32. JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]
    Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
    Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.
      Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.
    Keywords:  Endocrinology; Muscle biology; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.210523
  33. Front Aging Neurosci. 2026 ;18 1884207
    Striatal small RNA remodeling in MPTP-induced Parkinson's disease highlights coordinated downregulation of mitochondrial tsRNAs.
    Mingyu Mao, Yan Wang, Qing Deng, Jun Xiang, Wentao Li.
      Parkinson's disease (PD) is characterized by progressive nigrostriatal degeneration, yet the contribution of modification-rich small RNAs to PD pathology remains unclear. Here, we used PANDORA-seq to profile the striatal small RNA landscape in a subacute MPTP-induced mouse model of PD. MPTP-treated mice exhibited significant motor deficits together with reduced striatal tyrosine hydroxylase and dopamine transporter expression, confirming successful model establishment. Small RNA profiling revealed that transfer RNA-derived small RNAs and ribosomal RNA-derived small RNAs, rather than microRNAs, dominated the striatal small RNA transcriptome. Among the dysregulated small RNA classes, mitochondrial tsRNAs showed the most prominent and coordinated downregulation. Bioinformatic analysis suggested that predicted targets of differentially expressed mt-tsRNAs were enriched in synaptic organization, presynaptic function, membrane contact sites, and lipid-related pathways. In SH-SY5Y cells, transfection of an mt-tsRNA mimic partially reversed MPP+ induced increases in reactive oxygen species and restored mitochondrial membrane potential. These findings provide a modification-aware small RNA landscape of the PD striatum and identify mt-tsRNA downregulation as a notable feature of MPTP-induced parkinsonism.
    Keywords:  MPTP; Parkinson’s disease; mitochondrial dysfunction; mitochondrial tsRNAs; pANDORA-seq; striatum
    DOI:  https://doi.org/10.3389/fnagi.2026.1884207
  34. Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01051-X. [Epub ahead of print]45(9): 117973
    Integrated stress response inhibition decouples cardiotoxicity from anthracycline chemotherapy while enhancing antitumor efficacy.
    Simin Yang, Zhengyang Chen, Hongli Zhang, Jingjing Jin, Yuting Li, Zhentian Nie, Xiaoyan Sun, Hongyan Shu, Yawei Kong, Ziyu Wang, Shan Gao, Wei Chen.
      The clinical efficacy of anthracycline chemotherapeutics is severely limited by their dose-dependent cardiotoxicity, a condition lacking effective preventive strategies. We identify the maladaptive ATF4-dependent integrated stress response (ISR) program as a central driver of this pathology. In murine models, ISR inhibition achieved by either cardiomyocyte-specific knockout of the transcription factor ATF4 or the ISR inhibitor (ISRIB), provides robust protection from doxorubicin (DOX)-induced cardiac dysfunction, remodeling, and injury. Mechanistically, we delineate a regulatory pathway in which DOX-activated ATF4 directly upregulates the methyltransferase METTL1. This ATF4-METTL1 axis promotes N7-methylguanosine (m7G) methylation of NLRP3 mRNA, thereby triggering NLRP3 inflammasome activation, mitochondrial damage, and cardiomyocyte pyroptosis. Crucially, pharmacological ISR inhibition with ISRIB synergizes with DOX to enhance tumor regression in xenograft models without causing cardiac injury. These findings establish the ISR as a therapeutically actionable target to simultaneously prevent anthracycline-induced cardiotoxicity and enhance chemotherapeutic efficacy, offering a promising strategy to refine cancer treatment.
    Keywords:  ATF4; CP: cancer; anthracycline; cardiotoxicity; integrated stress response; pyroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117973
  35. Front Pharmacol. 2026 ;17 1886917
    Mitochondrial resilience: a convergent framework for pathogenesis and neuroprotection in Parkinson's disease.
    Oscar Arias-Carrión, Magdalena Guerra-Crespo, Luis O Soto-Rojas, Yeminia Valle, Emmanuel Ortega-Robles, Daniel Ortuño-Sahagún.
      Parkinson's disease (PD) is traditionally described as a dopaminergic neurodegenerative disorder driven by α-synuclein aggregation and selective neuronal loss in the substantia nigra pars compacta. While this characterization captures the core clinical and pathological features, it does not fully explain disease initiation and progression. Converging evidence from human genetics, cellular and structural biology, and systems neuroscience now supports a unified framework in which PD results from the progressive erosion of mitochondrial resilience. Here, mitochondrial resilience denotes the capacity of neuronal mitochondrial networks to withstand stress and recover bioenergetic and cellular homeostasis through coordinated quality control, metabolic adaptation, and organelle communication. Rare, high-impact monogenic mutations in PINK1, PRKN (encoding Parkin), PARK7 (DJ-1), LRRK2, and SNCA, along with common risk variants identified in genome-wide association studies, converge on interconnected pathways that govern mitochondrial quality control, bioenergetics, organelle dynamics, and cellular stress responses. These vulnerabilities are most pronounced in the highly energetic dopaminergic neurons of the substantia nigra, where sustained calcium cycling, high bioenergetic demand, and environmental stressors increase cellular susceptibility. Research has moved beyond early observations of respiratory chain impairment and oxidative stress to reveal context-specific disruptions in PINK1/Parkin-mediated mitophagy, lysosomal trafficking, mitochondrial-derived vesicle dynamics, and neuroimmune signaling. This integrated framework reframes PD as a disorder of impaired cellular maintenance rather than solely a consequence of late-stage degenerative processes. It provides a translational shift from mechanism-based biomarkers to early detection of mitochondrial failure and supports therapeutic strategies aimed at restoring mitochondrial function and resilience, offering a direct route to disease-modifying neuroprotection in PD and potentially other neurodegenerative disorders.
    Keywords:  LRRK2; Parkinson’s disease; alpha-synuclein; mitochondria dynamics; mitochondrial quality control; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fphar.2026.1886917
  36. Nat Commun. 2026 Aug 12. pii: 9683. [Epub ahead of print]17(1):
    TDP-43 controls RNA structure through high affinity lattice interactions.
    Rahul Vivek, Takuma Kume, Saeed Roschdi, M Thomas Record, Aaron A Hoskins, Samuel E Butcher.
      TDP-43 is an RNA binding protein implicated in neurodegenerative disease. TDP-43 binds to GU dinucleotide repeats, which are highly abundant sequences in human RNA. Here we show TDP-43 has one of the highest affinities and specificities measured for an RNA binding protein. Binding prevents formation of the pUG fold, an intramolecular quadruplex, and conversely pUG fold formation prevents TDP-43 binding. Slow pUG folding and a rapid on-rate enable TDP-43 to capture single-stranded RNA. The protein recognizes the RNA as a 1D lattice, in which overlapping binding sites produce efficient initial binding events that interfere with subsequent interactions. This effect is overcome by RNA facilitated protein-protein interactions, which serve to increase the on-rate of a second TDP-43 molecule, and an auto-inhibitory interaction that increases the off-rate. These data reveal how TDP-43 recognizes GU repeats and identify an interplay between RNA folding and protein recognition that may be relevant to human disease.
    DOI:  https://doi.org/10.1038/s41467-026-76721-y
  37. Invest Ophthalmol Vis Sci. 2026 Sep 01. 67(11): 21
    Single-Nucleus RNA Sequencing Highlights Endothelial and Müller Cell ER Stress During Retinal Neovascularization in Vldlr-/- Mouse.
    Angela Galdamez, Soyoung Park, William Temme, Allyssa Bradley, Ethan Stevenson, Leon Chea, Eun-Jin Lee, Jonathan H Lin.
       Purpose: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling are implicated in pathologic neovascularization, but their role in the spontaneous intraretinal/subretinal neovascularization in Vldlr-/- mice is unknown. We performed single-nucleus RNA sequencing (snRNA-seq) on adult Vldlr-/- retinas undergoing neovascularization and age-matched Vldlr+/+ control retinas. We examined differentially expressed genes in Vldlr-/- retinal cell types to identify stress signaling pathways selectively engaged in retinal cell types during pathologic neovascularization.
    Methods: The snRNA-seq was performed on P46 Vldlr-/- and Vldlr+/+ retinas, and differentially expressed genes and pathways associated with ER stress and UPR signaling were evaluated in retinal cell populations. KDEL and C/EBP homologous transcription factor protein (CHOP) immunostaining on retinal sections was performed to further identify retinal cell types with increased ER stress. Retinal neovascularization was evaluated by isolectin B4 (IB4) labeling of neovascular tufts and subretinal neovascularization. Retinal function was assessed by electroretinography (ERG), including oscillatory potentials.
    Results: IB4 staining revealed robust neovascular tufts and abnormal vessel extension into the outer retina/subretinal space. ERG and oscillatory potentials showed significantly reduced retinal function. The snRNA-seq revealed significant upregulation of ER stress/UPR signaling-associated genes selectively in endothelial cells and Müller cells. Strong KDEL and CHOP immunoreactivity was seen in IB4-positive abnormal vessels and activated Müller processes, supporting increased ER stress in these retinal cell populations.
    Conclusions: Endothelial cells and Müller cells show increased ER stress and UPR activation in Vldlr-/- retinas undergoing pathological neovascularization.
    DOI:  https://doi.org/10.1167/iovs.67.11.21
  38. Comp Biochem Physiol Part D Genomics Proteomics. 2026 Sep 04. pii: S1744-117X(26)00274-1. [Epub ahead of print]61 102015
    Transcriptomic characterization of the intestine in Stichopus monotuberculatus under gradient temperature stress and HSP gene family-mediated molecular adaptation.
    Lianghua Huang, Yetao Zeng, Langduorijie Cai, Chuanyan Pan, Fei Gao, Haiqing Wang, Qiang Xu.
      The increasing frequency of extreme temperature events under climate change poses a growing threat to the stability of tropical sea cucumber aquaculture. To characterize the molecular responses of the tropical sea cucumber Stichopus monotuberculatus to acute temperature stress, juveniles were exposed for 96 h to 15 °C, 20 °C, 25 °C, 30 °C, and 35 °C, followed by transcriptomic profiling of the intestine. By transcriptomic analysis, 2258, 634, 1618, and 2980 differentially expressed genes (DEGs) were identified at 15, 20, 30, and 35 °C compared to control, respectively. More DEGs were generally detected at temperatures further from 25 °C, with the 35 °C group showing the largest transcriptional response. Although cold and heat stress both affected metabolism and protein homeostasis, their enrichment profiles differed. At 15 °C, DEGs were mainly enriched in the spliceosome and p53 signaling pathways, highlighting RNA processing and p53 signaling as prominent features of the cold-stress response. At 35 °C, DEGs were mainly enriched in the PI3K-Akt signaling pathway, ubiquitin-mediated proteolysis, and mitophagy, indicating enhanced regulation of cell survival, protein turnover, and mitochondrial quality control. HSP genes also responded differently to cold and heat stress. Most HSP70 and HSP90 family members were downregulated at low temperatures, whereas HSP70 genes and small heat shock proteins were markedly upregulated at high temperatures. Overall, the intestinal transcriptome showed distinct responses to cold and heat stress. These results identify pathways and HSP genes potentially involved in the temperature response of S. monotuberculatus and provide useful information for evaluating temperature tolerance and defining suitable temperatures for its aquaculture.
    Keywords:  Heat shock protein; Stichopus monotuberculatus; Temperature stress; Transcriptomics
    DOI:  https://doi.org/10.1016/j.cbd.2026.102015
  39. Front Immunol. 2026 ;17 1926363
    YBX1 as an adaptive RNA hub in cancer: linking state-dependent RNA regulation to tumor immunity, metabolic reprogramming, and therapy resistance.
    Zhang XiaoTian, Wang YiTong, Feng Chongchong.
      Y-box binding protein 1 (YBX1) has been implicated across an unusually broad range of malignancies and processes: immune remodeling, epithelial plasticity, metabolic rewiring, epitranscriptomic reading, and resistance to chemotherapy, targeted agents, and checkpoint blockade. A linear one-gene/one-pathway oncogene model does not readily accommodate this breadth. We argue that the apparent diffuseness reflects a context-dependent regulatory node rather than experimental noise, and develop the hypothesis that YBX1 acts as an adaptive RNA/transcriptional hub, a regulator whose transcript outputs are set by cellular state rather than by a fixed binding program, which acts in both the transcriptional and post-transcriptional compartments, and which sits inside feedback loops linking downstream metabolic states back to its own activity. We organize the literature into three coupled layers: a state code, in which post-translational modifications, ubiquitin balance, localization, and phase separation determine which YBX1 is active (Layer 1); an RNA program, in which m5C reading and non-coding-RNA scaffolds are associated with a restricted survival transcriptome (Layer 2); and the immune, metabolic, and plasticity phenotypes these outputs generate (Layer 3). Evidence further suggests that tumor-specific dependency is carried by the configuration of the YBX1/YBX2/YBX3 family rather than by any single member. We specify what would falsify the framework: if state-resolved readouts do not predict downstream circuit activity better than total YBX1 abundance, the hub reduces to a promiscuous, abundant RNA-binding protein whose correlations are epiphenomenal. We give explicit weight to evidence resisting an oncogenic reading: circuits in which restraining YBX1 is tumor-suppressive, non-coding-RNA and family-level interactions running in opposite directions, and effectors regulated divergently between tumors, treating these as boundary conditions rather than exceptions. This reframing shifts the actionable question from whether YBX1 is high to which YBX1-dependent circuit a tumor uses; its value remains contingent on prospective, state- and circuit-level validation.
    Keywords:  YBX1; adaptive RNA hub; cancer metabolism; therapy resistance; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1926363
  40. Cell Rep. 2026 Sep 07. pii: S2211-1247(26)01037-5. [Epub ahead of print]45(9): 117959
    Complementation of a human disease phenotype by intercellular mRNA transfer.
    Gal Haimovich, Sandipan Dasgupta, Anand Govindan Ravi, Jeffrey E Gerst.
      There is growing evidence that mRNAs undergo intercellular transfer through cytoplasmic connections called tunneling nanotubes (TNTs), but whether transferred mRNAs are translated and affect cellular changes post-transfer is unknown. Using multiple lines of evidence, we show that transferred mRNAs undergo translation and can complement the phenotype of genetic mutations in vitro. For example, the human peroxisome biogenesis disorder, Zellweger Syndrome, results from mutations in genes such as PEX5 and PEX6. We demonstrate that the co-culture of patient-derived PEX6 mutant fibroblasts or PEX5 knockout cells with wild-type cells leads to de novo peroxisome biogenesis. We provide additional examples of genetic complementation via transfer of mRNAs encoding the HSF1 transcription factor or CRE recombinase. Complementation occurs by TNT-mediated mRNA transfer and translation in acceptor cells, but not by exosomes, nor by protein or peroxisome transfer. Our study provides evidence for the physiological significance of mRNA transfer and suggests another approach for mRNA therapeutics.
    Keywords:  CP: cell biology; CP: genomics; CRE; RNA trafficking; Zellweger syndrome; heat-shock; heat-shock factor 1; mRNA transfer; peroxisome; smFISH; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.celrep.2026.117959
  41. N Biotechnol. 2026 Sep 08. pii: S1871-6784(26)00106-8. [Epub ahead of print]96 32-43
    Global structure and determinants of transcriptomic adaptation in CHO cells.
    Markus Riedl, Nicolas Marx, Nicole Borth.
      Transcriptomic adaptation plays a central role in the phenotypic plasticity of Chinese hamster ovary (CHO) cells. While various gene expression studies have provided insights into condition-specific responses, a comprehensive, systems-level understanding of how CHO cell transcriptomes dynamically adapt across diverse experimental contexts remains limited. Here, we present a large-scale investigation of more than 600 RNA-seq samples across diverse cell lines, culture conditions and experimental designs to systematically dissect stable and adaptive components of the transcriptome. We consolidate robust expression variance measures across datasets to identify a global axis of gene expression variability that summarizes transcriptional adaptation across common experimental settings. Functional enrichment analyses reveal that highly variable genes are associated with stress response mechanisms, extracellular interactions, signaling and apoptosis, whereas low-variability genes are enriched for RNA metabolism, intracellular transport and basal transcription. Analyses of regulatory features of genes with different variabilities show distinct promoter architectures and epigenetic signatures consistent with dynamic transcriptional control. Beyond this global axis of transcriptional adaptation, we capture context-specific transcriptional programs linked to experimental designs, including temperature downshift and growth phase transitions. Together, these findings delineate a common, low-variability transcriptional core alongside a variable, flexible layer that enables adaptive responses. Our work advances the understanding of transcriptional robustness and plasticity in CHO cells, provides practical guidance for reference gene selection and may offer potential for rational engineering for more robust cell lines.
    Keywords:  CHO cells; Gene expression variation; Meta-analysis; Transcriptome
    DOI:  https://doi.org/10.1016/j.nbt.2026.09.001
  42. Front Physiol. 2026 ;17 1907325
    Post-translational control of MAVS signaling: linking mitochondrial antiviral immunity to metabolic and cellular stress contexts.
    Nao Morimoto, Tomohiko Okazaki.
      Mitochondria function not only as metabolic and bioenergetic centers but also as critical signaling hubs that integrate cellular context with innate immune response. The mitochondrial antiviral-signaling protein (MAVS), anchored to the outer mitochondrial membrane, is a central adaptor in the RIG-I-like receptor (RLR) pathway, orchestrating type I interferon (IFN) production and apoptosis. Although long regarded as a docking platform for RLR-derived signals, recent advances, particularly concerning its diverse post-translational modifications (PTMs), reveal MAVS as a dynamic integrator that decodes cellular stress and metabolic cues to fine-tune antiviral immunity. Canonical PTMs such as ubiquitination and phosphorylation highlight the importance of precisely controlling both the initiation and downregulation of MAVS signaling, but recent discoveries substantially broaden this regulatory landscape. Stress-responsive phosphorylation mediated via the ASK1-p38 MAPK pathway enhances MAVS signaling capacity under oxidative and ER stress, linking cellular damage to amplified interferon production. In parallel, a newly identified vitamin K-dependent carboxylation of MAVS reshapes downstream signaling by promoting interferon induction while restraining apoptosis, introducing a regulatory layer that may reflect the metabolic context surrounding GGCX activity, including vitamin K availability. Understanding this multilayered regulatory network not only redefines MAVS as a stress-sensitive mitochondrial signaling hub responsive to cellular context but also highlights new avenues for therapeutic modulation of innate immunity and cell fate during viral infection. This review summarizes emerging insights into PTM-mediated regulation of MAVS and outlines their broader implications for mitochondrial antiviral signaling.
    Keywords:  MAVS; apoptosis; cellular stress; innate immunity; mitochondria; post-translational modifications (PTM); type I interferon (IFN-I)
    DOI:  https://doi.org/10.3389/fphys.2026.1907325
  43. JBMR Plus. 2026 Oct;10(10): ziag142
    Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.
    Margarita E Carrasco Jeldres, Oksana Pichurin, Samantha R Weaver, Eric Cheang, Leah E Tokach, Jennifer J Westendorf, David R Deyle.
      Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction, and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in WT cells. Here, we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2 +/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.
    Keywords:  ER stress; EZH1; EZH2; ISR; OI; osteoblasts
    DOI:  https://doi.org/10.1093/jbmrpl/ziag142
  44. FEMS Yeast Res. 2026 Sep 09. pii: foag043. [Epub ahead of print]
    Transcriptomic Responses of Kveik Yeasts to Heat and Ethanol Stress.
    Daishi Shirasaya, Chris D Powell.
      Kveik strains are a group of Saccharomyces cerevisiae strains notable for their exceptional tolerance to environmental stress. To investigate the molecular basis of this robustness, the transcriptomes of three kveik strains and a conventional ale strain were compared under non-stress and stress conditions using RNA-seq. Under non-stress conditions, kveik strains showed elevated basal expression of environmental stress response genes, suggesting that part of the stress-responsive transcriptional program is active irrespective of stress exposure. Catalase activity was elevated, providing physiological support for the transcriptomic findings related to oxidative-stress defense. Under sublethal heat stress, conventional ale yeast displayed transcriptional patterns associated with cell-cycle restraint and chromosome organization, whereas kveik strains showed enrichment of genes related to protein refolding, ribosome biogenesis, and cell-wall biosynthesis, suggesting retention of a transcriptional emphasis on growth-associated processes alongside stress-protective responses. Under ethanol stress, both groups upregulated translation-related processes; however, metabolic functions were more strongly enriched in ale yeast, while kveik strains showed patterns consistent with maintenance of translation-related functions together with increased emphasis on cell surface-associated processes. Overall, kveik stress tolerance appears to reflect elevated basal preparedness and transcriptional patterns consistent with the maintenance of biosynthetic and structural processes under stress, supporting their potential suitability for intensive industrial fermentations.
    Keywords:  Brewing; environmental stress; novel yeasts, Saccharomyces; stress tolerance
    DOI:  https://doi.org/10.1093/femsyr/foag043
  45. Plant J. 2026 Sep;127(5): e71114
    Arabidopsis EMB2788/Npa1L1 is critical for pre-rRNA processing, ribosome biogenesis, and embryo development.
    Mei Liu, Shuailei Wang, Zhuoxuan Li, Zhaojiao Liu, Mengjuan Tong, Aiwei Zhang, Nan Chen, Yirui Zhu, Jingsheng Zhang, Lifen Chen, Yi Guo, Rui Li.
      Ribosome assembly, a fundamental process for cellular functions, requires the precise processing of precursor rRNA (pre-rRNA) into mature rRNAs, a transformation guided by ribosome biogenesis factors (RBFs). While this process is well characterized in yeast and mammals, the roles of RBFs in pre-rRNA processing in plants remain poorly understood. Here, we report the characterization of Arabidopsis EMB2788, previously linked to embryonic development but functionally uncharacterized. We identified EMB2788 as the homolog of yeast nucleolar pre-ribosomal-associated protein 1 (Npa1p), a key pre-rRNA processing regulator, and named it Npa1L1. npa1l1 embryos exhibited severe defects from the late globular stage onward, including altered cell division planes, slowed division rates, and a consequent disruption of bilateral symmetry, accompanied by delayed endosperm development, although a small proportion of embryos developed into morphologically abnormal seedlings. Npa1L1 was likely a nucleolar protein and its loss of function led to an increased abundance of 40S subunits and a reduced abundance of 60S subunits and 80S monosomes. Molecular analysis showed pronounced accumulation of 35S pre-rRNA and 18S rRNA precursors (P-A3) and a reduction in mature 18S rRNA levels. Furthermore, co-immunoprecipitation experiments indicated that Npa1L1 physically interacted with ribosome biogenesis factors, including the DEAD-box RNA helicases RH7 and RH27, and the GTPase NSN1. Collectively, our findings uncover that Npa1L1 is a crucial ribosome biogenesis factor in Arabidopsis that contributes to pre-rRNA processing, ribosomal subunit homeostasis, and embryo development. Nevertheless, the precise function of Npa1L1 in rRNA processing, and whether it differs from that of yeast Npa1p, requires further investigation.
    Keywords:  Arabidopsis; Npa1L1; embryo development; pre‐rRNA processing; ribosome biogenesis
    DOI:  https://doi.org/10.1111/tpj.71114
  46. EMBO Rep. 2026 Sep 05.
    uORF-mediated translational control of CAK and Cdk activation in response to low nutrients in yeast.
    Heidi M Blank, Eun-Gyu No, Ainsley E Nelson, Abigail Payne, Sofia Lykidis, Michael Polymenis.
      Cyclin-dependent kinases (Cdks) require activating T-loop phosphorylation, a modification considered constitutive. Here, we examine the regulation of the Cdk-activating kinase, Cak1, in budding yeast. We measure Cak1 levels and the activating T169 phosphorylation of Cdc28 (the budding yeast Cdk) in different nutrients. The abundance of Cak1 and T169 phosphorylation is reduced in cells that proliferate very slowly or enter quiescence. A small upstream open reading frame (uORF) in CAK1 represses Cak1 synthesis, especially in poor growth conditions. Eliminating the uORF increases Cak1 levels but does not alter proliferation kinetics under most laboratory contexts. Instead, it reduces the viability of quiescent cells. In cells lacking several type 2 C protein phosphatases, which remove the T169 phosphorylation, initiation of cell division is accelerated in the absence of the uORF in CAK1. Our results suggest an unexpected layer of control, impinging on the activating phosphorylation of the Cdk. The uORF-mediated repression of Cak1 synthesis directly couples protein synthesis to the activity of the core cell cycle machinery.
    DOI:  https://doi.org/10.1038/s44319-026-00916-z
  47. Sci Adv. 2026 Sep 11. 12(37): eaed4161
    Peroxiredoxin 1 safeguards the nucleolar genome from oxidative damage.
    Vaibhavi Gujar, Takashi Furusawa, Shalu Sharma, Frimpong Boateng, Haojian Li, Cyrinne Achour, Daiki Taniyama, Michael Kruhlak, Yves Pommier, Shalini Oberdoerffer, Travis H Stracker, Urbain Weyemi.
      Peroxiredoxin 1 (PRDX1) is a highly conserved, thiol-dependent peroxidase that rapidly scavenges reactive oxygen species to modulate redox signaling. PRDX1-null mice exhibited genomic instability, shortened life span, and accelerated tumorigenesis, including development of lymphomas, sarcomas, and carcinomas. Despite extensive characterization of these phenotypes, the molecular mechanism by which PRDX1 loss causes genomic instability remains poorly understood. Here, we show that PRDX1 deficiency alters nucleolar morphology, impairs RNA polymerase I (POL-I)-dependent transcription of pre-ribosomal RNAs, and triggers nucleolar genomic instability. This oxidative stress-induced nucleolar dysfunction promotes the stability of secondary DNA structures, such as RNA-DNA hybrids and G-quadruplex DNA, contributing to nucleolar genomic instability. We demonstrate that PRDX1 loss reduces nascent ribosomal RNA (rRNA) levels and impairs rRNA processing, further affecting ribosome biogenesis. Mechanistically, we established that PRDX1 loss triggers activation of the nucleolar DNA damage response characterized by activation of the DNA repair kinase ATM and elevated TCOF1 within the nucleolus. In addition, we observed recruitment of the MRE11-RAD50-NBS1 (MRN) complex subunit NBS1 to ribosomal DNA (rDNA) loci and this was further increased under oxidative stress. NBS1 accumulation correlates with the repression of rDNA transcription by POL-I, potentially delaying rRNA synthesis, and safeguarding the nucleolar genome from further oxidative damage. Collectively, these findings uncover a previously unrecognized, but critical role, for PRDX1 in maintaining nucleolar integrity and ribosomal biogenesis through redox-dependent regulation of rDNA transcription and processing machinery.
    DOI:  https://doi.org/10.1126/sciadv.aed4161
  48. J Lipid Res. 2026 Sep 07. pii: S0022-2275(26)00131-8. [Epub ahead of print] 101101
    Impact of renal lipid droplet dynamics on tubular health.
    Petr Heneberg, Daniela Heneberg Šimčíková.
      Lipid droplets (LDs) are dynamic organelles that regulate lipid storage, metabolism, and organelle crosstalk. In renal tubular cells, which rely heavily on fatty acid oxidation for energy, LDs play a dual role. The transient accumulation of LDs during acute stress may protect against excess fatty acid accumulation and reduce lipotoxicity, but persistent LD overload contributes to mitochondrial dysfunction, oxidative stress, inflammation, and fibrotic remodeling. This review synthesizes recent advances in LD biology in the kidney, highlighting mechanisms of biogenesis, turnover via lipolysis and lipophagy, and interactions of LDs with mitochondria, the endoplasmic reticulum, and peroxisomes. We compare adaptive versus maladaptive LD-mediated responses across acute kidney injury, chronic kidney disease, and diabetic nephropathy, integrating evidence from human biopsies, animal models, and in vitro studies. Preclinical studies indicate that restoring fatty acid oxidation and improving lipid turnover can reduce tubular injury and fibrosis. However, the effects of directly suppressing LD formation are context dependent because transient neutral-lipid storage may protect cells from excess free fatty acids, whereas persistent LD accumulation can accompany lipotoxic injury. Clinically, PPAR agonists, SGLT2 inhibitors, and GLP-1 receptor agonists improve selected renal outcomes, but direct evidence that they reduce tubular LD burden in humans is lacking. However, kidney-specific biomarkers and drug delivery strategies remain underdeveloped. Key research gaps include a complete understanding of nephron segment-specific LD biology, LD heterogeneity, organelle crosstalk, and sex- and age-related regulation of LDs. Advances in patient-derived organoids, tubuloids, and kidney-on-a-chip models provide new opportunities to evaluate LD dynamics and identify targeted interventions. With these tools, the understanding of LD biology and pathophysiology will increase, and LDs may become a therapeutic target for protecting tubular health and slowing the progression of kidney disease.
    Keywords:  fatty acid oxidation; lipid droplets; lipophagy; mitochondrial dysfunction; perilipins; tubular lipotoxicity
    DOI:  https://doi.org/10.1016/j.jlr.2026.101101
  49. FASEB Bioadv. 2026 Sep;8(9): e70148
    Conditional eIF2A Deletion Suggests Extra-Adipose Mechanisms Underlying Metabolic Syndrome in Total-Body eIF2A Knockout Mice.
    Adedeji Isaac Adeloye, Richard Anderson, Anchal Agarwal, Barsanjit Mazumder, Taras Y Nazarko, Atefeh Bagheri, Archana Prabahar, Peng Jiang, Frank Tedeschi, William C Merrick, David A Buchner, Maria Hatzoglou, Roman V Kondratov, Anton A Komar.
      Dynamic regulation of protein synthesis is essential for metabolic homeostasis, with translation initiation playing a key role in this process. Emerging evidence strongly indicates that in addition to canonical eukaryotic initiation factors (e.g., eIF2, eIF4E) non-canonical factors, such as eukaryotic initiation factor 2A can modulate metabolic homeostasis. eIF2A is a highly conserved eukaryotic protein originally proposed to function analogously to bacterial IF2, promoting initiator Met-tRNAi recruitment to the 40S ribosomal subunit, though its precise mechanism remains debated. To investigate its organismal role, we have previously generated the total-body eIF2A knockout mouse, which revealed eIF2A functions in lipid homeostasis, glucose tolerance, insulin sensitivity, and susceptibility to metabolic syndrome. To further determine whether adipose tissue drives these phenotypes, we presently generated adipose-specific eIF2A knockout mice. Despite dysregulation of some key adipokines, including for example, adiponectin, these mice did not develop metabolic syndrome, even under high-fat diet conditions, indicating that adipose tissue specific deficiency of eIF2A is insufficient to reproduce the metabolic defects observed in total-body knockout. However, we found that eIF2A deficiency in the liver of the total body eIF2A-KO mice can independently drive metabolic syndrome components via translational control of Lpin1 (a phosphatidate phosphatase and a transcriptional coactivator) that controls hepatic lipid storage and metabolism. eIF2A deficiency in the liver leads to disruption of fatty acid oxidation and the production of ketone bodies, not observed in adipose-specific eIF2A knockout mice. Our findings suggest that systemic metabolic effects observed in the total body eIF2A-KO mice may arise from coordinated functions across multiple organs.
    Keywords:  adipose tissue; conditional knockout; eukaryotic initiation factor 2A; lipid homeostasis; metabolic syndrome
    DOI:  https://doi.org/10.1096/fba.2026-00271
  50. Front Oncol. 2026 ;16 1927298
    Chaperone-mediated autophagy as a regulator of hallmarks of cancer.
    Meenakshi Tiwari, Lokendra Kumar Sharma, Bandana Chakravarti, Veena Kumari Singh, Shruti Singh, Ashutosh Shrivastava.
      Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains cellular homeostasis by degrading soluble proteins containing KFERQ-like motifs. Although CMA has traditionally been recognized for its role in protein quality control and cellular stress adaptation, increasing evidence shows that it is frequently altered in cancer, where it regulates multiple processes that promote tumor initiation, progression, and therapy resistance. The growing number of identified CMA substrates involved in cell proliferation, apoptosis, metabolism, DNA damage response, immune regulation, inflammation, and cellular plasticity suggests that CMA is much more than a protein degradation pathway; it is an important regulator of tumor adaptation. In this review, we bring together current evidence to provide a comprehensive understanding of how CMA contributes to the Hallmarks of Cancer, including sustained proliferative signaling, resistance to cell death, metabolic reprogramming, invasion and metastasis, immune evasion, and the enabling characteristics of genome instability and tumor-promoting inflammation. We further explore the emerging roles of CMA in cellular plasticity and cancer stem cell maintenance, two interconnected processes that drive tumor progression, metastasis, and therapeutic resistance. By integrating evidence from diverse tumor types, this review provides a comprehensive understanding of how CMA shapes multiple hallmarks of cancer by selectively degrading key regulatory proteins. Finally, we highlight the context-dependent roles of CMA, identify key gaps in our current understanding, and discuss the opportunities and challenges of targeting CMA for cancer therapy. Overall, this hallmark-based perspective provides an integrated understanding of how CMA contributes to multiple hallmarks of cancer and supports its potential as a therapeutic target.
    Keywords:  autophagy; carcinogenesis; chaperone-mediated autophagy; hallmarks of cancer; proteostasis
    DOI:  https://doi.org/10.3389/fonc.2026.1927298
  51. Nucleic Acids Res. 2026 Sep 07. pii: gkag854. [Epub ahead of print]54(17):
    Programmable in vivo mRNA circularization for enhanced gene expression in bacteria.
    Seongjun Park, Giho Kim, Min Ha Kim, Yong Hee Han, Geunyung Park, Gibyuck Byun, Hyeonwoo Mun, Ho Joon Kim, Sang Woo Seo.
      The minute-scale lifetime of mRNA strongly influences bacterial gene expression, whereas a robust and programmable approach to directly control the mRNA stability and topology remains elusive. Here, we develop CRESEnT (Circular RNA Expression for Stable and Enhanced Translation), a programmable in vivo mRNA circularization system based on a permuted intron-exon architecture to engineer mRNA topology. CRESEnT enables facile circularization of mRNA, which led to a substantial increase in protein expression across diverse promoters, RBS variants, genetic cargos, and bacterial hosts. Furthermore, application of CRESEnT to biosynthetic pathways increased the production of several value-added metabolites, demonstrating that mRNA circularization can be harnessed to improve the metabolic performance of microbial cell factories. Together, these results establish RNA topology engineering via circularization as a transformative axis for controlling bacterial gene expression and enhancing the functionality of microbial cells.
    DOI:  https://doi.org/10.1093/nar/gkag854
  52. Front Cell Dev Biol. 2026 ;14 1840428
    Spatiotemporal control of mitoribosome-mediated metabolic reprogramming in cancer: implications for heterogeneity and therapeutic targeting.
    Xiaojie Chen, Weidong Wang, Fangxin Shen, Zhiwei Zhao.
      Mitochondrial ribosomes (mitoribosomes), particularly mitochondrial ribosomal subunit proteins (MRPS), are emerging as contributors to cancer metabolic reprogramming. Rather than static components of mitochondrial translation, MRPS exhibit pronounced spatiotemporal heterogeneity that shapes tumor metabolic plasticity and therapeutic response. This review systematically summarizes evidence that MRPS functions are dynamically regulated across tumor progression and spatial microenvironments. Temporally, MRPS mediate metabolic switching between oxidative phosphorylation (OXPHOS) and glycolysis, contributing to metabolic adaptation, treatment resistance, and tumor evolution. Spatially, MRPS display context-dependent functions across tumor regions, cancer types, and metabolic microenvironments, thereby contributing to intratumoral metabolic diversity. We further highlight that MRPS-associated metabolic plasticity is linked with lactate metabolism and hypoxia-inducible factor (HIF) signaling, forming feedback networks associated with tumor growth, immune escape, and therapy resistance. This spatiotemporal regulatory axis challenges the traditional static view of mitochondrial dysfunction in cancer. Targeting MRPS-associated metabolic adaptation may provide therapeutic opportunities beyond the traditional Warburg framework. Emerging technologies, including lactate-sensitive nanoprobes, reactive oxygen species (ROS)-responsive delivery systems, and MRPS-related imaging platforms, may support metabolic monitoring and targeted therapeutic intervention. Collectively, this framework links mitochondrial translation with tumor metabolism and microenvironmental regulation, providing additional insight into metabolic adaptation in cancer.
    Keywords:  MRPs; cancer metabolic reprogramming; mitoribosomes; spatial heterogeneity; targeted therapy; temporal heterogeneity
    DOI:  https://doi.org/10.3389/fcell.2026.1840428
  53. Mol Ther. 2026 Sep 11. pii: S1525-0016(26)00777-X. [Epub ahead of print]
    D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.
    Jae Ho Shim, Ji Yeon Lee, Byung Kook Ahn, Sang Woo Woo, Jihye Han, Hyeon Soo Kim.
      Sarcopenia, the age-related loss of skeletal muscle mass and function, lacks FDA-approved pharmacotherapy. The mechanistic target of rapamycin complex 1 (mTORC1), activated by leucine via Sestrin2, is the master regulator of muscle protein synthesis, but L-leucine suffers from rapid catabolism and poor bioavailability. Here, we report D-leucine methyl ester hydrochloride (DLMEH), a metabolically stabilized prodrug incorporating D-stereoisomer conversion, methyl esterification, and hydrochloride salt formation. Three orthogonal biophysical methods demonstrate that DLMEH directly binds Sestrin2 (Kd 28.3 μM), equivalent to L-leucine. Sestrin2 siRNA knockdown and rapamycin co-treatment confirm Sestrin2-dependent, mTORC1-specific activation. In human primary myotubes, DLMEH (100 μM) restores dexamethasone-suppressed protein synthesis by 58.2%, significantly exceeding L-leucine (800 μM, 28.5%). In a rat dexamethasone-induced atrophy model, intravenous DLMEH (100 mg/kg/day, 14 days) preserves gastrocnemius mass (19.3% rescue), grip strength (90% of normal), and treadmill endurance (85% of normal), all superior to oral L-leucine. RNA-seq reveals 41.7% reversal of dexamethasone-induced transcriptomic changes with enrichment in mTOR signaling, ribosome biogenesis, and oxidative phosphorylation. Safety profiling establishes NOAEL at 2000 mg/kg with therapeutic index greater than 30. DLMEH represents a first-in-class Sestrin2-targeting mTORC1 activator for sarcopenia.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.09.007
  54. J Pineal Res. 2026 Sep;78(5): e70183
    Melatonin Inhibits Metastasis of Sunitinib-Resistant Renal Cell Carcinoma Cells Via the GRP78/p38/CTSD Expression.
    Po-Yu Huang, Yi-Hsien Hsieh, Yong-Syuan Chen, Tung-Wei Hung, Hui-Ling Chiou, Pei-Ni Chen, Chun-Wen Cheng, Jen-Pi Tsai.
      Sunitinib resistance contributes to poor outcomes in advanced renal cell carcinoma (RCC). This study investigated the anti-metastatic effects and underlying mechanisms of melatonin in sunitinib-resistant (SR)-RCC. Melatonin significantly inhibited the migration and invasion of A498-SR and Caki-1-SR cells. SR-RCC cells exhibited elevated CTSD expression, impaired endoplasmic reticulum (ER) stress signaling with reduced GRP78 and IRE1α, and enhanced p38 MAPK activation, all of which were reversed by melatonin. Silencing p38 MAPK further potentiated the inhibitory effects of melatonin on cell migration and invasion. Mechanistically, CTSD expression was regulated through both GRP78/p38 MAPK-mediated ER stress. In vivo, melatonin markedly reduced lung metastasis of Caki-1-SR cells without causing significant toxicity to major organs. Collectively, these findings demonstrate that melatonin inhibited the metastatic potential of SR-RCC by decreasing CTSD expression, restoring ER stress response, and decreasing p38 MAPK expression, supporting its potential as an anti-metastatic therapeutic agent for SR-RCC.
    Keywords:  CTSD; GRP78; melatonin; metastasis; p38 MAPK; renal cell carcinoma; sunitinib‐resistant
    DOI:  https://doi.org/10.1111/jpi.70183
  55. Mol Oncol. 2026 Sep 07.
    The VHL tumor suppressor at the crossroad of protein folding, aggregation, and cancer.
    Lara Abad, Silvio Carlo Ermanno Tosatto, Emanuela Leonardi.
      Protein aggregation is no longer viewed only as pathological but as a dynamic and reversible regulatory mechanism in cancer. Within the tumor microenvironment, proteins such as the von Hippel-Lindau tumor suppressor protein (pVHL) can transition from a folded state to aggregated states. Mutations, environmental stress, and dysfunctional chaperone systems further promote pVHL aggregation. Structural plasticity enables adaptive responses that support protein storage, cell survival, and dormancy, a reversible state promoting drug resistance and cancer recurrence. Targeting protein aggregation with chemical chaperones and amyloid inhibitors could represent a promising therapeutic strategy to rescue the tumor suppressor activity and overcome dormancy-associated drug resistance. In this review, we address the amyloid aggregation of pVHL, the factors contributing to this behavior, the correlation between protein aggregation and cellular dormancy, and potential therapeutic strategies that bridge protein aggregation and oncology.
    Keywords:  amyloid‐targeted therapy; cancer dormancy; protein aggregation; von Hippel–Lindau
    DOI:  https://doi.org/10.1002/1878-0261.70325
  56. Mol Genet Genomics. 2026 Sep 09. pii: 190. [Epub ahead of print]301(1):
    TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses.
    Zun Wang, Qian Wang, Yuqin Sa, Nan Ma, Shuo Wang, Chongmei Huang, Minhui Liu, Siyuan Tang.
      Asthma is a complex inflammatory airway disease with strong genetic determinants, yet the functional relevance of most asthma-associated non-coding variants remains unclear. Emerging evidence suggests that N6-methyladenosine (m6A) modification may serve as a critical epitranscriptomic link between genetic variation and immune regulation. In this study, we aimed to systematically identify functionally relevant m6A-regulated genes in asthma by integrating large-scale GWAS data, m6A-SNP annotations, and single-cell transcriptomic analyses, and to investigate their roles in monocyte-driven airway inflammation. We identified TET2 as a key m6A-regulated gene associated with both asthma and lung function, which was selectively upregulated in monocytes during asthma and accompanied by activation of inflammatory and PI3K signaling pathways. Mechanistic experiments further demonstrated that inflammatory stimulation induced ALKBH5 expression, reduced m6A modification of TET2 mRNA, and increased TET2 protein levels, thereby promoting PI3K/AKT signaling and pro-inflammatory cytokine production, whereas inhibition of TET2 or ALKBH5 attenuated these effects. Collectively, these findings demonstrate that ALKBH5-mediated m6A regulation of TET2 enhances PI3K/AKT signaling in monocytes, thereby promoting inflammatory responses in asthma. Our study establishes TET2 as a key m6A-regulated gene linking genetic susceptibility to monocyte-driven inflammation, and highlights the ALKBH5-m6A-TET2 axis as a potential therapeutic target for modulating aberrant immune responses in asthma.
    Keywords:  Asthma; Genome-wide association study (GWAS); Monocytes; N6-methyladenosine (m6A); Single-nucleotide polymorphism (SNP); Tet2
    DOI:  https://doi.org/10.1007/s00438-026-02497-x
  57. J Biol Chem. 2026 Sep 08. pii: S0021-9258(26)02412-9. [Epub ahead of print] 113540
    PARP16 is a Druggable Regulator of Ribosome MARylation and Protein Homeostasis in Ovarian Cancer Cells.
    Sridevi Challa, Morgan Dasovich, Jonathan C Abshier, Komal Pekhale, Lu Yang, Cristel V Camacho, W Lee Kraus.
      Cytosolic NAD+ synthesis supports ovarian cancer growth by enabling PARP16-dependent mono(ADP-ribosyl)ation (MARylation) of ribosomal proteins, thereby fine-tuning translation and maintaining protein homeostasis. While genetic depletion of PARP16 disrupts ribosome MARylation and impairs tumor cell growth, the therapeutic potential of pharmacologic PARP16 inhibition in this pathway remains unexplored. Here, we characterized the effects of DB008, a tool compound that functions as a selective inhibitor of PARP16, in ovarian cancer cells. Biochemical analyses demonstrated that PARP16 undergoes NAD+-dependent auto-MARylation and that NMNAT-2 supplies NAD+ to support this activity. DB008 potently inhibited PARP16 auto-MARylation in vitro. In ovarian cancer cells, DB008 engaged PARP16, reduced its MARylation, and decreased ribosome-associated MARylation. Consistent with PARP16 depletion, DB008 enhanced global protein synthesis, increased protein aggregation, and suppressed cell growth and anchorage-independent colony formation. CRISPR-mediated deletion of the PARP16 gene in ovarian cancer cells abolished the effects of DB008 on translation, protein aggregation, and proliferation, demonstrating on-target activity. Moreover, cells expressing a PARP16 mutant resistant to DB008 were unaffected by inhibitor treatment, further confirming that the cellular effects of DB008 require on-target inhibition. Finally, DB008 significantly inhibited tumor growth in OVCAR3 xenografts, with on-target engagement of PARP16 in the xenograft tumors. Collectively, these findings establish PARP16 as a druggable regulator of ribosome MARylation and protein homeostasis in ovarian cancer and provide pharmacologic proof-of-concept that disrupting ribosomal MARylation impairs tumor growth.
    Keywords:  ADP-ribosylation (ADPRylation); Cell growth; MARylation; Mono(ADP-ribosyl)ation; Ovarian cancer; PARP16; Ribosome; Xenograft
    DOI:  https://doi.org/10.1016/j.jbc.2026.113540
  58. Nucleic Acids Res. 2026 Aug 24. pii: gkag847. [Epub ahead of print]54(16):
    Dual regulation of transcription factor binding by tup11/12-mediated destabilization and DNA loop-mediated stabilization ensures stress-specific gene activation in fission yeast.
    Yusuke Tsuruta, Hirotaka Inoue, Kenta Hagiwara, Charles S Hoffman, Kouji Hirota.
      An appropriate transcriptional response to external stresses is crucial for all organisms. Gene expression is regulated by transcription factors (TFs) binding to specific DNA cis-elements. However, how individual TFs achieve stress-specific binding remains elusive. Here we examine the molecular basis of the stress-specific transcriptional response of the Schizosaccharomyces pombe fbp1 gene. The fbp1 gene is activated upon glucose starvation, with transcriptional co-repressors Tup11 and Tup12 playing pivotal roles in maintaining stress-specificity. In the absence of Tup11 and Tup12, nonspecific activation of fbp1 transcription occurs, which requires the TFs Atf1 and Rst2-both essential for fbp1 induction. Moreover, this aberrant fbp1 activation is diminished by the loss of Php5, a factor indispensable for DNA-loop formation between Atf1- and Rst2-binding sites. The defective nonspecific transcription in the tup11∆/tup12∆/php5∆ mutant is restored when Atf1- and Rst2-binding sites are artificially positioned in proximity to each other, indicating that reciprocal stabilization between these TFs facilitates their binding. These findings demonstrate that fbp1 achieves stress-specific transcriptional activation through the counteractive regulation of TF-binding: Tup11/12-mediated destabilization and DNA loop-mediated stabilization. The synergistic reduction in stress tolerance observed in the tup11∆/tup12∆/php5∆ mutant further suggests that this dual regulatory mechanism is crucial for cellular adaptation to environmental stresses.
    DOI:  https://doi.org/10.1093/nar/gkag847
  59. J Mol Biol. 2026 Sep 05. pii: S0022-2836(26)00387-6. [Epub ahead of print] 170014
    Nsp1 from divergent coronaviruses has conserved endonuclease activity.
    Michael Vetick, Shravani Balaji, Shannon Henry, Swapnil C Devarkar, Yong Xiong.
      All alpha- and beta-coronaviruses encode nonstructural protein 1 (Nsp1), a major virulence factor that restricts host gene expression. Herein, using Nsp1 from divergent alpha- and beta-coronaviruses (SARS-CoV-2, MERS-CoV, and HCoV-229E), we reveal all tested coronavirus Nsp1 proteins have intrinsic endonuclease activity. Furthermore, this endonuclease function is abolished when a conserved arginine-lysine motif in the N-terminal domain (NTD) is disrupted. For SARS-CoV-2 Nsp1, the eukaryotic Initiation Factor 3g (eIF3g) and the 40S ribosome act as cofactors for enhancing the endonuclease function, but these host factors are not conserved for the endonuclease function of MERS-CoV and HCoV-229E Nsp1. We propose that SARS-CoV-2 Nsp1 uses eIF3g and the 40S ribosome to enhance its affinity for RNA and target host mRNAs. Similar enhancement in endonuclease activity is observed when Nsp1 from SARS-CoV-2, MERS-CoV, and HCoV-229E are cis-tethered to an RNA-binding module. Collectively, our results show that endonuclease activity is intrinsic to Nsp1 across divergent coronavirus genera, and this endonuclease activity is likely targeted towards host mRNAs via a diverse set of host mRNA binding cofactors.
    Keywords:  Nsp1; alpha-coronavirus; beta-coronavirus; endonuclease; ribosome
    DOI:  https://doi.org/10.1016/j.jmb.2026.170014
  60. Mol Genet Genomics. 2026 Sep 09. pii: 183. [Epub ahead of print]301(1):
    Circular RNAs orchestrate integrated post-transcriptional responses to combined heat and drought stress in rice.
    Behzad Hajieghrari, Mousa Torabi Giglou.
      Circular RNAs (circRNAs) are emerging post-transcriptional regulators, yet their landscape and functional roles in rice under combined abiotic stress remain largely unexplored. Here, we systematically reanalyzed strand-specific RNA-seq data to characterize circRNAs responsive to simultaneous heat and drought stress. Following quality control, read mapping, and dual-algorithm prediction using CIRI2 and CIRCexplorer2, we identified 208 high-confidence circRNAs distributed across all 12 chromosomes. Comparative profiling revealed 83 circRNAs uniquely expressed in control samples, 51 in stressed samples, and 74 shared between conditions, indicating stress-dependent circularization. Junction-read analysis highlighted a spectrum of circularization strength, ranging from highly abundant circRNAs with dominant junction reads to low-confidence candidates masked by linear transcript background. Genomic annotation showed that circRNAs primarily originated from exonic and intergenic regions, with a pronounced negative-strand bias; several genes generated multiple circRNA isoforms via alternative back-splicing. Functional enrichment of host genes suggested involvement in protein folding, nutrient reservoir activity, RNA degradation, and branched-chain amino acid catabolism, implicating roles in stress adaptation and metabolic regulation. Differential expression analysis identified seven circRNAs specifically induced under combined stress conditions. Network topology analysis pinpointed key miRNAs-including osa-miR414, osa-miR1439, and osa-miR2919-as candidate topological hubs within the predicted network. Their predicted target genes, such as those encoding stress-responsive transcription factors and signaling proteins, suggest potential roles in coordinating post-transcriptional responses to combined stress. Network topology analysis pinpointed key miRNAs-including osa-miR414, osa-miR1439, and osa-miR2919-as candidate topological hubs within the predicted network. Their predicted target genes, such as those encoding stress-responsive transcription factors and signaling proteins, suggest potential roles in coordinating post-transcriptional responses to combined stress. Overall, this study provides a comprehensive map of circRNAs in rice under combined heat and drought stress, suggests their potential as ceRNAs based on predictive analysis, and lays a foundation for future experimental validation of circRNA-mediated regulation.
    Keywords:   Oryza sativa ; Combined heat and drought stress; RNA-seq data analysis; circRNA; circRNA–miRNA–mRNA regulatory networks
    DOI:  https://doi.org/10.1007/s00438-026-02516-x
  61. Autophagy. 2026 Sep 07. 1-17
    Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.
    Rubén Barrios, Rebeca Gracia-Domingo, Cristina Corral-Ramos, Élida Alechaga, Óscar J Pozo, José Ayté, Elena Hidalgo.
      TORC1 is a central regulator of cell growth whose inactivation under conditions of nutrient deprivation triggers adaptive responses, including macroautophagy/autophagy, amino acid uptake, and sexual differentiation. Autophagy-deficient fission yeast cells display mating defects and are unable to recover from amino acid starvation, even when external amino acids are available. Here, we investigate how TORC1 signaling and autophagy interact to control these processes. We show that both major phenotypes of autophagy-deficient cells - their inability to resume growth after amino acid starvation and their mating defects - stem from insufficient intracellular amino acid pools. Genetic or environmental enhancement of intracellular amino acid pools alleviates both defects. During leucine starvation, deletion of any1 rescues the growth defect of atg1Δ mutants by maintaining amino acid transporters at the plasma membrane, promoting amino acid uptake. Importantly, we uncover a previously unrecognized role for autophagy in the cell-cycle remodeling required for sexual differentiation. Nitrogen depletion-mediated TORC1 inactivation initiates these cell-cycle rearrangements required to start the mating/meiosis program, but autophagy is specifically required for the final G2-to-G1 arrest that precedes the program. This step correlates with the accumulation of the cyclin-dependent kinase inhibitor Rum1. Metabolomic analyses reveal that intracellular amino acid pools drop sharply during nitrogen starvation, especially in autophagy-deficient cells, and supplementation with trace amino acids restores their ability to complete the final G2-to-G1 transition. Together, our results reveal that autophagy sustains intracellular amino acid pools during prolonged stress, enabling TORC1 reactivation and cell-cycle remodeling necessary for successful mating and meiosis.Abbreviations: DNA: deoxyribonucleic acid; FACS: fluorescence-activated cell sorting; GATOR1: GAP activity toward Rags 1; GATOR2: GAP activity toward Rags 2; GFP: green fluorescent protein; MM: minimal medium; N: nitrogen; PCR: polymerase chain reaction; RNA: ribonucleic acid; S. cerevisiae: Saccharomyces cerevisiae; S. pombe: Schizosaccharomyces pombe; TOR: target of rapamycin; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; tRNA: transfer ribonucleic acid; YE5S: yeast extract 5 amino acid supplemented; WT: wild-type.
    Keywords:  Amino acid transporters; Eif21/eIf2α; Eliminate Gcn2; G1 arrest; Rum1; TORC1; leucine starvation
    DOI:  https://doi.org/10.1080/15548627.2026.2719430
  62. Appl Environ Microbiol. 2026 Sep 08. e0146526
    Amino acid reprogramming and biofilm-specific tricarboxylate transporters in PET-degrading Piscinibacter sakaiensis.
    Hao Wei Lim, Jiabao Xu, Jonas Koh, Bin Cao, Weiming Tu.
      Plastic-degrading bacteria predominantly colonize polymer surfaces as biofilms, yet it remains unclear whether the biofilm phenotype contributes to metabolism beyond retaining extracellular enzymes. Here, we combine population-level RNA-sequencing across three conditions-biofilm cells on polyethylene terephthalate (PET), planktonic cells incubated with PET, and planktonic cells on maltose-with single-cell Raman spectroscopy to characterize the PET response of Piscinibacter sakaiensis (formerly Ideonella sakaiensis). This integrated approach reveals two metabolically distinct response layers. A carbon-source-driven response shared by all PET-exposed cells is dominated by a broad amino acid reprogramming, led by upregulation of branched-chain amino acid transport genes, enhanced serine biosynthesis, and reduced chemotaxis. A biofilm-specific layer selectively induces tripartite tricarboxylate transporter genes from three distinct genomic loci. This transcriptional feature is accompanied by a single-cell phenotype consistent with a protein-rich and saturated membrane. These results suggest that biofilm formation is not limited to enzyme retention but is associated with selective activation of transport systems, consistent with a putative role in capturing PET-derived intermediates at the polymer interface. This two-layer model separates general metabolic adaptation to PET from biofilm-specific functions and provides a framework for understanding how surface-associated bacterial physiology contributes to plastic degradation.IMPORTANCEPolyethylene terephthalate (PET) degradation in natural and engineered environments is largely mediated by surface-attached microbial communities, yet the physiological role of biofilm state during plastic degradation remains poorly understood. Using the model PET degrader Piscinibacter sakaiensis, we show that biofilm-associated cells are not simply retained near the polymer surface but exhibit a distinct metabolic program characterized by selective induction of tripartite tricarboxylate transporters. In contrast, extensive amino acid reprogramming occurs in both biofilm and planktonic PET-exposed cells, indicating that it is driven by carbon source rather than surface attachment. These findings reveal that PET degradation involves two separable physiological layers: a general metabolic response to PET-derived carbon shared across cell phenotypes, and a biofilm-specific transport response potentially linked to substrate capture at the plastic interface. This work advances our understanding of how microbial physiology is organized during plastic biodegradation and identifies transport processes as previously unrecognized components of PET-degrading biofilms.
    Keywords:  PET biodegradation; bacterial transcriptomics; biofilm metabolism; single-cell Raman spectroscopy; terephthalate; tripartite tricarboxylate transporter
    DOI:  https://doi.org/10.1128/aem.01465-26
  63. Mediators Inflamm. 2026 ;2026(1): e3190064
    Identification of Integrated Stress Response-Related Biomarkers in Sepsis-Induced Acute Respiratory Distress Syndrome.
    Ye Gao, Ni Wang, Zhaoyang Xiao.
       BACKGROUND: Sepsis-induced acute respiratory distress syndrome (ARDS) is a fatal inflammatory lung injury. The integrated stress response (ISR) may play stage-dependent roles in lung injury, but its clinical relevance in sepsis-induced ARDS remains unclear. We aimed to identify ISR-related biomarkers and explore their potential mechanisms.
    METHODS: Public transcriptomic datasets of sepsis-induced ARDS were analyzed. Peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) was used to define key immune cell populations and intercellular communication. Differential expression analyses combined with machine learning were applied to screen ISR-associated biomarkers, and a nomogram was developed as an exploratory tool for ARDS risk stratification. Biomarker expression was validated in a cecal ligation and puncture (CLP)-based rat model representing early sepsis and ARDS-like lung injury. Lung injury was assessed by light and electron microscopy, histological scoring, lung wet/dry weight ratio, and BALF total protein measurement. Gene expression was quantified by qPCR and protein levels by Western blotting. Functional enrichment, immune infiltration, and trajectory analyses were performed to investigate underlying pathways and immune dynamics. The biomarkers were further validated in an independent external dataset.
    RESULTS: Nuclear factor erythroid 2-like 2 (NFE2L2) and ZFP36L1 were identified as potential ISR-associated biomarkers in sepsis-induced ARDS, and the two-gene nomogram showed good predictive performance. In vivo, peripheral blood Tnf and Il6 mRNA expression increased after CLP, while rats with ARDS-like lung injury exhibited marked lung injury and reduced tight junction markers. Nfe2l2 and Zfp36l1 mRNA levels were elevated in early sepsis but decreased in established ARDS-like lung injury, while their protein levels were generally reduced in established ARDS-like lung injury compared with early sepsis. Canonical ISR activation markers, including the p-eukaryotic translation initiation factor 2α (eIF2α)/total eIF2α ratio and Atf4, Ddit3/Chop, and Ppp1r15 a/Gadd34 expression, progressively increased from early sepsis to ARDS-like lung injury. Enrichment analyses implicated multiple ISR-related pathways. Immune infiltration analysis revealed altered immune cell composition, with NFE2L2 negatively correlated with activated B cell infiltration. Single-cell trajectory analysis demonstrated dynamic expression of these biomarkers during differentiation of key immune cell subsets.
    CONCLUSION: NFE2L2 and ZFP36L1 are potential ISR-associated biomarkers in sepsis-induced ARDS and may contribute to disease progression through stress-response regulation and immune modulation, supporting biomarker-driven risk stratification and providing a foundation for future mechanistic and interventional studies.
    Keywords:  acute respiratory distress syndrome (ARDS); integrated stress response; machine learning; sepsis; single-cell RNA sequencing
    DOI:  https://doi.org/10.1155/mi/3190064
  64. Adv Sci (Weinh). 2026 Sep 08. e77666
    FTSJ3-Mediated 2'-O-Methylation of HSPA5 mRNA Stabilizes BOP1 via SUMOylation to Drive DRP1-Dependent Mitochondrial Fission and Fatty Acid Oxidation in Lung Squamous Cell Carcinoma.
    Qin Hu, Jiaheng Lin, Yifei Zhu, Ying Liu, Guoren Zhou.
      Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with a dismal prognosis and limited targeted therapies. While post-translational and RNA modifications are implicated in tumor progression, their precise roles in LUSC remain elusive. Here, we identify the RNA methyltransferase FTSJ3 as a critical oncogenic driver. FTSJ3 is markedly upregulated in LUSC tissues, and its high expression correlates with poor patient survival. Mechanistically, FTSJ3 catalyzes 2'-O-methylation of HSPA5 mRNA, leading to transcript stabilization and increased protein abundance of the molecular chaperone HSPA5. Elevated HSPA5 facilitates the SUMOylation and subsequent stabilization of the ribosomal biogenesis factor BOP1. This modification event activates the DRP1/SREBP1 signaling axis, driving excessive mitochondrial fission and reprogramming cellular metabolism towards fatty acid oxidation (FAO), providing essential energy and biomolecular precursors for tumor growth. Silencing of FTSJ3 disrupts this HSPA5/BOP1/DRP1 cascade, inhibiting mitochondrial fragmentation, FAO, and the proliferation, migration, and invasion of LUSC cells. In vivo, delivery of FTSJ3-specific siRNA via liposomal nanoparticles suppresses tumor growth and metastasis in LUSC models. Our findings delineate a novel FTSJ3-HSPA5-BOP1-DRP1-SREBP1 axis that integrates RNA methylation with SUMOylation, mitochondrial dynamics and lipid metabolism to promote LUSC progression, nominating FTSJ3 as a therapeutic target for this cancer.
    Keywords:  2′‐O‐methylation; BOP1; FTSJ3; SUMOylation; fatty acid oxidation; liposome delivery; lung squamous cell carcinoma
    DOI:  https://doi.org/10.1002/advs.77666
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