bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–10–11
fifty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
  2. 5-oxoETE links redox control of epithelial damage detection and resilience.
  3. A non-canonical function of glutathione to suppress ferroptosis via FSP1.
  4. Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
  5. A guide to B cell metabolism.
  6. Ultraprocessed foods evoke distinct metabolic and neural responses.
  7. Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis.
  8. Global and specific mechanisms stimulate mistranslation in cancer.
  9. Inheritance and selection of the mitochondrial genome.
  10. Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.
  11. Mapping the functional dark proteome in cancer.
  12. Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
  13. Standardizing Cell Ontology terms for cross-study integration in the female reproductive tract.
  14. 2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel.
  15. Inhibiting fructose metabolism to treat fatty liver.
  16. Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.
  17. Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function.
  18. Ribosome remodeling drives translation adaptation during viral infection and cellular stress.
  19. Coordinated nicotinamide metabolism by NAMPT and NNMT: Integrating metabolic, epigenetic and immune crosstalk.
  20. Clonal hematopoiesis and biological aging: an interaction that increases cancer risk?
  21. Trade-off between flux efficiency and metabolic control shapes enzyme allocation.
  22. The urgent challenge of gastroesophageal cancer.
  23. Spatial omics resolves adrenergic and mesenchymal cell states in neuroblastoma.
  24. Dynamics of human cardiogenesis and its disruption in trisomy 21.
  25. Genes, fuel, and fate in lung cancer.
  26. Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma.
  27. Protecting axonal mitochondria prevents chemotherapy-driven neuropathy.
  28. Metabolic enzymes moonlighting as protein kinases and phosphatases.
  29. Longer lipids mark aging and constrain lifespan.
  30. Mitochondrial dysfunction and inflammaging: a mechanistic bridge between bioenergetic failure and senescence.
  31. Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.
  32. Arginine inhibits a key innate immune signalling hub.
  33. Punctuated mutagenesis promotes multi-step evolutionary adaptation in human cancers.
  34. A signal to boost cholesterol.
  35. L-Arginine inhibits NLRP3 inflammasome activation.
  36. Getting comfortable: clonal haematopoiesis creates a senescent niche for expansion.
  37. Tracing Stem and Progenitor Cells Using Sequential Administration of Three Thymidine Analogs In Vivo.
  38. Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases.
  39. Calorie restriction reduces somatic mutation burden in mice.
  40. Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism.
  41. Mycoplasma gallisepticum uses itaconate-associated mitochondrial inhibition to suppress host immunometabolism.
  42. Transcriptomic analysis uncovers dysregulated glycosylation pathways in clear cell renal cell carcinoma.
  43. 40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay.
  44. Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer.
  45. ENOPH1 orchestrates KRASG12D/G13D-driven glycolytic reprogramming and colorectal cancer progression through modulating the TGF-β/SMAD pathway.
  46. Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.
  47. Lymph node contraction links sex-biased naive CD8+ T cell decline to compromised antigen recognition during middle age.
  48. Sodium-Glucose Cotransporter SGLT2 Supports Metabolic Fitness and Ferroptosis Resistance in CAR-T Cells to Enhance Activity Against Solid Tumors.
  49. Metabolic Structure: A Paradigm Revisited in Light of the Fundamental Parameters of Living Systems.
  50. Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
  51. The Genetic and Epigenetic Mechanisms of mtDNA in Regulation of Inflammation and Metabolism.
  52. Near-atomistic simulations reveal the molecular principles that control chromatin structure and phase separation.
  1. Science. 2026 Oct 08. 394(6820): eadx9628
    Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
    Sho Aki, Mayuko Segawa, Vincent Anton, Suvagata R Chowdhury, Shun Nagashima, Isshin Shiiba, Dane M Wolf, Ikuko Koyama-Honda, Ayumu Sugiura, Joe Ganellin, Mark Johnson, Sakie Katsumura, Maki Sugaya, Yasunori Fujita, Koki Nakamura, Kazuaki Yoshioka, Hisamichi Naito, Yoh Takuwa, Ikuroh Ohsawa, Yusuke Hirabayashi, Shigeru Yanagi, Masahiro Morita, Tsuyoshi Osawa, Julien Prudent.
      Mitochondria are dynamic organelles that remodel their shape to regulate cell fate. Mitochondrial division involves interactions with the endoplasmic reticulum (ER), lysosomes, and trans-Golgi network-derived vesicles to facilitate membrane scission. How interorganelle contacts regulate mitochondrial membrane fusion remains largely unknown. Here, we identified a role for Golgi-derived vesicles enriched in phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] in regulating mitochondrial fusion. We found that these vesicles were recruited to ER- and mitofusin-marked fusion sites. Accordingly, loss of class II PI3-kinase isoforms α and β (PI3K-C2α and PI3K-C2β), which generate PI(3,4)P2, led to mitochondrial fragmentation resulting from impaired fusion. Furthermore, cardiomyocyte-specific PI3K-C2α and PI3K-C2β double-deletion mice exhibited mitochondrial fragmentation and heart failure. Thus, subpopulations of Golgi-derived vesicles carrying different phosphoinositides control mitochondrial membrane remodeling and homeostasis.
    DOI:  https://doi.org/10.1126/science.adx9628
  2. Nature. 2026 Oct 07.
    5-oxoETE links redox control of epithelial damage detection and resilience.
    Yanan Ma, Miklós Lengyel, King Lam Hui, Yohannes A Ambaw, Zaza Gelashvili, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias C Walther, Robert V Farese, Philipp Niethammer.
      Organisms harness oxidative stress to rapidly attract white blood cells to wound sites and to kill pathogens1-3. To this end, host tissues increase their own oxidative stress resilience and repair capacity via adaptive redox signalling4-6. Here, using live zebrafish and human cells, we identify a metabolic redox signalling mechanism that integrates oxidative immune defence with tissue adaptation. We demonstrate that DHRS7, an orphan short-chain fatty acid dehydrogenase-reductase, generates or consumes the pro-inflammatory lipid 5-oxoETE as a function of cytoplasmic NADP+/NADPH ratio. At wounds, where oxidative stress and NADP+ are high, 5-oxo-eicosatetraenoic acid (5-oxoETE) production by DHRS7 rapidly alerts antimicrobial white blood cells through the G-protein-coupled receptor OXER1. In undamaged tissue, where NADP+ is low, DHRS7 quenches unnecessary inflammation. Notably, we find that 5-oxoETE also supports epithelial redox resilience; OXER1-deficient zebrafish exhibit intestinal apoptosis, barrier disruption and microbial inflammation. Mechanistically, 5-oxoETE induces the expression of NUDIX hydrolases, which protect the cytoplasmic nucleotide pool from oxidation and prevent apoptosis in zebrafish and human intestinal cells. Thus, our data reveal a conserved mode of redox sensing and signalling-beyond classic thiol oxidation-that leverages NADPH metabolism to orchestrate the antimicrobial and pro-resilience functions of oxidative stress.
    DOI:  https://doi.org/10.1038/s41586-026-11121-2
  3. Cell. 2026 Oct 06. pii: S0092-8674(26)01126-8. [Epub ahead of print]
    A non-canonical function of glutathione to suppress ferroptosis via FSP1.
    Jing Han, Yu-Dan Zhang, Shuo Liu, Li Yang, Shuang-Li Sun, Ben Zhang, Ao-Kun Liu, Ling-Fan Zhu, Rong Wang, Dan-Dan Song, Xiao Zhuang, Yi-Jia Gao, Jing-Xin Li, Wen-Fei Li, Rong-Rong He, Heng-Xing Zhou, Lu Yu, Shi-Qing Feng, Ren-Jie Chai, Bo Chu.
      It is well established that glutathione (GSH) is mainly utilized by glutathione peroxidase 4 (GPX4) to diminish peroxidized phospholipids and defend against ferroptosis. However, we found that GSH robustly protects a variety of GPX4 knockout (KO) cells from ferroptosis, thus indicating that there is an alternative pathway for GSH to suppress ferroptosis. By carrying out genome-wide CRISPR-Cas9 screening, we identified that ferroptosis suppressor protein 1 (FSP1) is the key factor mediating the GPX4-independent protective effect of GSH. Mechanistically, FSP1 uses GSH to generate reduced ubiquinone, which scavenges oxidized lipids and suppresses ferroptosis. Inhibition of FSP1 abolishes this GSH-dependent ferroptosis protection both in vitro and in vivo. Distinct from NAD(P)H-mediated ubiquinone reduction, GSH-stimulated generation of reduced ubiquinone via FSP1 is independent of flavin adenine dinucleotide (FAD). Together, our work clarifies a new mechanism of GSH-mediated ferroptosis suppression, thus highlighting the potential that targeting GSH metabolism should be beneficial for ferroptosis-related diseases whether or not it is related to GPX4.
    Keywords:  FSP1; ferroptosis; glutathione metabolism; ubiquinone reduction
    DOI:  https://doi.org/10.1016/j.cell.2026.09.024
  4. Cell. 2026 Oct 06. pii: S0092-8674(26)01122-0. [Epub ahead of print]
    Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
    Huanpeng Chen, Chao Li, Yujing Ke, Zilong Wu, Ziwei Ou, Nanqi Huang, Zhenyu Lin, Huixin Gao, Xuehu Xu, Lijuan Lu, Zhaofeng Huang, Yingjie Bian.
      Metabolic competition between tumors and T cells drives immune evasion, but the transporters and mechanisms remain largely elusive. Here, we establish the CareSLCs platform and identify that SLC52A3-mediated vitamin B2 (VB2) uptake is indispensable for T cell antitumor immunity. Mechanistically, VB2 deficiency impairs mitochondrial respiration and glutathione regeneration, leading to mitophagy, labile iron accumulation, and lipid peroxidation that trigger T cell ferroptosis. Unexpectedly, tumors preferentially employ SLC52A2, not SLC52A3, to scavenge VB2 and outcompete T cells. Tumor SLC52A2 ablation enhances T cell function in immunocompetent hosts without appreciably affecting intrinsic tumor growth. Clinically, high tumoral SLC52A2 correlates with T cell dysfunction and poor survival, whereas dietary VB2 intake is associated with reduced cancer risks. Thus, VB2 supplementation or SLC52A3 overexpression augments CAR-T cell antitumor efficacy. Our results suggest that tumoral VB2 competition establishes a metabolic checkpoint driving T cell ferroptosis and that enhancing VB2 uptake reinvigorates T cells to improve cancer immunotherapy.
    Keywords:  CAR-T cell therapy; SLC52A2; SLC52A3; ferroptosis; metabolic competition; vitamin B2
    DOI:  https://doi.org/10.1016/j.cell.2026.09.020
  5. Nat Rev Immunol. 2026 Oct 07.
    A guide to B cell metabolism.
    Yavuz F Yazicioglu, Glenn R Bantug, Christoph Hess, Alexander J Clarke.
      The metabolism of immune cells must adapt dynamically to support their diverse functions. B cells, which are the key cellular mediators of humoral immunity, undergo extensive metabolic changes throughout their development and function, starting from their commitment to the B cell lineage in the bone marrow. In the periphery, further rounds of metabolic adaptation in B cells are driven by temporally regulated changes in signalling cues, energetic demands and nutrient availability within specialized tissue niches. Although they have historically been less well studied than other immune cell types, emerging evidence shows that B cells deploy mechanistically distinct metabolic strategies that are tightly linked to their effector identity. Recognizing B cell metabolism as its own biological entity is, therefore, crucial to the study of humoral immune responses. In this Review, we examine the metabolic pathways that regulate B cell homeostasis, their integration with cell signalling networks, and their adaptation to the metabolic environment across spatial and temporal scales. We further discuss how aberrations in these pathways can contribute to B cell-driven malignancies, autoimmunity, inborn errors of immunity, and B cell-tropic infections. We position B cell metabolism as a rapidly expanding frontier within immunometabolism in both health and disease.
    DOI:  https://doi.org/10.1038/s41577-026-01355-6
  6. Nat Metab. 2026 Oct 05.
    Ultraprocessed foods evoke distinct metabolic and neural responses.
      
    DOI:  https://doi.org/10.1038/s42255-026-01618-5
  7. Cell. 2026 Oct 08. pii: S0092-8674(26)01196-7. [Epub ahead of print]
    Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis.
    William N Colgan, Luke W Koblan, JoAnne Villagrana, Tien-Chi Jason Hou, Minming Wang, Gokul Gowri, Whitney Chandler, Leonardo A Sepúlveda, Didar Ciftci, Karina Smolyar, Kathryn E Yost, Alicia Young, Lars Wittler, Styliani Markoulaki, Kyle M Loh, Xiaowei Zhuang, Nir Yosef, Zachary D Smith, Jonathan S Weissman.
      A comprehensive cell fate map of mammalian embryogenesis has remained out of reach given the scale, cellular diversity, and non-deterministic nature of development in utero. Here, we use PEtracer to continuously install heritable genetic marks as development progresses, reconstructing lineage trees that resolve ∼75% of cell divisions across >1.4 million cells from 16 replicate embryos. We pair these trees with deep transcriptional profiling to resolve cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships throughout embryogenesis. Using this quantitative reference, we uncover strikingly reproducible lineage architecture between replicate embryos and chart the lineage dynamics driving fate specification across diverse tissues. Specific biological insights include the progressive restriction of neural crest fate, the relative contributions of distinct mesodermal origins to endothelium, and the dynamics of axial elongation. This work provides a foundation for a quantitative and predictive understanding of mammalian development.
    Keywords:  PEtracer; cell fate specification; lineage tracing; mouse embryogenesis; scRNA-seq; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2026.09.050
  8. Nat Cell Biol. 2026 Oct 05.
    Global and specific mechanisms stimulate mistranslation in cancer.
    Demi Wernaart, Amos Fumagalli, Mrittika Adhikary, Xiaodong Feng, Olaf Geintzer, Edwin S Kyei-Baffour, Onno B Bleijerveld, Liesbeth Hoekman, Ceri Zwart, Alexander Fish, Lisanne Giebel, Artur Burylo, Natalie Proost, Pierre-René Körner, Ferhat Alkan, Chao Yang, Janne Brouwer, Cecilia Anna Henriksen, Eric Westhof, Julien Champagne, Olaf van Tellingen, Marina Rodnina, Reuven Agami.
      Tryptophan codon-specific mistranslation, in the form of ribosomal frameshifting and tryptophan-to-phenylalanine (W > F) codon reassignments (substitutants), is induced in cancer cells by the limiting level of tryptophan imposed by anti-tumour immunity. While the oncogenic mitogen-activated protein kinase pathway drives frameshifting, whether substitutants are genetically regulated remains unknown. Here we screened for genes that control W > F substitutants following interferon-γ-mediated tryptophan shortage. This screen identified ADAR1, an enzyme that converts adenosine to inosine in double-stranded RNA molecules, and FTSJ1, an enzyme that 2'-O-methylates the anticodon region of several tRNAs. We demonstrate that ADAR1 sustains expression of key players in the ribosome quality control pathway, which in turn is essential for mistranslation events. FTSJ1, in contrast, specifically drives W > F mistranslation by methylation of tRNATrp to promote its binding to WARS1 loaded with phenylalanine instead of tryptophan. As ADAR1 and FTSJ1 levels are elevated in many cancer types, we propose that cancer cells deploy global and specific mechanisms to promote mistranslation in response to anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s41556-026-02088-3
  9. Nat Rev Genet. 2026 Oct 05.
    Inheritance and selection of the mitochondrial genome.
    Qin Xie, Harry E Walker, Michal Minczuk, Marcos R Chiaratti, Patrick F Chinnery.
      The functioning mitochondrial genome is essential for cellular energy production. Being strictly maternally inherited and possessing limited DNA repair capacity, mitochondrial DNA (mtDNA) replication errors tend to accumulate over time. If left unchecked, these errors can accumulate through the female germline over successive generations, potentially leading to species extinction. However, this outcome is not observed in most species, including humans, which implies the existence of mechanisms that counteract the progressive accumulation of deleterious mtDNA mutations. Recent technological advances are building a deeper understanding of the processes that preserve mtDNA integrity, including the molecular and cellular basis and timing of purifying selection. This new knowledge helps to explain how mtDNA can change rapidly over just a few generations, whilst remaining compatible with the independently inherited, evolving nuclear genome.
    DOI:  https://doi.org/10.1038/s41576-026-01019-0
  10. Cell Rep. 2026 Oct 06. pii: S2211-1247(26)01168-X. [Epub ahead of print]45(10): 118089
    Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.
    Suchandrima Saha, Fabiola N Velazquez, Fatemeh Dehpanah, Brianna L Bergfalk, Samantha Mulkeen, Karissa J Lopez, Cungui Mao, David C Montrose.
      Deoxysphingolipids (deoxySLs) are a class of non-canonical sphingolipids that can adversely impact mitochondrial function. Mitochondrial DNA release resulting from mitochondrial disruption can activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, and in turn, promote antitumor immunity. Here, we investigated whether inducing deoxySL accumulation in colon cancer cells drives immune-specific, antitumor effects. We show that depleting serine increased deoxySLs and enhanced immune cell infiltration in colon tumors, in parallel with suppressing tumor growth. Elevating tumor deoxySL levels in mice through mutation of serine palmitoyltransferase and feeding a high alanine diet exerted similar effects, including immune-mediated tumor growth suppression. Work conducted in multiple in vitro systems identified deoxySLs as key triggers of cGAS-STING activation, an effect mediated by the release of mitochondrial DNA under mitochondrial stress. Collectively, these findings demonstrate that deoxySLs drive antitumor immunity and identify a previously unrecognized metabolic strategy for cancer therapy.
    Keywords:  CP: cancer; CP: metabolism; amino acids; chemokines; colorectal cancer; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2026.118089
  11. Nat Rev Cancer. 2026 Oct 08.
    Mapping the functional dark proteome in cancer.
    John R Prensner, William A Freed-Pastor, Jennifer G Abelin, Catherine J Wu, Yifat Merbl, Yitzhak Pilpel, Ton N Schumacher, Jonathan S Weissman, Sebastiaan van Heesch, Reuven Agami.
      A generation after the genomics revolution, and with the advent of proteomic technologies, the dark proteome now stands as a potential new direction for cancer science and therapeutics. The dark proteome covers a vast terrain of previously undiscovered and uncharacterized protein molecules derived from alternative genomic loci or altered RNA translation. Over the past decade, an unprecedented depth of resolution of the dark proteome has been attained, identifying diverse classes of dark proteins with thousands of members each. Increasingly, individual dark proteins are also being characterized as functional components of cancer cell biology as well as potential therapeutic targets. Therefore, as a whole, the dark proteome offers the possibility to advance cancer science, diagnosis and treatment. Yet, many fundamental questions about the dark proteome remain, including key gaps in knowledge regarding its regulation, contribution to cancer phenotypes and antigenicity, and tractability for clinical-grade therapies. This Perspective outlines the current state of knowledge of the dark proteome in cancer, highlighting critical areas in which further research is needed. Furthermore, it poses guiding questions that illuminate important directions of growth for the field of the cancer dark proteome.
    DOI:  https://doi.org/10.1038/s41568-026-00985-1
  12. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2617216123
    Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
    Alexandra Bermudez, Zoe Latham, Johnny Diaz, Weihong Yan, Jerry Chen, Dapeng Bi, Andrew S Goldstein, Jimmy K Hu, Neil Y C Lin.
      Epithelial tissues undergo dynamic transitions between fluid-like collective motion and mechanically jammed states during development, injury repair, and disease progression. However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multiomics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition. Restricting mitochondrial pyruvate import increased collective cell motility and delayed jamming in crowded monolayers. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility. These findings identify mitochondrial pyruvate utilization as an important regulatory input linking metabolic remodeling to the endocytic control of epithelial fluidity.
    Keywords:  collective cell migration; epithelial jamming transition; mechanobiology
    DOI:  https://doi.org/10.1073/pnas.2617216123
  13. Sci Adv. 2026 Oct 09. 12(41): eaef2358
    Standardizing Cell Ontology terms for cross-study integration in the female reproductive tract.
    Huan Ting Ong, Diane C Saunders, Caroline Eastwood, Aleix Puig-Barbe, Alison Kochersberger, Anna Galligos, Bailey Marshall, Benjamin K Johnson, Caroline E Kratka, Chen Jin, Daniela Betancur, Gabriela Rapozo Guimarães, Jordan H Machlin, Jose V V Isola, Katelyn M Adam, Osmaray Morales-Casanova, Svetlana Djirackor, Taylor Schissel, Valentina Lorenzi, Xifan Wang, Xingyu Shen, Bikem Soygur, Brian Aevermann, Eliza A Gaylord, Mariko H Foecke, Norbert K Tavares, Ryan M Samuel, Sophia Szady, Srinivasan Mahalingam, Subhasri Biswas, Will Liao, Bérénice A Benayoun, Hattie Chung, Wipawee Winuthayanon, Jun Z Li, Matteo A Molè, Michael Angelo, Patricia Jeudin, Ronny Drapkin, Ariella Shikanov, Diana J Laird, Francesca Duncan, Hui Shen, Jennifer L Garrison, Mariana Boroni, Michael B Stout, Roser Vento-Tormo, Sophia H L George, Yousin Suh, Jennifer L Young, Monica M Laronda.
      The female reproductive tract is essential for fertility, pregnancy, and overall health, yet many of its cellular components remain poorly defined. Recent advances in single-cell and spatial transcriptomics have begun to reveal this complexity, but inconsistent naming of cell types and states has limited the ability to compare findings across studies. To address this challenge, an international group of reproductive biologists and ontology experts collaborated to harmonize annotations within Cell Ontology, focusing on the ovary, fallopian tube, and uterus. Standardized terms are proposed for major epithelial, stromal, and germ cell populations, supported by marker gene sets and anatomical linkages. This framework provides a shared reference that can be used to harmonize existing datasets and guide annotation of future studies, enabling consistent classification of oocytes, granulosa, theca, luteal, epithelial, stromal, and immune cells across tissues. By establishing a unified taxonomy, this work lays the foundation for integrating datasets, supporting cross-tissue comparisons, and advancing the understanding of reproductive biology, health, and disease.
    DOI:  https://doi.org/10.1126/sciadv.aef2358
  14. bioRxiv. 2026 Aug 13. pii: 2026.08.12.744465. [Epub ahead of print]
    2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel.
    Niv Vigder, Amit Chandra, Nishith Shrimali, Sergey Tumanov, Vlad Elgart, Huamei He, Ryan Mulhern, Ram P Chakrabarty, Navdeep S Chandel, Stuart Cordwell, Steven P Gygi, João A Paulo, Joseph Loscalzo.
      The role of 2-hydroxyglutarate in lipid metabolism is currently unknown. Here we show that 2HG redistributes the partitioning of fatty acids into triglyceride storage and away from membrane phospholipid synthesis, mitochondrial oxidation, and lipotoxic intermediates. In primary human cardiac and vascular cells, both enantiomers, D2HG and L2HG, expanded triglyceride stores and lipid droplets while selectively depleting phosphatidylethanolamine, with L2HG acting more potently than D2HG despite lower intracellular accumulation. Mechanistically, L2HG increases DGAT-dependent triglyceride synthesis, slows triglyceride turnover, and constrains the ethanolamine branch of the Kennedy pathway. This response limits fatty acid oxidation, long-chain acylcarnitine accumulation, and lipid peroxidation independently of pseudohypoxic transcription or canonical lipid storage regulators, while also remodeling the phosphoproteome and redox proteome. L2HG accumulation induces hypertriglyceridemia in mice, redistributes the acyl chain composition of cardiac triglycerides, and limits ischemia-induced acylcarnitine accumulation in the heart, mirroring a positive association between circulating 2HG and triglycerides in humans. Thus, 2HG expands metabolic flexibility from whether fatty acids are used as fuel to how that fuel is allocated among storage, membrane synthesis, and oxidation.
    DOI:  https://doi.org/10.64898/2026.08.12.744465
  15. Nat Metab. 2026 Oct 07.
    Inhibiting fructose metabolism to treat fatty liver.
    Richard J Johnson, Miguel A Lanaspa, Dean R Tolan.
      
    DOI:  https://doi.org/10.1038/s42255-026-01627-4
  16. PLoS Genet. 2026 Oct 08. 22(10): e1012330
    Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.
    Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.
      Chromatin is dynamically regulated in response to nutrient flux to promote the transcriptional changes needed for adaptation. The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation.
    DOI:  https://doi.org/10.1371/journal.pgen.1012330
  17. J Biol Chem. 2026 Oct 09. pii: S0021-9258(26)02502-0. [Epub ahead of print] 113630
    Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function.
    Maryam Jamil, Anna Kovilakath, Yolander Valentine, Saaid Farooq, David Montefusco, Yang Yue, Gisela Beutner, Qun Chen, Jeremy Thompson, Komuraiah Myakala, Xiaoxin Wang, Christiane Carter, Jinze Liu, Arjun Rijal, Charles E Lyons, Devanand Sarkar, Moshe Levi, George A Porter, Sushil Mahata, Tytus Bernas, Edward J Lesnefsky, L Ashley Cowart.
      Sphingolipids constitute essential membrane lipids that also function as signaling molecules mediating fundamental cellular processes. Disruption of constitutive sphingolipid metabolism contributes to a range of metabolic diseases. Sphingolipid biosynthesis is initiated by serine palmitoyltransferase (SPT), a heteromeric enzyme composed of Sptlc1 and either Sptlc2 or the less-characterized subunit Sptlc3. While the canonical Sptlc1/Sptlc2 complex generates most sphingolipids, Sptlc1/Sptlc3 produces non-canonical sphingolipids that remain poorly understood. Sptlc3 expression increases in liver disease in both mouse models and humans, yet its biological role remains unclear. To address this, we generated a liver-specific SPTLC3 knockout (SPT3-hKO) mouse model. Loss of SPTLC3 resulted in severe mitochondrial dysfunction in hepatocytes, characterized by reduced oxygen consumption, decreased ATP production, and elevated NADH/NAD+ ratios with a concomitant increase in glycolytic activity. Mechanistically, we found a defect in the electron transport chain (ETC) which stemmed not from intrinsic impairment of the ETC complexes but rather from hindered electron flow between complex I and complex III likely due to reduced availability of Coenzyme Q. While atypical ceramides constituted (∼4% of total ceramides) when measured in liver homogenates, there measurements in mitochondria-enriched fractions revealed enrichment in this cell compartment. Together, our findings identify SPTLC3 as a critical modulator of mitochondrial ceramide composition and ETC function, revealing a specialized role for non-canonical sphingolipids in hepatocyte energy metabolism.
    Keywords:  Ceramides; Complex I; ETC; Hepatocytes; SPTLC3
    DOI:  https://doi.org/10.1016/j.jbc.2026.113630
  18. Mol Cell. 2026 Oct 07. pii: S1097-2765(26)00629-5. [Epub ahead of print]
    Ribosome remodeling drives translation adaptation during viral infection and cellular stress.
    Hsin-Yu Tsai, Luochen Liu, Rebecca H Fleming, Julian Mintseris, Derrick Ekanayake, Jing A Guo, Xin Gu, Steven P Gygi, Amy S Y Lee.
      The ribosome is the highly conserved molecular machine that decodes mRNAs during protein synthesis. Here, we discover that, while traditionally thought to consist of a uniform set of proteins, ribosome composition is reprogrammed to adapt to intrinsic and external cellular perturbations. During infection of human cells by non-segmented negative-sense viruses, viral entry into cells recruits the large ribosomal subunit protein rpL40 to a non-canonical site on the small subunit of 80S ribosomes near the mRNA entry site. These specialized ribosomes preferentially bind viral mRNAs to drive enhanced viral protein synthesis that is critical for replication under host pressures. Unexpectedly, we find that viruses have co-opted this translation pathway from a previously unrecognized endogenous ribosome remodeling program in which metabolic stress alters ribosome structure to promote mRNA translation required for cell survival. Thus, ribosome remodeling is a conserved mechanism that enables dynamic protein synthesis across pathogen and cellular adaptation.
    Keywords:  cell stress; ribosome; ribosome heterogeneity; rpL40; translation regulation; virus
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.008
  19. Cancer Lett. 2026 Oct 07. pii: S0304-3835(26)00639-7. [Epub ahead of print]661 218875
    Coordinated nicotinamide metabolism by NAMPT and NNMT: Integrating metabolic, epigenetic and immune crosstalk.
    Irene Fiorilla, Beatrice Ghezzi, Agata Carreira, Andrea Mantovan, Alessia Ponzano, Filippo Casone, Giulia Rizza, Valentina Audrito.
      Cancer cells adapt to microenvironmental cues through the coordinated integration of metabolic reprogramming, epigenetic remodeling, and immune regulation. An emerging central regulator of this adaptive network is coordinated nicotinamide metabolism, which controls both nicotinamide adenine dinucleotide (NAD) biosynthesis and cellular methylation potential. Within this network, the nicotinamide-metabolizing enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide N-methyltransferase (NNMT) govern the metabolic fate of nicotinamide (NAM), thereby coupling energy metabolism to epigenetic regulation and adaptive cellular responses. NAMPT, the rate-limiting enzyme of the NAD salvage pathway, sustains intracellular NAD pools required for redox homeostasis, mitochondrial function, DNA repair, and stress responses. Conversely, NNMT diverts NAM from NAD biosynthesis by catalyzing its methylation while consuming S-adenosylmethionine (SAM), thereby creating a methylation sink that remodels chromatin organization and promotes transcriptional plasticity. Beyond intracellular metabolism, coordinated nicotinamide metabolism extends to the tumor microenvironment through extracellular mediators, including extracellular NAMPT (eNAMPT), the emerging extracellular functions of NNMT (eNNMT) and its metabolite 1-methylnicotinamide (1-MNA), which regulate stromal remodeling, immune cell function, chronic inflammation, and immune evasion. Collectively, these complementary intracellular and extracellular activities establish a multilevel adaptive network that integrates metabolic homeostasis, epigenetic remodeling, and immunometabolic communication, thereby promoting tumor plasticity, therapeutic adaptation, and resistance. Here, we propose a conceptual framework in which NAMPT and NNMT function as complementary regulators of coordinated nicotinamide metabolism operating across interconnected intracellular and extracellular levels. By integrating metabolic, epigenetic, and immune crosstalk into a unified model of tumor adaptation, this perspective provides new insights into tumor progression and therapy resistance while highlighting context-dependent opportunities for mechanism-based combination therapies in cancer.
    Keywords:  Drug resistance; Epigenetics; Immune crosstalk; Metabolism; Microenvironment; NAD; NAMPT; NNMT
    DOI:  https://doi.org/10.1016/j.canlet.2026.218875
  20. J Natl Cancer Inst. 2026 Oct 03. pii: djag309. [Epub ahead of print]
    Clonal hematopoiesis and biological aging: an interaction that increases cancer risk?
    Jake Tobin, George S Vassiliou.
      
    DOI:  https://doi.org/10.1093/jnci/djag309
  21. Mol Syst Biol. 2026 Oct 04.
    Trade-off between flux efficiency and metabolic control shapes enzyme allocation.
    Kai Sun, Weiyan Zheng, Wenchao Fan, Chuyun Ding, Dan Huang, Ziwei Dai.
      Efficient use of limited cellular resources is fundamental to metabolism. Although flux optimization is widely recognized as a central objective of metabolic networks, how flux efficiency influences the allocation of the metabolic proteome remains unclear and lacks direct validation. Here, we derive a simple analytical relationship linking the equilibrium constant (K) and the catalytic-abundance quotient (CAQ) of reactions within a pathway that defines the condition for maximal efficiency. By integrating reaction thermodynamics, enzyme kinetics, transcriptomic, and proteomic data, we compared enzyme allocation in glycolysis and the TCA cycle with this K-CAQ relationship across evolutionarily distant species, and showed that deviation from it can be explained by a trade-off between maximizing flux efficiency and concentrating flux control. Moreover, the drive to optimize glycolytic efficiency is strengthened under oncogenic signaling and a limited cellular budget for glycolytic enzymes. These findings establish a principle of Pareto optimality governing enzyme allocation in metabolic pathways and reveal key determinants of efficiency optimality in glycolysis.
    DOI:  https://doi.org/10.1038/s44320-026-00250-5
  22. Nat Rev Cancer. 2026 Oct 09.
    The urgent challenge of gastroesophageal cancer.
    Charles Swanton, Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Sandra Ryeom, David Scott.
      
    DOI:  https://doi.org/10.1038/s41568-026-00990-4
  23. Cancer Cell. 2026 Oct 08. pii: S1535-6108(26)00427-7. [Epub ahead of print]
    Spatial omics resolves adrenergic and mesenchymal cell states in neuroblastoma.
    Anand G Patel, Orr Ashenberg, Natalie B Collins, Justina McEvoy, Melody Allensworth-James, Felipe Segato Dezem, Samantha Turk, Natalie Geiger, Arjumand Wani, Luke Zhang, Åsa Segerstolpe, Sizun Jiang, Cody Ramirez, Michal Slyper, Xin Huang, Chiara Caraccio, Hongjian Jin, Heather Sheppard, Meifen Lu, Ke Xu, Ti-Cheng Chang, Brent A Orr, Selene Koo, Abbas Shirinifard, Chia-Wei Hsu, Richard H Chapple, Amber Shen, Michael R Clay, Ruth G Tatevossian, Colleen Reilly, Jaimin Patel, Marybeth Lupo, Cynthia Cline, Danielle Dionne, Caroline B M Porter, Julia Waldman, Yunhao Bai, Bokai Zhu, Irving Barrera, Evan Murray, Sébastien Vigneau, Sara Napolitano, Isaac Wakiro, Jingyi Wu, Grace Grimaldi, Laura Dellostritto, Karla Helvie, Asaf Rotem, Ana Lako, Nicole Cullen, Kathleen L Pfaff, Åsa Karlström, Judit Jané-Valbuena, Ellen Todres, Aaron Thorner, Paul Geeleher, Scott J Rodig, Xin Zhou, Bruce E Johnson, Gang Wu, Fei Chen, Jiyang Yu, Yury Goltsev, Jasmine Plummer, Garry P Nolan, Orit Rozenblatt-Rosen, Haitao Pan, Aviv Regev, Elizabeth Stewart, Michael A Dyer.
      Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage. Although cell lines derived from neuroblastoma patients have features of either adrenergic (ADRN) or mesenchymal (MES) cells, identifying MES cells in patient tumors is challenging and controversial. Here, to characterize intra- and inter-patient cellular heterogeneity, we analyze 54 neuroblastoma tumors spanning broad clinical, genetic, and histologic features using single-cell/single-nucleus RNA sequencing (sc/snRNA-seq), bulk RNA sequencing, spatial transcriptomics, and spatial proteomics. We show that tumor cells occupy distinct cellular neighborhoods separated from nonmalignant immune and stromal cells, yet established cell line-derived gene expression signatures fail to identify MES neuroblastoma cells. We therefore develop ADRN/MES signatures from early-passage orthotopic patient-derived xenografts, enabling the identification of MES tumor cells, validated by transcriptomic, epigenomic, proteomic, ultrastructural, and functional assays. In patients, high MES gene expression correlates with worse event-free and overall survival. Together, this study provides a framework for defining clinically relevant neuroblastoma cell states.
    Keywords:  adrenergic and mesenchymal cell states; cancer cell state; chemoresistance; clinical response; neuroblastoma; patient-derived xenograft; spatial proteomics; spatial transcriptomics; sympathoadrenal lineage; tumor cell heterogeneity
    DOI:  https://doi.org/10.1016/j.ccell.2026.09.008
  24. Nature. 2026 Oct 07.
    Dynamics of human cardiogenesis and its disruption in trisomy 21.
    James Cranley, Kazumasa Kanemaru, Semih Bayraktar, Vincent Knight-Schrijver, Rebecca Hulbert, Eva Lana-Elola, Rifdat Aoidi, Jan Patrick Pett, Anna Wilbrey-Clark, Krzysztof Polanski, Monika Dabrowska, Ilaria Mulas, Harriet Johnson, Noemie Combemorel, Yizhou Yu, Jack A Palmer, Woochan Lee, Jore Van Wauwe, John-Poul Ng-Blichfeldt, Laura Richardson, Claudia I Semprich, Rakeshlal Kapuge, Shani Perera, Xiaoling He, Siew Yen Ho, Nadav Yayon, Liz Tuck, Kenny Roberts, Hongorzul Davaapil, Laure Gambardella, Anna Philpott, Minal Patel, Richard C V Tyser, Andreia Sofia Bernardo, Victor L J Tybulewicz, Sanjay Sinha, Sarah A Teichmann.
      Developmental dynamics involve the specification of diverse cell types and their spatial organization into multicellular niches1. Here we combine single-cell and spatial multiomics to define 21 distinct tissue niches in the developing heart, which we use to develop a context-aware, resolution-agnostic niche classification tool (TissueTypist). Applying high-resolution spatial profiling to the developing sinoatrial node, we resolve three pacemaker cell subtypes arrayed along a linear axis. First trimester subpopulations, such as pacemaker cells in the sinus horn and sinoatrial node head region, display neuroattractant programs and interact with parasympathetic neurons via interactions that include Eph-ephrin and semaphorin-plexin signalling. Temporal trajectories map the maturation of atrial and ventricular cardiomyocytes and uncover a lipid-metabolic switch and potential key regulators of cell-type identity. In the ventricle, we identify cellular and transcriptional gradients along both pseudotime and transmural axes, which provide molecular insights into myocardial compaction and maturation. Comparative profiling revealed that hearts with trisomy 21 are depleted in compact cardiomyocytes and exhibit increased apoptosis relative to euploid hearts. This finding was validated in isogenic-matched trisomy 21 and euploid cardiomyocytes derived from induced pluripotent stem cells. These early developmental perturbations may contribute to the increased risk of congenital heart disease associated with Down's syndrome. In summary, we present a spatially resolved framework of human cardiac development to enable systematic explorations of developmental niches in health and disease.
    DOI:  https://doi.org/10.1038/s41586-026-11125-y
  25. Biochem Soc Trans. 2026 Oct 28. 54(10): 1419-1430
    Genes, fuel, and fate in lung cancer.
    Julia S Scott, Catrin Lutz, Stefan Prekovic.
      Cellular plasticity is a central feature of malignant progression, allowing tumour cells to change identity during tumour evolution, therapeutic adaptation, and metastatic dissemination. This issue is especially acute in lung cancer, where the respiratory epithelium is intrinsically permissive to cell-state change. Genetic lesions, chromatin regulation, and metabolic adaptation are often framed as parallel determinants of lineage plasticity. Emerging evidence instead points to functional coupling across these layers. Oncogenic alterations can weaken lineage fidelity and open alternative trajectories, chromatin regulators can stabilise transitional states and enforce new transcriptional programmes, and metabolic rewiring can supply the biochemical conditions required for these states to emerge and persist. Microenvironmental cues further influence which trajectories are selected and maintained. Here, we discuss the genetic, epigenetic, and metabolic determinants of lineage plasticity in lung cancer, focusing on the points at which they intersect. We propose that plasticity is most usefully understood as a coupled regulatory state, arising from the interaction between oncogenic context, chromatin control, and metabolic support. Defining how these dependencies arise and become functionally coupled within high-plasticity transitional states should help identify points at which lineage switching can be intercepted before alternative lineage programmes are stabilised.
    Keywords:  cell fate; epigenetics; metabolism; mutation
    DOI:  https://doi.org/10.1042/BST20250546
  26. J Clin Invest. 2026 Oct 06. pii: e204613. [Epub ahead of print]
    Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma.
    Katrine N Madsen, Soki Kashima, Hanna Soulati, Lena Wirth, Katsuhiro Ito, Zachary A Yochum, Vivien Moritz, Julia Walker, Marc Machaalani, Fady Ghali, Patrick Kenney, Adebowale Adeniran, Michael Hurwitz, Toni K Choueiri, David A Braun.
      Hypoxia-inducible factor 2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC) and a therapeutic target of the small-molecule inhibitor belzutifan. Genetic studies in murine models have suggested that hypoxia signaling may support T cell effector programs, raising concern that HIF-2α inhibition could impair antitumor immunity. However, whether pharmacologic HIF-2α inhibition alters human T cell biology remains unknown. Here, we investigated the cell-intrinsic effects of EPAS1 (encoding HIF-2α) perturbation in primary human T cells. CRISPR/Cas9-mediated deletion of HIF-2α demonstrated no notable transcriptional effects. Similarly, pharmacologic treatment with belzutifan produced minimal transcriptional changes and did not impair proliferation, cytokine production, polyfunctionality, or cytotoxic activity in T cells derived from healthy donor peripheral blood, peripheral blood from patients with ccRCC, or tumor-infiltrating lymphocytes under hypoxic conditions. High- dimensional immunophenotyping revealed preserved T cell differentiation and activation states following pharmacologic HIF-2α inhibition in vitro and in peripheral blood from patients receiving HIF-2α inhibitor therapy. Together, these findings demonstrate that pharmacologic HIF-2α inhibition preserves key effector programs, providing a mechanistic basis for the immunologic safety of HIF-2α-targeted therapy in ccRCC.
    Keywords:  Cancer; Hypoxia; Immunology; Oncology; T cells
    DOI:  https://doi.org/10.1172/JCI204613
  27. Trends Cancer. 2026 Oct 08. pii: S2405-8033(26)00216-5. [Epub ahead of print]
    Protecting axonal mitochondria prevents chemotherapy-driven neuropathy.
    Lorenzo Galluzzi, Jorge Gómez-Deza.
      Peripheral neuropathy is a poorly understood yet extraordinarily relevant obstacle to the effective implementation of cytotoxic chemotherapy in patients with cancer. Recent findings from Heles et al. demonstrate that safe neuroactive molecules that promote mitochondrial fitness in axons effectively prevent peripheral neuropathy in preclinical tumor models, thereby supporting clinical translation.
    Keywords:  5-HT(2A); ATP synthesis; mitophagy; neuroprotection; psilocybin; psychedelics
    DOI:  https://doi.org/10.1016/j.trecan.2026.09.005
  28. Trends Biochem Sci. 2026 Oct 09. pii: S0968-0004(26)00284-7. [Epub ahead of print]
    Metabolic enzymes moonlighting as protein kinases and phosphatases.
    Min Li, Guijun Liu, Li Yuan, Zhimin Lu.
      Protein phosphorylation is a central and reversible mechanism regulating virtually all cellular processes and is classically mediated by the canonical protein kinome and phosphatome. However, beyond their traditional roles as metabolic catalysts, a subset of metabolic enzymes also exhibits noncanonical 'moonlighting' activities as protein kinases or phosphatases, directly linking metabolic states to phosphorylation-dependent signaling. These unexpected functions of enzymes involved in glucose, fructose, lipid, nucleotide, and creatine metabolism influence a broad spectrum of cellular processes, including chromatin remodeling, transcription, cell cycle progression, metabolism, autophagy, cell survival and death, and immune responses. As a result, metabolic enzymes are increasingly recognized as key regulators that bridge cellular metabolism and signaling networks, with important implications for both normal physiology and disease.
    Keywords:  cancer; creatine metabolism; fructose metabolism; glycolysis; lipid metabolism; nucleotide metabolism
    DOI:  https://doi.org/10.1016/j.tibs.2026.09.006
  29. Nat Aging. 2026 Oct 06.
    Longer lipids mark aging and constrain lifespan.
    Weisha Li, Bauke V Schomakers, Maria M Trętowicz, Laura Hartshorne, Jonathan Sulc, Helgi I Ingólfsson, Tugba N Ozturk, Rob Ofman, Luc Legon, Kasandra Ippel, Michel van Weeghel, Martin A T Vervaart, Eric J M Wever, Simone W Denis, Signe Mosegaard, Adriana S Passadouro, Arwen W Gao, Hans R Waterham, Joris Hoeks, Patrick Schrauwen, Gajja S Salomons, Evan G Wiliams, Paul M L Janssen, Vincent A J Warnaar, Linda Partridge, Johan Auwerx, Sebastian Grönke, Mirre J P Simons, Jolanda van der Velden, Frédéric M Vaz, Riekelt H Houtkooper, Georges E Janssens.
      Aging drives molecular changes that impair cellular and tissue function. Lipids are central to membrane structure, signaling and energy storage, yet their remodeling during aging remains unclear. Here, using cross-species, multi-tissue lipidomics, we identify elongation of lipid acyl chains as a conserved hallmark of aging across mice, Caenorhabditis elegans, Drosophila and humans. Similar lengthening occurs during the progression of human heart disease, whereas dietary restriction shortens cardiac lipids in mice. Integrated analyses reveal that aging is characterized by a shift toward longer lipids accompanied by depletion of shorter species, indicating ratiometric remodeling. Following this, we identify the lipid remodeler Plb1 as a regulator of this process, with expression correlating with lifespan in mice and genetic analyses supporting a causal role in human frailty. In C. elegans, Plb1 knockdown reverses lipid elongation and extends lifespan in a lipid-length-dependent manner. Together, these findings establish lipid chain length remodeling as a conserved, actionable hallmark of aging.
    DOI:  https://doi.org/10.1038/s43587-026-01223-x
  30. Geroscience. 2026 Oct 09.
    Mitochondrial dysfunction and inflammaging: a mechanistic bridge between bioenergetic failure and senescence.
    Salvatore Nesci, Cristina Algieri.
      Ageing is characterized by a progressive decline in mitochondrial integrity that extends beyond impaired energy production to include redox imbalance, defective quality control, altered organelle dynamics, and persistent inflammatory signalling. This review examines mitochondrial dysfunction as a mechanistic bridge linking bioenergetic failure to cellular senescence and inflammaging, two central features of biological ageing. We discuss how impaired oxidative phosphorylation, loss of mitochondrial membrane potential, increased electron leak, and excessive reactive oxygen species progressively damage mitochondrial DNA, proteins, and lipids, thereby amplifying organelle dysfunction and compromising cellular homeostasis. Particular emphasis is placed on the threshold effect of mitochondrial DNA mutations, whose age-dependent clonal expansion can drive respiratory chain deficiency in vulnerable tissues. We further analyze mitochondria as signalling platforms that integrate regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, and as sources of mitochondrial damage-associated molecular patterns promoting sterile inflammation. Finally, we highlight mitochondrial dysfunction-associated senescence as a central process through which persistent mitochondrial stress reshapes the senescence-associated secretory phenotype and reinforces inflammaging. Overall, the evidence supports a model in which dysfunctional mitochondria act as both initiators and amplifiers of senescence and inflammation, contributing to tissue degeneration and age-related functional decline. Understanding these interconnected mechanisms may help identify therapeutic strategies targeting mitochondrial bioenergetics, inflammatory signalling, and senescent cell burden in ageing.
    Keywords:  Ageing; Cell death; DAMPs; Inflammation; Mitochondria
    DOI:  https://doi.org/10.1007/s11357-026-02588-y
  31. bioRxiv. 2026 Aug 13. pii: 2026.08.12.744280. [Epub ahead of print]
    Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) compromise ETC activity and impair oxidative phosphorylation. Since eukaryotic cells contain multiple copies of mtDNA, the resulting phenotype depends on the proportion of mutant mitochondrial genomes (the heteroplasmy level). Using isogenic cell lines carrying similar mtDNA deletions, a linear decline in cellular respiration was observed as mitochondrial DNA heteroplasmy increased. Despite this, cellular redox imbalance did not change until heteroplasmy exceeded 50%. As heteroplasmy increased past 70%, cells also exhibited an integrated stress response (ISR) and impaired translation was observed. These defects were reversed by either addition of asparagine or overexpression of pyruvate carboxylase (PC). The dependence on exogenous asparagine in other respiration-deficient cells was found to correlate inversely with the PC expression level. For example, patient-derived thyroid tumor cells, harboring high heteroplasmy for a Complex I mtDNA mutation and low levels of PC, exhibited asparagine auxotrophy, and L-asparaginase treatment suppressed tumor growth. Together, these findings demonstrate a role for mitochondrial pyruvate carboxylase in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.64898/2026.08.12.744280
  32. Nat Metab. 2026 Oct 06.
    Arginine inhibits a key innate immune signalling hub.
    Quang Nang Truong, Alex R Trainor, Jay Penney.
      
    DOI:  https://doi.org/10.1038/s42255-026-01638-1
  33. Elife. 2026 Oct 09. pii: RP108058. [Epub ahead of print]14
    Punctuated mutagenesis promotes multi-step evolutionary adaptation in human cancers.
    Christopher J Graser, Wenbo Wu, Cole Christini, Mia Peljak, Franziska Michor.
      The rate of acquisition of genomic changes in cancer has been the topic of much discussion, with several recent investigations finding evidence of punctuated evolution instead of gradual accumulation of such changes. Despite forays into the description and quantification of these punctuated events, the effects of such changes on subsequent cancer evolution remain incompletely understood. Here we investigate how non-gradual mutagenesis affects the ability of tumor cells to acquire and retain fitness-enhancing adaptations. We find that punctuated mutagenesis significantly facilitates adaptation in scenarios where adaptation requires crossing a fitness valley, that is when multiple mutations are required which individually are maladaptive but jointly confer a fitness advantage. By increasing the probability that multiple mutations occur in close succession, punctuation increases the chance that mutants in a fitness valley mutate further to reach a fitness peak before going extinct. Analyzing data from The Cancer Genome Atlas, we find that tumors with signatures of APOBEC mutagenesis, which has been shown to proceed in episodic bursts, exhibit patterns consistent with higher rates of crossing fitness valleys. Lastly, we characterize how the interplay between this enhanced ability to cross fitness valleys and adaptation-limiting effects of clonal interference affects overall adaptability in complex fitness landscapes.
    Keywords:  APOBEC; adaptation; cancer; cancer biology; evolutionary biology; human; punctuated evolution; punctuated mutagenesis; valley crossing
    DOI:  https://doi.org/10.7554/eLife.108058
  34. Nat Cell Biol. 2026 Oct 09.
    A signal to boost cholesterol.
    Melina Casadio.
      
    DOI:  https://doi.org/10.1038/s41556-026-02084-7
  35. Nat Metab. 2026 Oct 06.
    L-Arginine inhibits NLRP3 inflammasome activation.
    Feng Liu, Wanxin Zhuang, Yuan Yang, Wenting Zhao, Chao Zhang, Siyuan Li, Xudong Liu, Qingyuan Cao, Shunguo Zhu, Bingyu Liu, Xiangyu Ma, Lintai Da, Chengjiang Gao.
      Nutritional status and metabolic homeostasis are intricately associated with the inflammatory response. However, the direct mechanistic link between nutrition, metabolism and inflammation remains unclear. Here, we show that the amino acid L-arginine (L-Arg) is a potent endogenous inhibitor of the NLRP3 inflammasome, a central component of the inflammatory signalling pathway. We show that L-Arg binds directly to the Asp31 site of the NLRP3 protein, blocking its interaction with the adaptor ASC and subsequent inflammasome assembly and activation. L-Arg supplementation inhibits the NLRP3 inflammasome activation in macrophages, while deprivation promotes it. Treatment with L-Arg in mice alleviates monosodium urate crystal-induced arthritis and aluminium-induced peritonitis. In addition, L-Arg supplementation alleviates neuroinflammation and motor deficits in mouse models of Parkinson's disease, whereas L-Arg deprivation exacerbates pathology. In patients with Parkinson's disease, L-Arg levels are reduced in serum. Our study establishes L-Arg supplementation as a promising therapeutic avenue for managing NLRP3-driven inflammatory pathologies.
    DOI:  https://doi.org/10.1038/s42255-026-01636-3
  36. Cancer Res. 2026 Oct 05.
    Getting comfortable: clonal haematopoiesis creates a senescent niche for expansion.
    Nieves Garcia-Gisbert, Giovanna Mantica, Elisa Laurenti.
      Clonal haematopoiesis (CH) is characterized by the age-associated expansion of mutant haematopoietic clones. How these clones expand, interact with the niche, and maintain a competitive advantage remains poorly understood. In a recent study published in Nature Cell Biology, Mistry and colleagues uncover that senescence in the bone marrow stromal microenvironment is a key contributor to the clonal growth of haematopoietic stem and progenitor cells (HSPCs) carrying CH mutations. Using mouse models and primary human samples, they show that mutant haematopoietic cells induce MSC senescence through contact-independent, cytokine-mediated signalling involving TNF-α, IL-6 and STAT3. Senescent MSCs preferentially support mutant haematopoietic stem and progenitor cells (HSPCs) over wild-type cells. Moreover, genetic or pharmacological depletion of senescent non-haematopoietic cells reduces CH burden and delays progression towards myeloid neoplasia in mice. By demonstrating that the premalignant niche is actively remodelled to favor mutant haematopoiesis, this study identifies MSC senescence as a relevant mechanism regulating CH evolution and a potential target for early disease intervention.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-4171
  37. Methods Mol Biol. 2026 Oct 09.
    Tracing Stem and Progenitor Cells Using Sequential Administration of Three Thymidine Analogs In Vivo.
    Sierra H Ball, Rina N Helt, Claudia Capdevila, Jonathan Miller, Liang Cheng, Hyeonjeong Lee, Laura A Jenny, Elena Wang, Sarah N Weinshel, Arnold S Han, Kelley S Yan.
      Imaging of adult stem cells and their progeny in the gastrointestinal (GI) epithelium is useful for constructing cellular hierarchies, revealing stem cell location, and understanding stem cell dynamics, all of which provide an understanding of how they sustain tissues during homeostasis and injury. Pulse-chase approaches can be used to track stem and progenitor cells and understand tissue kinetics by using nucleotide analogs that irreversibly incorporate into DNA during S-phase. Existing pulse-chase approaches that use multiple analogs require harsh DNA denaturation which obscures nuclear staining and the ability to visualize colocalization of analog signals with DNA. This can prevent the ability to distinguish between diluted thymidine analog signal and auto fluorescent secretory granules in cells abundant in the GI epithelium. Here we build upon a method which combines three thymidine analogs for triple pulse-chase labeling of proliferating cells in mice to understand tissue kinetics and S-phase length while maintaining strong nuclear signals in the colon epithelium. This approach may be applied to other tissues to study cell proliferation kinetics.
    Keywords:  Cellular hierarchy; Lineage tracing; Pulse-chase; S-phase; Thymidine analog
    DOI:  https://doi.org/10.1007/7651_2026_721
  38. EMBO Mol Med. 2026 Oct 05.
    Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases.
    Claire Almyre, Anne-Louise Cayer, Nolwenn Bounaix, Anaïs Hoarau, Marie-Alix Derieppe, Julie Martineau, Pierre Costet, Camille Charles, Mélody Dufossée, Cécile Duplaa, Jim Dompierre, Bénédicte Salin, Marc-Alexandre D'Elia, Corinne Blancard, Aurélie Massoni-Laporte, Stéphane Claverol, Caroline Tokarski, Yaser Hashem, Alexandre Favereaux, Yeranuhi Hovhannisyan, Juliette Jouhet, Cyrille Guimaraes, Jean-François Dumas, Olivier R Baris, Laetitia Dard, Jérémy Richard, Vanessa Bergeron, Naïg Gueguen, Valérie Desquiret-Dumas, Jordan Rivron, Douglas Strathdee, Carole H Sellem, Nathalie Bonnefoy, Laurent Monassier, Estelle Ayme-Dietrich, Onnik Agbulut, Stéphane Azoulay, Jean-Paul di Rago, Vincent Procaccio, François Godard, Déborah Tribouillard-Tanvier.
      Despite major advances in the genetic diagnosis of mitochondrial disorders, effective disease-modifying therapies remain scarce. Here, we identify ebselen (EBS) as a promising therapeutic candidate through a phenotypic drug screen in a yeast model of Barth syndrome, a cardiomyopathy caused by defective cardiolipin maturation. EBS improved oxidative phosphorylation-dependent growth across diverse fungal models of mitochondrial diseases, including defects in complex I, complex IV, mitochondrial DNA maintenance, mitochondrial translation, and ATP synthase. Therapeutic efficacy was further validated in patient-derived fibroblasts, iPSC-derived cardiomyocytes, and a cardiolipin-deficient mouse model. Mechanistically, EBS acts independently of its established antioxidant activity by engaging a conserved metabolic program that suppresses cytosolic translation while stimulating pyruvate dehydrogenase-dependent tricarboxylic acid cycle activity, thereby improving proteostasis and mitochondrial bioenergetic function. These effects are likely coordinated through lysosome-associated mTOR signaling, consistent with the localization of EBS to lysosomes and its colocalization with mTOR. Together, our findings identify a conserved mechanism for enhancing mitochondrial function and establish ebselen as a strong candidate for therapeutic repurposing in Barth syndrome and a broad spectrum of inherited mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s44321-026-00518-1
  39. Nat Genet. 2026 Oct;58(10): 2424
    Calorie restriction reduces somatic mutation burden in mice.
    Hui Hua.
      
    DOI:  https://doi.org/10.1038/s41588-026-02803-8
  40. Nat Commun. 2026 09 04. pii: 10520. [Epub ahead of print]17(1):
    Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism.
    Alba Fernández-Rodrigo, Celia García-Vilela, Abel Eraso-Pichot, Irene B Maroto, María D G Moreno, Esperanza López-Merino, Silvia Gutiérrez-Eisman, Carla Sánchez-Castillo, Cristina Boers-Escuder, Eneko Merino-Casamayor, Mariona Graupera, Albert Quintana, María I Cuartero, Maite Solas, Giovanni Marsicano, José A Esteban.
      Astrocytes modulate neuronal activity by gliotransmission and through metabolic regulation, yet the relationship between these functions remains poorly understood. Here we show that phosphatidylinositol 3-kinase (PI3K) signaling in astrocytes controls synaptic plasticity and memory by regulating cellular metabolism. Deletion of the p110α isoform of PI3K in hippocampal astrocytes impairs NMDA receptor activation during the induction of hippocampal long-term potentiation (LTP). This defect is rescued by either D-serine (co-agonist of synaptic NMDA receptors) or its precursor L-serine, indicating that PI3K regulates synaptic plasticity through serine availability. Indeed, deletion of p110α rewires astrocyte metabolism, reducing glycolytic flux while enhancing mitochondrial respiration. This, in turn, would limit L-serine biosynthesis through the phosphorylated pathway. Consistently, mice lacking astrocytic p110α display memory deficits that are rescued by in vivo L-serine administration. These findings identify astrocytic PI3K p110α as a key link between cellular metabolism, synaptic plasticity and cognition.
    DOI:  https://doi.org/10.1038/s41467-026-77319-0
  41. bioRxiv. 2026 Aug 14. pii: 2026.08.12.744485. [Epub ahead of print]
    Mycoplasma gallisepticum uses itaconate-associated mitochondrial inhibition to suppress host immunometabolism.
    Soren Z Coulson, Reihane Eric, Chidambaram Ramanathan, Katie M Talbott, Francis E Tillman, Anna Perez-Umphrey, Truc Chi Thi Pham, Paul S Simone, Brandt D Pence, James S Adelman, Yufeng Zhang.
      Many pathogens actively suppress early host immune responses to enhance their fitness. Mitochondria function as key regulators of immune activation, yet whether pathogens suppress host immunity by manipulating mitochondrial metabolism in vivo remains largely unknown. During an innate immune response, the metabolite itaconate increases in abundance and acts as an immunomodulator, due to its inhibition of succinate dehydrogenase (SDH), a key mitochondrial regulator of cellular immunity. We hypothesized that Mycoplasma gallisepticum (MG), a recently emerged pathogen of wild songbirds, most notably house finches ( Haemorhous mexicanus ), suppresses early host immune responses by limiting SDH-dependent immune activation via itaconate. We tested these hypotheses using experimental 3-day infection of finches with heat-killed MG, live MG or pharmacological elevation of the SDH inhibitor itaconate. Following inoculation, we quantified intracellular itaconate and mitochondrial respiratory function in peripheral blood mononuclear cells (PBMCs) and pro-inflammatory cytokine gene expression in erythrocytes, in addition to infected tissues (trachea and conjunctiva). Heat-killed MG increased SDH-dependent mitochondrial respiration in PBMCs and cytokine gene expression in erythrocytes, but live MG did not show these increases, but revealed increased itaconate accumulation in PBMCs. Dimethyl itaconate administration reproduced the suppressed metabolic and immune phenotype in blood cells observed with live MG, suggesting an itaconate-associated mechanism. In contrast, live MG increased mitochondrial respiration and gene expression levels of cytokines in eyelid conjunctiva, whereas other treatments did not. These findings indicate that MG suppresses host metabolic and cytokine signaling in systemically circulating immune cells through a mechanism consistent with itaconate-mediated inhibition of SDH-dependent mitochondrial respiration, while still inducing an inflammatory response at the site of infection. Our data suggest that MG, like other pathogens, can commandeer host immunometabolic pathways during infection to their benefit and that mitochondria are a key site of competition between host and pathogen.
    DOI:  https://doi.org/10.64898/2026.08.12.744485
  42. J Biol Chem. 2026 Oct 08. pii: S0021-9258(26)02492-0. [Epub ahead of print] 113620
    Transcriptomic analysis uncovers dysregulated glycosylation pathways in clear cell renal cell carcinoma.
    Ru M Wen, G Edward W Marti, Rosalie Nolley, Nathan Lam, Hongjuan Zhao, Donna M Peehl, James D Brooks.
      Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by altered metabolism, immune remodeling, and aberrant glycosylation. Although glycosylation regulates tumor-cell signaling, adhesion, angiogenesis, and immune recognition, its relationship with the ccRCC immune microenvironment remains incompletely defined. Here, we analyzed RNA-sequencing profiles from ccRCC tumors and adjacent normal kidney tissues. Glycan-related genes and glycogenes involved in glycan biosynthesis distinguished ccRCC tumors from normal tissues and revealed altered sulfatase, nucleotide sugar, glycosyltransferase, glycosaminoglycan pathways. CIBERSORTx analysis showed distinct immune cell distributions in tumors, and Spearman correlation analysis linked glycosylation pathway activity with immune cell abundance. Glycogene expression further classified ccRCC tumors into two subtypes with different immune signatures, Siglec expression patterns, and overall survival. The transcriptional differences between normal and tumor tissues are dominated by immune/inflammatory activation and ion/membrane transport regulation. Our results underscore the importance of targeting cancer-associated changes in glycosylation machinery using novel strategies to improve the specificity and efficacy of cancer therapeutics in ccRCC.
    Keywords:  Clear cell renal cell carcinoma; Siglec; glycosylation; immune cell subtypes; survival
    DOI:  https://doi.org/10.1016/j.jbc.2026.113620
  43. Mol Cell. 2026 Oct 09. pii: S1097-2765(26)00665-9. [Epub ahead of print]
    40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay.
    Akruti Shah, Aaztli R Coria, Jennifer T Miller, Emilien Orgebin, Wilfried Guiblet, Acong Yang, Shuo Gu, Colin Chih-Chien Wu.
      Eliminating defective ribosomes through quality control is essential for accurate protein synthesis. However, the mechanisms that commit defective ribosomal subunits to decay remain poorly defined. Here, we identify a tandem mechanism in which ubiquitin-dependent ribosome remodeling and 18S rRNA uridylation lead to 40S ribosomal subunit decay. Specifically, we use an in vitro reconstitution system to show that the atypical kinase RIOK3 remodels 40S ribosomal subunits, thereby exposing the 3' end of 18S rRNA. Nanopore direct RNA sequencing reveals that this remodeling event promotes oligo-uridylation, generating uridylated 18S rRNA decay intermediates. Uridylated 18S rRNA is further degraded by the 3'-5' exoribonuclease DIS3L2. Moreover, DIS3L2-mediated exoribonucleolytic cleavage triggers endoribonucleolytic decay of the 18S rRNA, amplifying turnover. Together, our findings define a stepwise mechanism in which ribosome remodeling and RNA tailing commit defective 40S subunits to elimination, establishing a mechanistic framework for ribosome surveillance in mammalian cells.
    Keywords:  18S rRNA decay; DIS3L2; RIOK3; RNF10; TUT4/7; ribosome turnover; uridylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.022
  44. bioRxiv. 2026 Aug 14. pii: 2026.08.13.744642. [Epub ahead of print]
    Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer.
    Johnvesly Basappa, Cosimo Lobello, Anneliese M Faustino, Cristina Uribe-Alvarez, David Rushmore, Niel Sen, Li Wang, Andrey Efimov, Kathy Q Cai, Jaime L Schneider, Lori Rink, Aaron N Hata, Luca Mologni, Wujuan Zhang, Aaron R Goldman, Hsin-Yao Tang, Reza Nejati, Roland Dunbrack, Jonathan Chernoff, Joseph A Baur, Mariusz A Wasik.
      Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage pathway, is frequently upregulated in cancer, yet mechanisms regulating its catalytic activity remain undefined. We identify NAMPT as a direct substrate of multiple proto-oncogenic tyrosine kinases, including ALK, insulin receptor, IGF1R, and PDGFRA. Phosphoproteomics identified NAMPT Y188 as the major phosphorylation site, including the oncogenic fusion kinase NPM1::ALK. NAMPT interacted with NPM1::ALK in the cytoplasm, nucleus, and mitochondria, while Y188 phosphorylation enhanced catalytic activity, NMN/NAD⁺ biosynthesis, and downstream metabolism. Conversely, the Y188F mutant reduced enzymatic activity, proliferation, and clonogenicity, whereas disrupting dimerization similarly impaired phosphorylation and function. Interactome analyses showed phosphorylation and dimerization cooperatively remodel NAMPT-associated networks, enriching phosphorylated dimers for metabolic/redox regulators and monomeric NAMPT for ribosome biogenesis. NAMPT inhibition suppressed the growth of both ALK inhibitor-sensitive and -resistant lymphoma cells and enhanced the efficacy of ALK inhibition, revealing kinase-dependent NAMPT activation as a metabolic vulnerability in oncogene-driven cancers.
    DOI:  https://doi.org/10.64898/2026.08.13.744642
  45. Int Immunopharmacol. 2026 Oct 06. pii: S1567-5769(26)01363-9. [Epub ahead of print]190 117515
    ENOPH1 orchestrates KRASG12D/G13D-driven glycolytic reprogramming and colorectal cancer progression through modulating the TGF-β/SMAD pathway.
    Xin Chen, Yiren Su, Zhizhan Ni, Yujia Lu, Yao Zhou, Jianfei Huang, Jiebang Jiang.
      Oncogenic KRAS mutations (G12D/G13D) drive metabolic reprogramming in colorectal cancer (CRC), yet targetable downstream effectors remain poorly defined. Here, we identify enolase-phosphatase 1 (ENOPH1) as an essential transducer directly upregulated by the KRAS-MEK-ERK axis. ENOPH1 is markedly elevated in KRAS-mutant patient tumors and is required for CRC proliferation, migration, invasion, and tumor growth in vivo. Mechanistically, ENOPH1 sustains oncogenic TGF-β/SMAD signaling through a non-catalytic mechanism: it promotes TGFβ transcription and secretion, while concurrently suppressing the E3 ligase STUB1 to prevent ubiquitin-mediated degradation of SMAD4 and preserve p-SMAD2/3 phosphorylation and nuclear accumulation. Notably, ENOPH1 depletion does not alter cellular methylation potential (SAM/SAH ratio), and reconstitution with the catalytic-dead D16A mutant effectively restores SMAD4 abundance, p-SMAD2/3 levels, and cell proliferation, indicating a mechanism largely independent of its canonical enzymatic activity. Downstream, TGF-β/SMAD-induced glycolysis serves as an indispensable metabolic engine powering epithelial-mesenchymal transition (EMT); pharmacological inhibition of glycolysis with 2-deoxy-d-glucose (2-DG) abolishes TGF-β1-restored EMT and malignant phenotypes, phenocopying SMAD2/3 silencing. Together, our findings establish ENOPH1 as a non-catalytic molecular hub linking KRAS signaling, TGF-β output, and glycolytic addiction, uncovering a rational therapeutic vulnerability for KRASG12D/G13D-driven CRC.
    Keywords:  Colorectal cancer; ENOPH1; Glycolysis; KRAS(G12D/G13D); TGF-β/SMAD signaling
    DOI:  https://doi.org/10.1016/j.intimp.2026.117515
  46. FEBS J. 2026 Oct 07.
    Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.
    Anamika Acharyya, Riddhiman Dhar.
      Mitochondrial DNA (mtDNA) copy number determines the functional state of mitochondria and thus, influences cellular energy production, growth, metabolism, and stress response. Variation in mtDNA copy number has been observed across many cancer types and has been linked to changes in gene expression. However, whether mtDNA copy number has any link to mutation accumulation in cancer is unknown. Further, how mtDNA copy number variation alters expression of cancer-associated pathways and thereby influences cancer progression remains unclear. Here, through an analysis of whole genome data in multiple cancer types, we show that mtDNA copy number increases with an increase in mutational load in cancer samples and the increase in mtDNA copy number bears a signature of compensation for mitochondrial function. We also show that the samples with low-mtDNA generally have increased expression of cancer-promoting genes, including genes involved in cell migration and epithelial-mesenchymal transition (EMT). Taken together, these results reveal a close association of mtDNA copy number with mutational load and disease progression in cancer. These findings provide a way forward toward a better understanding of the role of mtDNA copy number and mitochondrial functional state in cancer progression.
    Keywords:  MtDNA copy number; cancer progression; differential expression; epithelial–mesenchymal transition; multicancer analysis; mutational load
    DOI:  https://doi.org/10.1111/febs.70736
  47. Nat Aging. 2026 Oct 09.
    Lymph node contraction links sex-biased naive CD8+ T cell decline to compromised antigen recognition during middle age.
    Lutz Menzel, Maria Zschummel, Meghan J O'Melia, Mårten Sandstedt, Hengbo Zhou, Pin-Ji Lei, Lingshan Liu, Hang Lee, Debattama R Sen, Lance L Munn, Lena Jonasson, Timothy P Padera.
      The abundance of diverse naive CD8+ T cell clones is essential for broad protection against infection and cancer, but how sex and aging jointly shape this compartment remains poorly understood. Here, using mouse models with supporting human data, we uncover a sex-biased mechanism of immune aging in which early male-biased depletion of naive CD8+ T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells combines with thymic involution, limiting naive CD8+ T cell replenishment. These mechanisms led to more rapid lymph node contraction and reduced local naive T cell clone availability in males, limiting cancer antigen recognition. Therapeutic thymus regeneration via androgen ablation repopulated naive CD8+ T cells in lymph nodes, reinvigorated cancer-specific T cell responses and enhanced responsiveness to immune checkpoint blockade in male mice. These findings reveal the impact of sex and age on naive T cell clone abundance in lymph nodes and suggest strategies to restore immune competence in middle-aged men.
    DOI:  https://doi.org/10.1038/s43587-026-01238-4
  48. Cancer Res. 2026 Oct 08.
    Sodium-Glucose Cotransporter SGLT2 Supports Metabolic Fitness and Ferroptosis Resistance in CAR-T Cells to Enhance Activity Against Solid Tumors.
    Yaoxin Gao, Xinbin Yang, Xiaowen Mao, Luoming Zhang, Pengju Lv, Baodong Ma, Fuli Qin, Ranran Jin, Lin Wang, Songge Liu, Jianping Ye, Shoukui Hu, Dandan Guo, Xu Wu, Xiwen Ma, Juntang Lin, Zhengyuan Xia.
      Antitumor T-cell function is tightly coupled with cellular metabolism, which is severely compromised by glucose deprivation and elevated sodium chloride (NaCl) in the solid tumor microenvironment (TME). Here, we demonstrated that glucose restriction markedly impaired activation, cytotoxicity, and persistence of CAR-T cells while promoting exhaustion, whereas high NaCl partially reversed these defects. Overexpression of the sodium-glucose cotransporter SGLT2 in CAR-T cells to simultaneously enhance glucose and NaCl uptake led to stronger antitumor activity in multiple solid tumor xenograft models. Mechanistically, SGLT2 overexpression elevated glycolysis and mitochondrial fitness, inhibited ferroptosis, and activated the AKT-mTOR pathway. These findings establish a metabolic engineering strategy that boosts glucose utilization in CAR-T cells to overcome TME stress and enhance solid tumor control.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1157
  49. Bioessays. 2026 Oct;48(10): e70193
    Metabolic Structure: A Paradigm Revisited in Light of the Fundamental Parameters of Living Systems.
    Jacques Fantini.
      The concept of 'metabolic structure', which considers metabolism as a stable, genetically encoded architecture with enzymes occupying fixed control positions, is indispensable but incomplete, and it obscures metabolism's true nature. I propose redefining metabolism as a dynamic field of emergent biochemical fluxes, governed by six fundamental parameters: time, water, entropy, quantum effects, space, and electrostatic potential, shaping the thermodynamic trajectories of living matter. Metabolic control analysis already supports this view: flux control coefficients are state- and time-dependent coordinates within a thermodynamic field, not intrinsic enzyme properties. This perspective manifests across scales: electrostatics govern fructose 1,6-bisphosphate cleavage in aldolase; hepatic zonation shows spatial reorganization through a single parameter; glucose deprivation quantitatively redirects intestinal cancer cell metabolism from glycolytic to oxidative flux, driving differentiation into an enterocyte-like state; post-meal walking redirects glucose flux from storage to oxidation without pharmacological intervention; inherited metabolic diseases can sometimes be managed without correcting the causal mutation. These examples converge into a new framework: metabolism possesses not only a sophisticated architecture but also states that shape its fluxes. And states, unlike static structures, can be reconfigured.
    Keywords:  Warburg effect; electrostatic potential; emergent properties; flux control coefficients; fundamental biological parameters; hepatic zonation; inherited metabolic diseases; lipid rafts; metabolic control analysis
    DOI:  https://doi.org/10.1002/bies.70193
  50. Nat Aging. 2026 Oct 05.
    Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
    Rebecca Sereda, Kristen Lindenau, Antonio Diaz, Zhaohui Liu, Olaya Santiago-Fernández, Rabia R Khawaja, Ronald Cutler, Jazmin Calyeca, Mericka McCabe, Sylvére Durand, Fanny Aprahamian, Natalia Del Pilar Vanegas, Hu Chen, Felipe Vilicich, Bhakti Chavda, Yair Botbol, Guido Kroemer, Toren Finkel, Evripidis Gavathiotis, Simone Sidoli, Ana L Mora, Mauricio Rojas, Susmita Kaushik, Ana Maria Cuervo.
      Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.
    DOI:  https://doi.org/10.1038/s43587-026-01240-w
  51. FASEB J. 2026 Oct 15. 40(19): e72346
    The Genetic and Epigenetic Mechanisms of mtDNA in Regulation of Inflammation and Metabolism.
    Yulin Zhang, Yanjiang Zheng, Hongyu Duan, Yifei Li.
      Mitochondria serve as the primary cellular powerhouses, generating ATP through oxidative phosphorylation (OXPHOS) to sustain essential cellular processes. Beyond energy production, mitochondria function as critical regulators of metabolic homeostasis, intracellular signaling networks, and programmed cell death pathways. The mitochondrial genome comprises 37 genes encoding 13 OXPHOS subunits, 22 transfer RNAs, and 2 ribosomal RNAs, all transcribed and translated within the organelle. Mitochondrial DNA integrity becomes compromised through diverse pathological stimuli, including metabolic dysregulation, oxidative stress, and inflammatory cascades, contributing to disease pathogenesis across multiple organ systems. This review synthesizes current knowledge on the multifaceted roles of mtDNA in health and disease. We propose a framework of three interconnected mechanisms through which mtDNA exerts its effects: (1) retrograde signaling to the nucleus, reprogramming nuclear gene expression; (2) cytosolic and extracellular release of mtDNA as a damage-associated molecular pattern (DAMP), activating innate immune pathways like cGAS-STING and NLRP3; and (3) intrinsic epigenetic modifications that directly modulate mitochondrial gene expression. We critically evaluate the evidence linking mtDNA alterations to a spectrum of diseases, including cancer, cardiovascular and metabolic disorders, neurodegeneration, and psychiatric conditions. We conclude that a comprehensive understanding of mtDNA's multifaceted nature, moving beyond its perception as a mere DAMP, is essential for translating mitochondrial biology into effective clinical interventions.
    Keywords:  diseases process; mitochondrial function; molecular mechanisms; mtDNA; pathophysiology
    DOI:  https://doi.org/10.1096/fj.202600927R
  52. Nat Commun. 2026 10 03. pii: 10532. [Epub ahead of print]17(1):
    Near-atomistic simulations reveal the molecular principles that control chromatin structure and phase separation.
    Kieran Russell, Yifang Chen, Jorge R Espinosa, David Farré-Gil, Huabin Zhou, M Julia Maristany, Jose Ignacio Perez-Lopez, Jan Huertas, Modesto Orozco, Michael K Rosen, Rosana Collepardo-Guevara.
      Understanding how chromatin's physicochemical properties shape its emergent organization is central to deciphering genome function. To address this, we present OpenCGChromatin, a high-performance coarse-grained model that achieves near-atomistic simulations of chromatin systems an order of magnitude larger than previously possible, spanning biomolecular condensates and fibers tens of kilobases in length. OpenCGChromatin simulations independently predict, from physicochemical principles, the linker-DNA-dependent chromatin structures observed by cryo-ET and the relative thermodynamic stability of condensates inferred from biochemical assays. Crucially, OpenCGChromatin resolves histone-tail dynamics and interaction networks that remain inaccessible experimentally, explaining how linker-DNA length controls histone tail accessibility and the resulting multiscale structure of chromatin condensates. Extending simulations to 108-nucleosome fibers shows that acetylation disrupts chromatin compaction in a pattern-specific manner by weakening key tail-mediated interactions, with H4K16 and H3K9 emerging as the most energetically disruptive modifications. These results position OpenCGChromatin as a powerful framework for linking molecular detail to emergent chromatin organization.
    DOI:  https://doi.org/10.1038/s41467-026-78050-6
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