bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–02–15
sixty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Metabolic permissiveness: how tissue context shapes cancer.
  2. Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in preclinical models of H3K27M-mutant gliomas.
  3. Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
  4. Spatiotemporal metabolic mapping reveals diet-independent remodeling of the postnatal mouse brain.
  5. Circadian rhythm heterogeneity modulates drug response variations in neuroblastoma models.
  6. Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.
  7. Substrate availability and citrate alter TCA cycle metabolism and SLC13A3 in macrophage immune responses.
  8. MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.
  9. Structural and molecular basis for allosteric regulation and catalytic coupling of human phosphoribosylformylglycinamidine synthase.
  10. Career pathways, part 19.
  11. Simulating tumor mitochondrial energetics through engineering-style energy metrics.
  12. On why cancer cells require a great amount of glucose.
  13. Targeting NHEJ activates STING signaling through MYC degradation to boost antitumor immunity in SCLC.
  14. The state of imaging glycolytic metabolism in cancer with magnetic resonance.
  15. Mechanisms and disease relevance of mitochondrial translation in humans.
  16. M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress.
  17. Ubiquitin control of cytosolic DNA sets immune responses to DNA damage.
  18. Cytotoxic lymphocytes counteract viral type I interferon immune evasion.
  19. SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance.
  20. HuR-Driven Reversible Mitochondrial Shuttling Buffers Cytosolic miRNA Levels in Hepatic Cells.
  21. "Tumor-to-endothelium mitochondrial transfer licenses endothelial cells for CD8 + T cell recognition via mitochondrial neoantigen presentation".
  22. Metabolic modeling and functional genomics reveal taxa and host gene interactions in colorectal cancer.
  23. Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species.
  24. Induction of TFEB promotes Kupffer cell survival and reduces lipid accumulation in MASLD.
  25. Computational assessment of the relationship between metabolism and histone methylation in cancer cells.
  26. Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.
  27. Deep-coverage single-cell metabolomics enabled by ion mobility-resolved mass cytometry.
  28. F26BP enables control of glycolysis rate independent of energy state.
  29. Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types.
  30. The bottleneck of fat burning.
  31. Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis.
  32. Frailty phenotype reveals heterogeneity in aging and distinct taurine associations.
  33. NAPRT-mediated deamidated NAD biosynthesis enhances colon tissue resiliency and suppresses tumorigenesis.
  34. Genome-wide CRISPRi screen identifies basigin loss as protective in cardiac hypoxia.
  35. What's in a name? Metabolite identification: challenges and pitfalls in untargeted metabolomics.
  36. Nutrients and Metabolites as Signalling Molecules in Osteoclasts.
  37. Autophagy in kidney physiology: from cellular quality control to organ metabolism.
  38. The aging mouse lipidome.
  39. LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.
  40. Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.
  41. AADAT-Driven Metabolic Control of Malate and CoQ 10 Shapes Immune Evasion in Triple-Negative Breast Cancer.
  42. Role of vinculin in metabolism.
  43. Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
  44. Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.
  45. Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma.
  46. Mitochondrial Transfer in the Tumor Microenvironment.
  47. Mammalian Mitochondrial DNA Accumulates Insertions and Deletions with Age in Energetically Demanding Tissues.
  48. Briefing Chat: Caffeine slows brain ageing, suggests decades of data.
  49. Clonal hematopoiesis boosts response to immune checkpoint therapy.
  50. Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses.
  51. Peroxisomes in Aging: Guardians of Cellular Resilience and Function.
  52. Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death.
  53. Systems Biology of Aging, Metabolism, and Mitochondria.
  54. Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.
  55. FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.
  56. Robust partitioning of cell contents by physical instabilities and biological clocks.
  57. RAD51 succinylation regulates homologous recombination and contributes to the chemosensitivity in cancer.
  58. Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
  59. A genetically encoded ionic-stress sensor reveals protons as a sleep driver.
  60. A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
  61. Methionine metabolism and the NOP2 methyltransferase are essential for MYC-Driven liver tumorigenesis.
  1. Genes Dev. 2026 Feb 09.
    Metabolic permissiveness: how tissue context shapes cancer.
    Chrysanthi Moschandrea, Christian Frezza.
      An emerging paradox in cancer metabolism is that identical oncogenic mutations produce profoundly different metabolic phenotypes depending on tissue context, with many mutations exhibiting striking tissue-restricted distributions. Here we introduce metabolic permissiveness as the inherent capacity of a tissue to tolerate, adapt to, or exploit metabolic disruptions, providing a unifying framework for explaining this selectivity. We examine tissue-specific metabolic rewiring driven by canonical oncogenes (MYC and KRAS), tumor suppressors (p53, PTEN, and LKB1), and tricarboxylic acid (TCA) cycle enzymes (FH, SDH, and IDH), demonstrating that baseline metabolic architecture, nutrient microenvironment, redox buffering, and compensatory pathways determine whether mutations confer a selective advantage or metabolic crisis. We further discuss how the tumor microenvironment shapes metabolic adaptation and therapeutic vulnerability. This framework reveals shared principles of tissue-specific metabolic vulnerability in cancer and provides a mechanistic basis for precision metabolic therapies.
    Keywords:  cancer; metabolism; permissiveness
    DOI:  https://doi.org/10.1101/gad.353516.125
  2. Sci Transl Med. 2026 Feb 11. 18(836): eadw0834
    Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in preclinical models of H3K27M-mutant gliomas.
    Georgios Batsios, Céline Taglang, Suresh Udutha, Anne Marie Gillespie, Timothy Phoenix, Sabine Mueller, Sriram Venneti, Carl Koschmann, Pavithra Viswanath.
      Hyperactivation of glucose metabolism to lactate is a metabolic hallmark of cancer. However, the functional role of lactate in pediatric diffuse midline glioma (DMG) cells is unclear. Here, using stable isotope tracing and loss-of-function studies in clinically relevant patient-derived DMG models, we show that the oncogenic histone H3K27M mutation epigenetically up-regulates the rate-limiting glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U-13C]-glucose in DMGs. Mechanistically, lactate posttranslationally activates the nucleoside diphosphate kinase NME1 through lactylation and facilitates the synthesis of nucleoside triphosphates that are essential for DNA replication and tumor proliferation. This mechanistic link between glycolysis and nucleotide biosynthesis provides the opportunity for deuterium metabolic imaging of tumor growth and response to therapy. Spatially mapping 2H-lactate production from [6,6-2H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard of care and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations in tumor tissues in preclinical DMG models in vivo at clinical field strength (3 T). Overall, we have identified an H3K27M-lactate-NME1 axis that drives DMG proliferation and facilitates noninvasive in vivo metabolic imaging of DMGs.
    DOI:  https://doi.org/10.1126/scitranslmed.adw0834
  3. Nat Cell Biol. 2026 Feb 11.
    Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
    Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.
      Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.
    DOI:  https://doi.org/10.1038/s41556-026-01879-y
  4. NPJ Metab Health Dis. 2026 Feb 10. 4(1): 7
    Spatiotemporal metabolic mapping reveals diet-independent remodeling of the postnatal mouse brain.
    Elisa M York, Anne Miller, Sylwia A Stopka, Nathalie Y R Agar, Gary Yellen.
      Developing cells undergo extensive metabolic adaptations to support growth and differentiation. Here, using spatially resolved mass spectrometry imaging and stable isotope tracing, we systematically investigate metabolic remodeling in mouse brains at postnatal day 14 and day 28, a period coinciding with the transition from a maternal milk diet to solid food. Untargeted metabolomics reveals global shifts in lipid composition, and region-specific remodeling of central energy metabolism, including increased glycolytic intermediates in grey matter-enriched regions and a global decrease in tricarboxylic acid (TCA) cycle metabolites after weaning. Despite these marked changes in metabolite levels, the glucose incorporation rate remains constant across these developmental stages. Notably, weaning mice onto a milk-replacement diet demonstrates that the observed metabolic adaptations are largely diet-independent. Together, our data suggest that postnatal brain metabolic remodeling is an intrinsically programmed feature of maturation providing region-specific metabolic reorganization to support developmental demands.
    DOI:  https://doi.org/10.1038/s44324-025-00098-7
  5. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00053-7. [Epub ahead of print]45(2): 116975
    Circadian rhythm heterogeneity modulates drug response variations in neuroblastoma models.
    Carolin Ector, Christoph Schmal, Jeff Didier, Sébastien De Landtsheer, Johannes H Schulte, Ulrich Keilholz, Thomas Sauter, Achim Kramer, Hanspeter Herzel, Adrián E Granada.
      Circadian clocks regulate essential cellular functions and influence cancer development and treatment outcomes. Aligning therapy with circadian rhythms can improve efficacy and reduce toxicity, yet whether neuroblastoma, a heterogeneous pediatric tumor, maintains circadian function remains unclear. Here, we systematically profiled circadian dynamics across 12 neuroblastoma cell models using long-term bioluminescence assays and computational analysis. Our findings reveal heterogeneous circadian patterns ranging from robust to arrhythmic, which we linked to distinct neuroblastoma genetic features. By integrating drug sensitivity data, we identified candidate compounds whose effectiveness correlates with circadian expression profiles. Moreover, time-of-day treatment assays with the ALK inhibitor lorlatinib and frontline chemotherapeutics revealed distinct temporal drug responses that were more pronounced in circadian-competent than weakly rhythmic cell lines. Together, these findings establish circadian heterogeneity as a previously unrecognized dimension of neuroblastoma biology and highlight the therapeutic potential of chronotherapy approaches for improved treatment efficacy.
    Keywords:  CP: cancer; CP: metabolism; cancer; chronotherapy; circadian clock; circadian rhythms; neuroblastoma; systems biology; time-of-day sensitivity
    DOI:  https://doi.org/10.1016/j.celrep.2026.116975
  6. bioRxiv. 2026 Jan 29. pii: 2026.01.27.702014. [Epub ahead of print]
    Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.
    Beth Kelly, Minsun Cha, Tatjana Gremelspacher, Jacob L Martin, Massimo Andreis, Gustavo E Carrizo, Mia Gidley, Michal A Stanczak, Petya Apostolova, David E Sanin, Ananya Majumdar, Erika L Pearce.
      Delineating how acquired nutrients are partitioned into different intracellular pathways, and how these various fates support distinct functions in T cells is limited. We show that CD8 + T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS-cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8 + T cells promotes exhaustion and dampens anti-cancer immunity, while blocking cysteine flux into GSH, or enforcing FeS metabolism, enhance tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human HCC. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.
    DOI:  https://doi.org/10.64898/2026.01.27.702014
  7. Immunol Lett. 2026 Feb 09. pii: S0165-2478(26)00020-9. [Epub ahead of print] 107147
    Substrate availability and citrate alter TCA cycle metabolism and SLC13A3 in macrophage immune responses.
    Lea Woyciechowski, Hanna F Willenbockel, Thekla Cordes.
      Cell culture media are commonly formulated to enhance cell growth and often lack the physiological nutrient composition found in human blood plasma. The impact of substrate availability on immune cell metabolism and function remains incompletely understood. Here, we demonstrate that changes in culture medium composition affect mitochondrial metabolic pathways, immune responses, and transport in macrophages. Using mass spectrometry and stable isotope tracing, we identify citrate as a mediator linking extracellular substrate availability to intracellular metabolism. We also observe increased IL-6 secretion and elevated expression of plasma membrane transporter NaDC3 (SLC13A3) under physiological carbon source conditions that are reversed when citrate is excluded from the medium. Our findings demonstrate that extracellular substrate composition influences macrophage immunometabolism and identify citrate as an extracellular signal that modulates immune responses. This work highlights the importance of physiologically relevant nutrient availability in studying and targeting immunometabolic pathways.
    Keywords:  SLC13A3; citrate; immunometabolism; itaconate; mass spectrometry; mitochondrial metabolism; substrate availability; tracing
    DOI:  https://doi.org/10.1016/j.imlet.2026.107147
  8. Gut. 2026 Feb 09. pii: gutjnl-2025-336323. [Epub ahead of print]
    MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.
    Yang Chen, Gao-Wei Jin, Li-Hong He, Yu Dong, Yan-Na Zhang, Han-Xiang Guo, Yi-Ting Xu, Zi-Yang Wei, Bin-Fei Dang, Chun-Yang Mu, Wan-Yue Cao, Yi-Ze Zhang, Xiao-Bao Wei, Yu-Xiong Feng, Yun-Hua Liu, Qi Zhang, Ting-Bo Liang.
       BACKGROUND: Liver metastasis is a common and fatal event for patients with pancreatic ductal adenocarcinoma (PDAC). Dysregulated mitochondrial dynamics reshape biological processes, including metabolism reprogramming, which disrupts immune cell function and promotes metastatic progression.
    OBJECTIVE: To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.
    DESIGN: Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screening, in vivo mouse model screening and in vitro anoikis-resistant cell selection were employed to identify key drivers during PDAC liver colonisation. PDAC organoids, metabolic flux analysis, single-cell RNA sequencing, spatial metabolomics and glutathione S-transferase (GST) pull-down assay were used to explore the regulation of mitochondrial fission process protein 1 (MTFP1) on PDAC liver colonisation and unravel the underlying mechanism.
    RESULTS: We revealed MTFP1, a protein that plays an important role in cell viability and mitochondrial dynamics, as a driver of PDAC liver colonisation. Mechanistically, MTFP1 is recognised as a novel ATP synthase modulator through its interaction with numerous ATP synthase subunits, thereby enhancing oxidative phosphorylation (OXPHOS). Increased mitochondrial fission and subsequent redox signalling (ROS production) upregulates solute carrier family A1 member 5 (SLC1A5) expression by activating the PI3K/AKT/c-MYC pathway, competing for glutamine uptake and impaired antitumour responses of CD8+ T cells. By performing virtual screening, we identified KPT 9274 (ATG-019) as an effective inhibitor of MTFP1. Limitation of glutamine uptake in PDAC cells or MTFP1 inhibition reverses the immunosuppressive TME and reduces liver colonisation of PDAC.
    CONCLUSION: Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis.
    Keywords:  CANCER IMMUNOBIOLOGY; LIVER METASTASES; OXIDATIVE METABOLISM; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-336323
  9. Nat Commun. 2026 Feb 13.
    Structural and molecular basis for allosteric regulation and catalytic coupling of human phosphoribosylformylglycinamidine synthase.
    Nandini Sharma, Weijie Zhou, Jarrod B French.
      Purine nucleotides are ubiquitous molecules essential for all life. The de novo biosynthesis of purines is a metabolic dependency that is frequently reprogrammed in cancers and is a well-established target for chemotherapies, immune modulation and antivirals. Here, we report cryo-electron microscopy structures of the multi-domain human phosphoribosylformylglycinamidine synthase, a central purine biosynthetic enzyme and foundational feature of the purinosome metabolon. These data capture, the proposed iminophosphate intermediate and provide the structural elucidation of an ammonia channel connecting the active sites of the glutaminase and synthase domains. Analysis of this series of structures and the accompanying biochemical data also reveal the molecular features and transient conformational changes that underlie allosteric regulation and catalytic coupling of the domains. This data resolves several longstanding mechanistic questions about this enzyme class and provides a strong foundation for therapeutic development.
    DOI:  https://doi.org/10.1038/s41467-026-69423-y
  10. Nat Metab. 2026 Feb 12.
    Career pathways, part 19.
    Xiaofei Yu, Michael Lukey.
      
    DOI:  https://doi.org/10.1038/s42255-026-01470-7
  11. Biosystems. 2026 Feb 05. pii: S0303-2647(26)00029-8. [Epub ahead of print]262 105719
    Simulating tumor mitochondrial energetics through engineering-style energy metrics.
    Arturo Tozzi.
      Cancer progression is linked to alterations in cellular energetics, where malignant cells reprogram their metabolism to sustain proliferation, resist stress and adapt to nutrient limitations. Recent work has shown that tumors actively remodel their microenvironment by acquiring functional mitochondria from surrounding stromal or immune cells. Mitochondrial transfer enhances tumor bioenergetics while simultaneously depleting immune cells of metabolic competence, thereby reinforcing both tumor growth and immune evasion. The energetic consequences in terms of throughput, efficiency and stored energy of these exchanges are not captured by conventional assays focused on oxygen consumption or glycolytic flux. We introduce a simulation-based framework for theoretical analysis of mitochondrial energetics that adapts engineering-style energy metrics to mitochondrial biology. Three theoretical, model-defined bioenergetic metrics are introduced: mitochondrial power density, expressing ATP production per unit mitochondrial volume; mitochondrial surface power density, relating ATP production to inner membrane area; and mitochondrial energy density, quantifying stored chemical free energy per unit volume. Using controlled in silico simulations of tumor and immune cell populations before and after modeled mitochondrial transfer, we examine how these descriptors vary under explicit simulation assumptions. Within our simulation framework, results indicate model-predicted differences between cell populations, with tumor-associated mitochondria occupying higher energetic throughput and immune-associated mitochondria exhibiting complementary reductions. Although exploratory and hypothesis-generating rather than validated biomarkers or clinical tools, our metrics provide a quantitative physical framework that may inform experimental studies of mitochondrial transfer and its energetic consequences, including efforts to disrupt pathogenic transfer and restore metabolic competence in immune cells.
    Keywords:  Cristae morphology; Immune evasion; Metabolic profiling; Oxidative phosphorylation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biosystems.2026.105719
  12. Quant Biol. 2026 Jun;14(2): e70025
    On why cancer cells require a great amount of glucose.
    Xuechen Mu, Aoran Liu, Rui Shi, Long Xu, Zhenyu Huang, Ye Zhang, Ying Xu.
      The traditional thinking has been that cancer cells require a great amount of glucose to support their rapid growth, but the reality may be different. We have previously demonstrated that all cancer cells in The Cancer Genome Atlas harbor persistent Fenton reactions in their cytosol, which generate OH- and ultimately kill the cells by alkalosis if not neutralized timely. Here, we present data to show that (1) cancer cells uptake large amounts of glucose to produce sufficient levels of H+ ions to keep the cytosolic pH stable, hence keeping the cells viable; (2) de novo nucleotide biosynthesis represents the predominant acidifying pathway and gets on average the largest allocation of glucose metabolic flux among the 19 cancer types investigated; and (3) although the H+ ions produced by nucleotide biosynthesis and other acidifiers keep the cells alive, the synthesized nucleotides drive cancerous cell proliferation. Taken together, it is not that cancerous cell division requires high levels of glucose imports, instead it is the life-saving nucleotide syntheses that drive cell division. Understanding this causal relationship correctly is significant since it explains why cancers depend so heavily on glucose but not on other nutrients. More importantly, this realization may lead to fundamentally novel and more effective ways to treat cancer.
    Keywords:  Fenton reaction; cancer metabolism; cancer proliferation; nucleotide biosynthesis; pH homeostasis
    DOI:  https://doi.org/10.1002/qub2.70025
  13. Nat Commun. 2026 Feb 10.
    Targeting NHEJ activates STING signaling through MYC degradation to boost antitumor immunity in SCLC.
    Subhamoy Chakraborty, Andrew Elliott, Utsav Sen, Charles Coleman, Vrinda Jethalia, Kedwin Ventura, Chih-Wei Fan, Ramja Sritharan, Avisek Banerjee, Yazhini Mahendravarman, Ari Vanderwalde, Balazs Halmos, Elisa de Stanchina, Hirokazu Taniguchi, Deniz Demircioglu, Dan Hasson, Triparna Sen.
      Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Paradoxically, this tumor displays a high mutation burden; however, a modest response to immunotherapy. Improving Immunotherapy response in SCLC patients remains an unmet need. Here, we report that across 24 tumor types, including over 179,000 real-world patient tumors, SCLC has the highest expression of nonhomologous end joining (NHEJ) DNA repair regulator PRKDC (DNAPKcs). High PRKDC expression predicts poor response to immunotherapy in SCLC. DNAPKcs depletion causes activation of cGAS/STING pathway due to cytoplasmic accumulation of double-stranded DNA, inducing immunogenicity and enhancing sensitivity of SCLC models to immunotherapy. Analyses in SCLC cell lines and mouse models shows that depletion of DNAPKcs leads to proteasomal degradation of MYC via GSK3β pathway. We show that DNAPKcs upregulation contributes to immunotherapy resistance and DNAPKcs inhibition represents a promising therapeutic strategy to induce antitumor immunity and potentiate immunotherapy efficacy in immunologically suppressed SCLC.
    DOI:  https://doi.org/10.1038/s41467-026-69262-x
  14. Npj Imaging. 2026 Feb 10. 4(1): 9
    The state of imaging glycolytic metabolism in cancer with magnetic resonance.
    Mario C Chang, Matthew E Merritt, Kayvan R Keshari.
      Imaging is essential for probing cancer biology and tumor surveillance in humans. Combining isotopically labeled substrates with advanced imaging approaches yields a new platform, metabolic imaging. Although cancer metabolism research began ~100 years ago, breakthroughs in magnetic resonance imaging (MRI) like hyperpolarization, deuterium metabolic imaging, and novel probes have revolutionized our ability to appreciate deregulated glycolysis in cancer. Here, we discuss the state and future of glycolytic imaging with MRI.
    DOI:  https://doi.org/10.1038/s44303-026-00146-x
  15. Nat Rev Mol Cell Biol. 2026 Feb 13.
    Mechanisms and disease relevance of mitochondrial translation in humans.
    Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.
      Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41580-026-00948-2
  16. Cell Death Differ. 2026 Feb 13.
    M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress.
    Camilla Reiter Elbæk, Sophie Gradinaru, Anna M Dahlström, Alexander Frueh, Akhee S Jahan, Joyceline Cuenco, Anna L Aalto, John Rizk, Simon A Hawley, Sarah N J Franks, Michael Stumpe, Srinivasa Prasad Kolapalli, Chris Kedong Wang, Cara J Ellison, Ximena Hildebrandt, Klara Nielsen, Dominik Priesmann, Julian Koch, Mathilde Deichmann, Josef Gullmets, Lien Verboom, Geert van Loo, Nieves Peltzer, Lisa B Frankel, Paul R Elliott, Mads Gyrd-Hansen, Jörn Dengjel, Brent J Ryan, D Grahame Hardie, Annika Meinander, Kei Sakamoto, Rune Busk Damgaard.
      Methionine-1 (M1)-linked ubiquitin chains, assembled by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, are critical regulators of inflammation and immune homoeostasis. Genetic loss or mutation of the LUBAC subunits HOIP and HOIL-1 or of OTULIN causes autoinflammatory syndromes accompanied by metabolic defects, including amylopectinosis, lipodystrophy, and fatty liver disease. Yet, it remains unclear how LUBAC and OTULIN control metabolic signalling. Here, we demonstrate that LUBAC and OTULIN dynamically regulate the energy-sensing kinase AMPK, a central sensor and switch for cellular and organismal energy balance. LUBAC's activity through the catalytic subunit HOIP is required for full AMPK activation in response to energetic stress, whereas OTULIN antagonises this response. LUBAC and OTULIN form a complex with AMPK, and LUBAC can directly ubiquitinate AMPKα and β subunits in cells and in vitro, establishing AMPK as a bona fide M1-linked ubiquitin substrate. Loss of LUBAC blunts AMPK activation, reduces bioenergetic adaptability, impairs autophagy, and sensitises cells to starvation-induced death, while Drosophila lacking Lubel - the fly orthologue of LUBAC - exhibit defective AMPK activation and reduced survival during starvation. Our findings identify M1-linked ubiquitination as a previously unrecognised regulatory layer controlling AMPK activation, metabolic adaptability, and the cellular response to energetic stress.
    DOI:  https://doi.org/10.1038/s41418-026-01675-z
  17. Cancer Cell. 2026 Feb 09. pii: S1535-6108(26)00048-6. [Epub ahead of print]44(2): 257-259
    Ubiquitin control of cytosolic DNA sets immune responses to DNA damage.
    Samuel F Bakhoum, Ashley M Laughney.
      In this issue of Cancer Cell, Li et al. uncover a novel SPOP-USP7-TREX1 axis that controls cytosolic DNA clearance after DNA damage, thereby gating tumor-cell-intrinsic cyclic GMP-AMP synthase (cGAS)-STING activation and response to radioimmunotherapy. Compellingly, targeting USP7 and TREX1 might sharpen patient selection and combination strategies.
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.009
  18. PLoS Pathog. 2026 Feb 09. 22(2): e1013955
    Cytotoxic lymphocytes counteract viral type I interferon immune evasion.
    Michael Y Schakelaar, Liling Shan, Shuang Li, Rianne G Bouma, Josefien W Hommes, Jorine G F Sanders, Jan Meeldijk, Laura L Winkler, Toine Ten Broeke, Robert F Kalejta, Niels Bovenschen.
      Viruses are recognized by host cell innate immunity through viral RNA/DNA sensing by cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING). However, many viruses evade cGAS-STING signaling and antiviral IFN-β response. Here, we show that natural killer (NK) cells counteract immune evasion of type I interferon response upon human cytomegalovirus (HCMV) infection. NK cells enhance IFN-β response in virus-infected cells more efficiently than perforin-knockout and GrM-knockout NK cells. Mechanistically, GrM cleaves viral pp71 into two fragments, the first, like full-length pp71, still inhibits cGAS-STING-IFN-β response but is rapidly degraded by the proteasome, and the second fragment that rather augments IFN-β and outperforms full-length pp71 inhibition of STING. NK cells cannot enhance IFN-β response in cells infected with HCMV that harbors a pp71 with a mutated GrM cleavage site. We conclude that NK cells use GrM to counteract cytomegaloviral innate immune evasion through pp71-mediated inhibition of cGAS-STING-IFN-β innate immune response.
    DOI:  https://doi.org/10.1371/journal.ppat.1013955
  19. Cancer Res. 2026 Feb 11.
    SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance.
    Mao Li, Yaqi Chen, Anyi Liu, Qi Wu, Changsheng Huang, Da Song, Fuqing Hu, Jingqin Lan, Chen Huang, Junbo Hu, Guihua Wang.
      Regulatory T cells (Tregs) within the tumor microenvironment critically undermine the efficacy of PD-1 immune checkpoint blockade. Metabolic reprogramming has emerged as a critical determinant of antitumor immunity, highlighting the need to define the metabolic cues that program Treg differentiation in cancer. Here, we identified the purine biosynthesis intermediate succinylaminoimidazole carboxamide ribose-5'-phosphate (SAICAR) as a key metabolic driver of Treg induction and resistance to anti-PD-1 immunotherapy. Mechanistically, SAICAR directly bound to the serine/threonine phosphatase PPM1A, inhibiting SMAD3 dephosphorylation and thereby sustaining TGF-β-SMAD3 signaling. Persistent SMAD3 activation enhanced FOXP3 transcription and stabilized the Treg lineage. In both human tumors and mouse models, elevated intratumoral SAICAR levels were associated with increased Treg accumulation, suppression of effector T cell function, and failure of PD-1 blockade. Genetic or pharmacological reduction of SAICAR restored antitumor immunity and sensitized tumors to PD-1 therapy. Notably, low-dose 6-mercaptopurine disrupted SAICAR-driven immunosuppression and synergized with anti-PD-1 treatment without inducing systemic immune toxicity. Together, these findings establish SAICAR as an immunometabolic regulator that links purine metabolism to immune evasion and highlight a therapeutically actionable pathway to overcome metabolite-driven resistance to immune checkpoint blockade.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4373
  20. J Biol Chem. 2026 Feb 06. pii: S0021-9258(26)00125-0. [Epub ahead of print] 111255
    HuR-Driven Reversible Mitochondrial Shuttling Buffers Cytosolic miRNA Levels in Hepatic Cells.
    Saikat Banerjee, Sourav Hom Choudhury, Susanta Chatterjee, Guoku Hu, Kamalika Mukherjee, Suvendra N Bhattacharyya.
      Subcellular compartmentalization may be an effective way of controlling the abundance and activity of miRNAs in mammalian cells. Exploring the regulatory processes that control miRNA activity, we found that specific miRNAs are reversibly localized to the mitochondrial matrix in a context-dependent manner. Our data suggest a de novo role of mitochondria as miRNA storage site in mammalian cells. miR-122 is a key hepatic miRNA regulating metabolic processes in the mammalian liver. In this study, we observed increased mitochondrial targeting of miR-122 in amino acid-starved hepatic cells. Interestingly, when cells are refed with amino acids, mitochondrial miR-122 is relocalized to the cytosol and reused for translational repression. Moreover, this phenomenon is not limited to miR-122, as other mitochondrial miRNAs (mito-miRs) follow similar transient storage inside mitochondria in stressed cells. Bioinformatic analysis revealed that mitochondria-localized mito-miRs preferentially target mRNAs encoding crucial mitochondrial components related to apoptosis. Hence, hepatic cells regulate apoptosis pathways during the starvation-refeeding cycle by shuttling a specific set of miRNAs to and from mitochondria, thereby balancing cytosolic miRNA content. Stress response miRNA binder ELAVL1 or HuR protein was found to be both necessary and sufficient for transporting the mito-miRs to the mitochondrial matrix - a process also controlled by the interaction between mitochondria and the endoplasmic reticulum.
    Keywords:  Ago2; HuR; miRNA; miRNA import to mitochondria; mito-miRs; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2026.111255
  21. bioRxiv. 2026 Feb 02. pii: 2026.01.30.702567. [Epub ahead of print]
    "Tumor-to-endothelium mitochondrial transfer licenses endothelial cells for CD8 + T cell recognition via mitochondrial neoantigen presentation".
    Francesca Costabile, Pierini Stefano, Renzo Perales-Linares, Nektaria Leli, Adham Bear, Cameron J Koch, Beatriz M Carreno, Michael Lotze, Lerry Singh, Marny Falck, Andrea Facciabene.
      Renal cell carcinoma (RCC) frequently exhibits resistance to immune checkpoint blockade, highlighting the need for strategies that enhance tumor-specific T cell priming and improve immune access to the tumor microenvironment. Here we show that vaccination targeting tumor-associated mitochondrial antigens (TAMAs), derived from tumor-specific mitochondrial DNA (mtDNA) missense mutations, synergizes with PD-1/PD-L1 blockade to overcome checkpoint refractoriness in the RENCA RCC model. TAMAs vaccination elicits antigen-specific T cell responses, increases intratumoral CD8 + T cell infiltration, and reduces immunosuppressive myeloid populations, resulting in delayed tumor progression and improved survival when combined with checkpoint inhibition. In parallel, TAMAs + checkpoint blockade induces vascular remodeling characterized by increased pericyte coverage, reduced vascular leakage, improved perfusion and reduced hypoxia. Mechanistically, vascular remodeling is driven by CD8 + T cell-dependent, IFN γ -associated immune activity and is associated with endothelial apoptosis and diminished intratumoral CD31 signal. We further identify tumor-to-endothelium mitochondrial transfer as a mechanism linking mitochondrial neoantigens to the tumor vascular compartment: tumor-derived mitochondria enter human and mouse endothelial cells in vitro and in vivo , and tumor-associated mtDNA mutations are detectable in endothelial fractions from murine tumors and human RCC specimens. Human endothelial cells can present mitochondrial neoantigens via MHC class I and become targets of TAMAs-specific CD8 + T cell cytotoxicity, including following mitochondrial acquisition from tumor cells. Together, these findings establish mitochondrial neoantigen immunity as a tractable approach to enhance checkpoint responses and reveal mitochondrial transfer as an antigenic bridge that expands immune targeting to the tumor vasculature.
    DOI:  https://doi.org/10.64898/2026.01.30.702567
  22. bioRxiv. 2026 Jan 28. pii: 2026.01.26.700635. [Epub ahead of print]
    Metabolic modeling and functional genomics reveal taxa and host gene interactions in colorectal cancer.
    Katja Della Libera, Elizabeth M Adamowicz, Amanda Muehlbauer, Sambhawa Priya, Adnan Alazizi, Francesca Luca, Ran Blekhman.
      Colorectal cancer (CRC) is associated with changes in the microbial communities in the tumor microenvironment. Although metabolic reprogramming is an important feature of host cells in CRC, little is known about metabolic changes in the tumor-associated microbiota and how these microbial metabolic alterations can contribute to disease. Here, we investigated metabolic host-microbiome interactions in CRC using complementary computational and experimental approaches. Using patient-specific in silico metabolic models across three independent datasets, we discovered that Fusobacterium , a cancer-promoting taxon, consistently grows faster in tumor-associated versus normal tissue-associated microbiomes. This finding prompted us to investigate whether host metabolic changes drive these microbial growth advantages. By integrating our metabolic predictions with host transcriptomics data, we identified correlations between tumor gene expression and the growth of CRC-associated taxa (including Porphyromonadaceae , Blautia , and Streptococcus ), as well as associations between host genes and microbial metabolism of dietary components (including choline, amino acids, and starch). To test whether these correlations reflect causal relationships, we simulated spent medium experiments in silico , demonstrating that Blautia preferentially grows on metabolites produced by tumor versus normal host cells. We further validated the direct impact of microbes on host metabolism using an in vitro system, where colon cancer cells exposed to human microbiomes showed gene expression changes in response to specific taxa including Bilophila , Anaerotruncus , and Escherichia . Together, these findings reveal a metabolic dialogue between host and microbiome in CRC, where tumor metabolic reprogramming creates a favorable environment for pathogenic microbes, which in turn may reinforce tumorigenic processes through metabolic crosstalk.
    DOI:  https://doi.org/10.64898/2026.01.26.700635
  23. Nat Metab. 2026 Feb 11.
    Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species.
    Anjali Amrapali Vishwanath, Typhaine Comyn, Rodrigo G Mira, Claire Brossier, Carlos Pascual-Caro, Maya Faour, Kahina Boumendil, Chaitanya Chintaluri, Carla Ramon-Duaso, Ruolin Fan, Kishalay Ghosh, Helen Farrants, Jean-Paul Berwick, Riya Sivakumar, Mario Lopez-Manzaneda, Eric R Schreiter, Thomas Preat, Tim P Vogels, Vidhya Rangaraju, Arnau Busquets-Garcia, Pierre-Yves Plaçais, Alice Pavlowsky, Jaime de Juan-Sanz.
      From insects to mammals, essential brain functions, such as forming long-term memories (LTMs), increase metabolic activity in stimulated neurons to meet the energetic demand associated with brain activation. However, while impairing neuronal metabolism limits brain performance, whether expanding the metabolic capacity of neurons boosts brain function remains poorly understood. Here, we show that LTM formation of flies and mice can be enhanced by increasing mitochondrial metabolism in central memory circuits. By knocking down the mitochondrial Ca2+ exporter Letm1, we favour Ca2+ retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H+/Ca2+ exchange. The resulting increase in mitochondrial Ca2+ over-activates mitochondrial metabolism in neurons of central memory circuits, leading to improved LTM storage in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in neurons and indicate its involvement in shaping higher brain functions, such as LTM.
    DOI:  https://doi.org/10.1038/s42255-026-01451-w
  24. Hepatol Commun. 2025 Dec 01. pii: e0853. [Epub ahead of print]9(12):
    Induction of TFEB promotes Kupffer cell survival and reduces lipid accumulation in MASLD.
    Mandy M Chan, Sabine Daemen, Wandy Beatty, Kathleen Byrnes, Kevin Cho, Daniel Ferguson, Natalie Feldstein, Christopher Park, Zhen Guo, Arick C Park, Christina F Fu, Kira L Florczak, Li He, Bin Q Yang, Ali Javaheri, Gary J Patti, Brian N Finck, Babak Razani, Joel D Schilling.
       BACKGROUND: Kupffer cells (KCs) are the tissue-resident macrophages of the liver, where they serve a critical role in maintaining liver tissue homeostasis and act as a filter for circulation. The composition of hepatic macrophages changes during metabolic dysfunction-associated liver disease (MASLD), with the loss of resident KCs being a hallmark of disease progression. The mechanism(s) and consequences of KC death in metabolic liver disease have yet to be defined. Transcription factor EB (TFEB) is a master regulator of lysosome function and lipid metabolism, which has been shown to protect macrophages from lipid stress in atherosclerosis. We hypothesized that TFEB would improve KC fitness in MASLD.
    METHODS: To investigate the potential beneficial effect of TFEB induction in KCs, we created a transgenic mouse in which TFEB was overexpressed specifically in KCs and evaluated its impact on disease pathogenesis in high-fat, high-sucrose (HFHS) and choline-deficient diet models of MASLD.
    RESULTS: We found that TFEB induction protected KCs from cell death in both models of MASLD. KC preservation through TFEB induction reduced liver steatosis with HFHS diet via mechanisms that were dependent on macrophage lysosomal lipolysis and mitochondrial fatty acid oxidation. Fibrosis was unchanged in choline-deficient diet studies. TFEB protected KCs from cell death by diminishing oxidative stress and reducing ferroptosis through a mechanism that involved enhanced NADPH levels.
    CONCLUSIONS: TFEB induction promotes KC fitness upon lipid stress during MASLD. Preservation of lipid-adapted KCs demonstrates beneficial effects against liver steatosis and protects portal filtration during MASLD.
    Keywords:  de novo lipogenesis; ferroptosis; lipid peroxidation; macrophages; oxidative stress
    DOI:  https://doi.org/10.1097/HC9.0000000000000853
  25. PLoS One. 2026 ;21(2): e0340968
    Computational assessment of the relationship between metabolism and histone methylation in cancer cells.
    Mohammad Rasouli Koohi, Mahya Mehrmohamadi.
      Aberrant histone methylation and metabolic alterations are key hallmarks of cancer. Metabolic reprogramming during tumorigenesis could impact the histone methylation pattern by altering the availability of substrates and cofactors required for histone methyltransferases (HMTs) and demethylases (HDMs) activities. Despite advances in understanding this complex interplay, quantitative information about the contributions of specific metabolic shifts and histone methylation dynamics remains poorly understood. Here, we used multi-omics data integrated with machine learning models to discover key metabolites, genes, and pathways predictive of histone methylation levels in cancer cell lines. Our cell line models highlighted the significant role of metabolites associated with one-carbon, nucleotide, redox and lipid metabolism on histone marks. Validation in primary tumors confirmed the cell line models' findings. Overall, this study quantifies the contributions of the metabolic network to histone methylation variation in cancer cells.
    DOI:  https://doi.org/10.1371/journal.pone.0340968
  26. Exp Mol Med. 2026 Feb 13.
    Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.
    Tae Hyun Kim, Seong Hun Lim, Hyesung Lee, Young Chan Chae, Do Sik Min.
      The tumor microenvironment (TME) is a complex ecosystem composed of not only malignant cells but also diverse stromal and immune cell populations that collectively shape tumor behavior. Metabolism is a central regulator of the TME, orchestrating intercellular communication through altered nutrients and signaling pathways to influence both the metabolic plasticity of cancer cells and functional balance of immune populations, ultimately determining tumor progression and antitumor immunity. Although tumor-intrinsic metabolic programs have been extensively characterized, emerging evidence highlights stromal metabolism as the dominant force sculpting immune responses within the TME. Among the nonmalignant stromal constituents, cancer-associated fibroblasts and cancer-associated adipocytes have emerged as metabolically active hubs that release and redistribute key metabolites, such as lactate, fatty acids and amino acids, to modulate the activity of both tumor and immune cells. Here we integrate recent advances in the understanding of stromal-immune metabolic crosstalk and elucidates how diverse metabolic mechanisms, including nutrient competition, mitochondrial remodeling, redox imbalance and immunometabolic rewiring, collectively reinforce an immunosuppressive TME and drive therapeutic resistance. Our study highlights the emerging strategies for selectively reprogramming these metabolic networks as potential therapeutic avenues. Deciphering these multilayered interactions will establish a conceptual and mechanistic foundation for reprogramming TME, restoring immune competence and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions.
    DOI:  https://doi.org/10.1038/s12276-026-01650-1
  27. Nat Methods. 2026 Feb 09.
    Deep-coverage single-cell metabolomics enabled by ion mobility-resolved mass cytometry.
    Mingdu Luo, Tianzhang Kou, Yandong Yin, Shengyi Zhou, Xiaolan Zhu, Xinhao Zeng, Junhao Hu, Zheng-Jiang Zhu.
      Current single-cell metabolomics approaches are limited by insufficient sensitivity, robustness and metabolite coverage. We present an ion mobility-resolved mass cytometry technology that integrates high-throughput single-cell injection with ion mobility-mass spectrometry for multidimensional metabolomic profiling. Ion mobility-enabled selective ion accumulation and cell superposition-based amplification strategies substantially enhance sensitivity, robustness and overall analytical performance. Combined with our computational tool, MetCell, this technology allows high-throughput analysis while achieving exceptional profiling depth, detecting over 5,000 metabolic peaks and annotating approximately 800 metabolites per cell-representing a 3-fold to 10-fold improvement over existing methods. It offers attomole-level sensitivity and captures a broad dynamic range of metabolites within individual cells. Applied to 45,603 primary liver cells from aging mice, it enabled accurate cell-type and cell-subtype annotation and revealed distinct metabolic states and heterogeneity in hepatocytes during aging. This platform sets a new benchmark for high-throughput single-cell metabolomics, advancing our understanding of metabolic heterogeneity at single-cell resolution.
    DOI:  https://doi.org/10.1038/s41592-025-02970-2
  28. bioRxiv. 2026 Jan 31. pii: 2026.01.31.703051. [Epub ahead of print]
    F26BP enables control of glycolysis rate independent of energy state.
    Megan M Kober, Xinyi Yang, Bradley A Webb, Denis V Titov.
      Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. Multiple allosteric regulators control glycolytic enzymes in vitro . For example, phosphofructokinase (PFK) is allosterically regulated by fructose-2,6-bisphosphate (F26BP), ATP, ADP, AMP, citrate, acyl-CoA, and inorganic phosphate. It is not well understood which properties of homeostasis are enabled by each of these regulators, and whether they perform redundant or distinct functions. Using mathematical modeling and experiments with human cells lacking F26BP, we demonstrate that F26BP alters glycolytic rate independent of cellular ATP demand-a unique function not shared by other regulators. We also identified several downstream glycolytic intermediates as novel regulators of F26BP levels. Our findings clarify the role of F26BP as a unique regulator that controls the glycolytic rate independently of the cellular energy state in response to hormone and biosynthetic precursor levels. The F26BP regulatory circuit enables respiratory fuel selection and biosynthesis from glycolytic intermediates.
    DOI:  https://doi.org/10.64898/2026.01.31.703051
  29. Nat Genet. 2026 Feb 13.
    Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types.
    Andrew Everall, Avraam Tapinos, Aliah Hawari, Alex J Cornish, Amit Sud, Daniel Chubb, Ben Kinnersley, Anna Frangou, Miguel Barquin, Josephine Jung, David N Church, Ludmil B Alexandrov, Richard S Houlston, Andreas J Gruber, David C Wedge.
      Whole-genome sequencing (WGS) enables exploration of the full spectrum of oncogenic processes that generate characteristic patterns of mutations. Mutational signatures provide clues to tumor etiology and highlight potentially targetable pathway defects. Here alongside single-base substitution, doublet-base substitution, small insertion and deletion and copy number aberration signatures previously covered by the Catalogue of Somatic Mutations in Cancer (COSMIC), we report signatures from an additional mutation type, structural variations (SVs), extracted de novo from WGS in 10,983 patients across 16 tumor types recruited to the 100,000 Genomes Project. Across the five mutation classes, we report 134 signatures, 26 of which are new to COSMIC, including an SV signature reference set. By relating signatures to genomic features and clinical phenotypes, we provide further insights into mutagenic processes and the application of signature analysis to precision oncology.
    DOI:  https://doi.org/10.1038/s41588-025-02474-x
  30. Science. 2026 Feb 12. 391(6786): 659-660
    The bottleneck of fat burning.
    Angela M Ramos-Lobo, Pierre Maechler.
      A mitochondrial transport protein promotes carnitine synthesis in mice when fat consumption is needed.
    DOI:  https://doi.org/10.1126/science.aef2173
  31. Cell Chem Biol. 2026 Feb 10. pii: S2451-9456(26)00026-7. [Epub ahead of print]
    Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis.
    Peter Geon Kim, Christopher B Hergott, Aidan P Miller, Amy Deik, Meaghan Boileau, Kevin Bullock, Kerry A Pierce, Angelina H Choy, Wesley Shin, Marie McConkey, Justin Loke, Birgitta A Ryback, Michael N Trinh, Justine C Rutter, Hong Yue, Hojong Yoon, Paul Park, Shourya S Roy Burman, Matthew G Vander Heiden, Eric S Fischer, Scott A Armstrong, Clary Clish, Benjamin L Ebert.
      Somatic mutations in TET2 drive hyper-inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the molecular link between TET2 inactivation and myeloid immune activation remains unclear. We used in vivo genome-wide genetic perturbations enabled by ultra-diverse barcoding in primary wild-type (WT) or Tet2 knockout (KO) Cas9+ hematopoietic stem-progenitor cells (HSPCs) to elucidate the basis of Tet2 KO inflammation. We uncover a metabolic circuit by which Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor. Tet2 loss disrupts this inhibitory Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified that ATP citrate lyase (Acly) is decorated with O-GlcNAc and is a critical node for lipid accumulation and inflammation in Tet2 KO. These findings reveal that Tet2 suppresses inflammation by gating nutrient-responsive chromatin remodeling and nominate metabolic interventions to restrain inflammatory disease in TET2-mutant clonal hematopoiesis.
    Keywords:  Tet2-mutant inflammation; clonal hematopoiesis; hematopoietic stem-progenitor screens; lipid droplets
    DOI:  https://doi.org/10.1016/j.chembiol.2026.01.006
  32. NPJ Aging. 2026 Feb 10.
    Frailty phenotype reveals heterogeneity in aging and distinct taurine associations.
    April Kim, Rebecca Keener, Ashton Omdahl, Michael Bene, Reyhan Westbrook, Anne Le, Cissy Zhang, Pratik Khare, Mohammed Khadeer, Luigi Ferrucci, Ruin Moaddel, Alexis Battle, Peter Abadir.
      Frailty, characterized by diminished physiological reserve and increased vulnerability to stressors, is a common geriatric syndrome associated with adverse health outcomes. While recent seminal studies have reported conflicting findings regarding taurine, a sulfur-containing amino acid with antioxidant properties, and its relationship with aging, these discrepancies may reflect the heterogeneity of aging trajectories among older adults that chronological age alone fails to capture. Here, we propose that frailty status may better capture this heterogeneity and reveal associations between taurine and aging that are obscured when using age alone. We examined taurine and upstream metabolites in the taurine biosynthesis pathway in 146 community-dwelling adults aged 20-97 years, focusing on older adults (≥69 years) stratified by frailty phenotype. We observed a non-monotonic relationship where taurine levels were highest in robust individuals, lowest in prefrail, and intermediate in frail groups. Analysis of the taurine biosynthesis pathway revealed distinct metabolic profiles across frailty states. Robust individuals demonstrated efficient pathway flux, while the prefrail group exhibited maximal metabolic disruption characterized by bottlenecks. Frail individuals showed persistent metabolic disruption but partial taurine restoration, suggesting compensatory mechanisms. Inflammatory marker associations varied by frailty status, with TNF-α showing a significant negative correlation with taurine specifically in prefrail individuals. These findings demonstrate that frailty status reveals distinct shifts in taurine metabolism and immunological regulation not captured by chronological age alone, providing a more biologically meaningful framework for understanding taurine biology in aging populations.
    DOI:  https://doi.org/10.1038/s41514-026-00342-4
  33. Nat Commun. 2026 Feb 10.
    NAPRT-mediated deamidated NAD biosynthesis enhances colon tissue resiliency and suppresses tumorigenesis.
    Xiaoyue Wu, Jason G Williams, Haoyang Liang, Artiom Gruzdev, Joshua Hartsell, Jack Shpargel, Rabina Mainali, Yi Fang, Ming Ji, Caroline Duval, Xin Xu, Zixin Zhang, Heather Winter, Peter Pediaditakis, Arun R Pandiri, Marie E Migaud, Alan K Jarmusch, Huimin Yu, Xiaojing Liu, Jian-Liang Li, Xiaojiang Xu, Igor Shats, Xiaoling Li.
      Nicotinamide adenine dinucleotide (NAD) is synthesized through both amidated salvage and deamidated pathways. Although NAD-producing enzymes are often overexpressed in cancer cells to meet the high metabolic demands of rapid proliferation and are considered oncogenic, we report that physiological levels of nicotinic acid phosphoribosyl transferase (NAPRT), the first enzyme in the Preiss-Handler arm of the deamidated pathways, suppress tumorigenesis. We show that NAPRT is enriched in gut epithelial cells, where it sustains the NAD pool for an efficient response to stress-induced acute NAD depletion. Consequently, NAPRT deficiency impairs the activity of poly-(ADP-ribose) polymerases and DNA repair, sensitizes mice to chemical-induced colitis and tumorigenesis, as well as to age-associated spontaneous tumor development. Moreover, low NAPRT expression correlates with poor prognosis in several human cancer types. Thus, homeostatic levels of deamidated NAD biosynthesis contribute to tumor suppression, and boosting this pathway may offer a strategy for cancer prevention.
    DOI:  https://doi.org/10.1038/s41467-026-68998-w
  34. bioRxiv. 2026 Jan 27. pii: 2026.01.26.701810. [Epub ahead of print]
    Genome-wide CRISPRi screen identifies basigin loss as protective in cardiac hypoxia.
    Will R Flanigan, Ayush D Midha, Skyler Y Blume, Yolanda Marti-Mateos, Mauro W Costa, Yu Huang, Alan H Baik, Helen Huynh, Gautam Susarla, Neal K Bennett, Romana A Nowak, Deepak Srivastava, Ken Nakamura, Isha H Jain.
      Cardiac function depends on continuous oxidative metabolism, rendering cardiomyocytes highly vulnerable to oxygen deprivation. Here, we performed a genome-wide CRISPR interference (CRISPRi) screen in human iPSC-derived cardiomyocytes to identify genes that modulate survival during chronic hypoxia. This screen revealed that knockdown of basigin (BSG), a chaperone for the monocarboxylate transporters MCT1 and MCT4, confers robust protection. Canonically, hypoxic cells suppress pyruvate dehydrogenase (PDH) activity to reduce the oxidation of major fuel sources, thereby limiting TCA cycle flux, lowering oxygen consumption, and minimizing reactive oxygen species generated by an overly reduced electron transport chain (ETC). In contrast, we found that BSG inhibition reverses this response, prioritizing ATP maintenance during hypoxia and enhancing cardiomyocyte survival. Mechanistically, BSG loss restricts lactate efflux, leading to decreased PDH phosphorylation and increased glucose uptake for oxidation. Consistent with this, ETC subunits are more essential under hypoxia, highlighting cardiomyocytes' unusual reliance on aerobic ATP production even when oxygen is limited. These findings challenge prevailing models of hypoxic adaptation by revealing cardiomyocyte-specific bioenergetic requirements and motivating future therapeutic efforts.
    DOI:  https://doi.org/10.64898/2026.01.26.701810
  35. Metabolomics. 2026 Feb 09. 22(2): 22
    What's in a name? Metabolite identification: challenges and pitfalls in untargeted metabolomics.
    Georgios Theodoridis, Oliver Fiehn, Michal Holčapek, Royston Goodacre, Daniel Raftery, Robert Plumb, Timothy M D Ebbels, Michael Witting, Helen Gika, Ian D Wilson.
       BACKGROUND: The aim of metabolic phenotyping (metabotyping) is to discover and identify metabolites (including lipids) that can be used to characterize biological samples and differentiate between different physiological states. The identification of the metabolites responsible for this differentiation is essential if mechanistic understanding is to be obtained. Confident metabolite identification arguably represents the most important outcome of untargeted metabolomics studies but currently the standards used for metabolite identification reported in many publications do not strictly follow the various published guidelines and thus these identifications lack sufficient proof.
    AIM OF REVIEW: In this perspective we define problems that currently plague the field of metabolite identification using MS-based techniques, particularly LC-MS, in untargeted metabolic phenotyping. Despite considerable efforts by the community (researchers, instrument manufacturers, software, and database developers) this continues to be a contentious and error-prone step in the metabolomics workflow. The majority of publications provide only sparse data on the evidence for metabolic markers "identified" and we have observed an alarming increase in the frequency of erroneous metabolite identifications. Here, we describe the problem and provide several illustrative case studies. Our goal is to raise awareness and highlight the issue of poor metabolite identification, since it is also increasingly apparent that these errors are not always recognised during the reviewing process, such that papers with potentially erroneous metabolite identities reach publication.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: Poor metabolite identification potentially represents an existential threat to the credibility of untargeted "discovery" metabolomics and can pollute the literature. Here we describe the aetiology of the problem and explain how and why this issue affects the field. We argue that coordinated action is required by researchers, database managers, scientific societies and the reviewers, editors and publishers of scientific journals to both acknowledge and address this important problem.
    Keywords:  Biomarkers; Lipidomics; Mass spectrometry; Metabolite annotation; Metabonomics; Research integrity
    DOI:  https://doi.org/10.1007/s11306-025-02387-0
  36. Curr Osteoporos Rep. 2026 Feb 09. 24(1): 6
    Nutrients and Metabolites as Signalling Molecules in Osteoclasts.
    Kavishadhi Chandrasekaran, Sitao Hu, Kara Farstad-O'Halloran, Killugudi Swaminatha Iyer, Haibo Jiang, Nathan Pavlos, Kai Chen.
       PURPOSE OF REVIEW: This review aims to highlight the emerging concept that nutrients and metabolites act not merely as energy sources or biosynthetic precursors, but also as instructive signalling molecules in osteoclasts. While much is known about transcriptional and genetic pathways governing osteoclast differentiation and function, comparatively little attention has been given to the role of cellular metabolism and nutrient-sensing mechanisms. This review seeks to categorise key metabolites based on their signalling roles and examine how they influence osteoclastogenesis through metabolic, epigenetic, and inflammatory pathways.
    RECENT FINDINGS: Recent studies have demonstrated that nutrients such as glucose, amino acids, and lipids, along with their intermediary metabolites such as succinate, itaconate, α-ketoglutarate (αKG), S-adenosylmethionine (SAM), and acetyl-CoA, regulate osteoclast formation and function by modulating signalling cascades and epigenetic landscapes. These molecules engage nutrient sensors (e.g., aldolase, mTORC1, CPT1) and transcriptional regulators (e.g., NFATc1, PPARs), while also affecting chromatin structure, inflammatory responses, and organelle dynamics. Osteoclast metabolism is tightly linked to cellular fate through nutrient-sensing and metabolite-driven signalling. Elucidating these pathways will reshape our understanding of osteoclast regulation and help identify new metabolic targets for treating bone diseases.
    Keywords:  Bone; Epigenetics; Immunometabolites; Metabolites; Nutrient sensor; Osteoclast
    DOI:  https://doi.org/10.1007/s11914-026-00955-4
  37. Autophagy Rep. 2026 ;5(1): 2622228
    Autophagy in kidney physiology: from cellular quality control to organ metabolism.
    Takeshi Yamamoto, Satoshi Minami, Yoshitaka Isaka.
      Autophagy is a cellular process that maintains kidney physiology by recycling intracellular components to preserve homeostasis. In the kidney, autophagy supports energy metabolism and integrity across multiple cell types. Its regulation is tightly governed by nutrient availability, hormonal cues, and oxygen levels, primarily through signaling pathways such as mechanistic target of rapamycin kinase (mTOR), AMP-activated protein kinase (AMPK), and transcription factor EB (TFEB). Under physiological conditions, autophagy is dynamically regulated to meet metabolic demands. However, aging, obesity, and metabolic stress impair lysosomal function, leading to a pathological state termed autophagic stagnation, in which autophagosomes accumulate but degradative flux is compromised. Rather than being uniformly protective, this stagnation promotes cellular damage and contributes to kidney disease progression. Notably, autophagic stagnation in proximal tubular epithelial cells (PTECs) contributes to acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition and exacerbates lipotoxicity in obesity-related kidney disease. Recent studies highlight the importance of transcriptional regulators - including TFEB and MondoA - in maintaining autophagic activity and mitochondrial homeostasis. Therapeutic strategies aimed at restoring autophagic flux - pharmacologically or through lifestyle interventions such as caloric restriction - hold promise for preserving kidney function. Deeper understanding of cell type - specific autophagy regulation will be critical for developing targeted and context-specific therapies.
    Keywords:  Mitophagy; Rubicon; autophagic stagnation; fibroblast growth factor 21 (FGF21); lipophagy; lysophagy; proximal tubular epithelial cells (PTECs)
    DOI:  https://doi.org/10.1080/27694127.2026.2622228
  38. bioRxiv. 2026 Feb 04. pii: 2026.02.02.703178. [Epub ahead of print]
    The aging mouse lipidome.
    Edgar Esparza, Steven E Pilley, Xuanyi Shi, Preeti Iyengar, Shruti Sivaraman, George Wang, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Aeowynn J Coakley, Ryo Higuchi-Sanabria, Whitaker Cohn, Peter J Mullen.
      Aging is associated with widespread metabolic changes that contribute to functional decline and disease. While prior studies have characterized age-associated changes in lipids, it still remains incompletely understood how the lipidome changes across tissues and between sexes during aging. Here, we performed targeted lipidomics across 10 organs collected from male and female mice at five ages spanning adolescence to old age. We analyzed 775 lipids across multiple lipid classes and found that aging affects the lipidome in an organ-specific manner. The thymus and quadriceps muscle had the most age-associated lipid changes, whereas lipid levels in organs such as the kidney and lung remained more stable. In quadriceps muscle, aging was associated with a decrease in specific phosphatidylcholine and phosphatidylethanolamine lipids, particularly those containing adrenic acid. We also identified sex-dependent differences in lipid composition, with the spleen showing differences throughout life. Spleens from female mice had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine compared to males. Together, these data provide a comprehensive atlas of age- and sex-associated lipid changes across mouse organs and complement existing metabolic and transcriptomic resources to support studies of mouse aging.
    DOI:  https://doi.org/10.64898/2026.02.02.703178
  39. Cancer Res. 2026 Feb 13.
    LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.
    Zhihong Luo, Kangdi Li, You Yu, Yi Liu, Hong Weng, Xian-Tao Zeng, Yi Zheng, Wenhua Li.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and often undergo metabolic reprogramming. Metabolic shifts within CAFs can influence cancer cell behavior. In this study, we revealed that the loss of lactate dehydrogenase B (LDHB) in CAFs drives a metabolic shift that significantly enhances breast cancer metastasis. LDHB loss in CAFs drove a shift towards an inflammatory fibroblast phenotype. Mechanistically, LDHB deficiency led to lactate accumulation, which disrupted the interaction between dual specificity phosphatase 16 (DUSP16) and p38, causing sustained p38 activation. Persistent p38 signaling reprogrammed CAFs into an inflammatory phenotype characterized by abundant secretion of the chemokine CXCL8, which in turn enhanced metastasis of breast cancer cells. In summary, these findings identify LDHB as a key metabolic regulator in CAFs and provide insights into how metabolic reprogramming promotes the inflammatory, pro-metastatic phenotype of CAFs, highlighting activating LDHB as a potential strategy for limiting cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2792
  40. Cell Metab. 2026 Feb 06. pii: S1550-4131(26)00007-0. [Epub ahead of print]
    Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.
    Fenfen Ji, Pingmei Huang, Qiming Zhou, Lok Hin Ko, Qinyao Wei, Charis Cheuk-Lok Chan, Danyu Chen, Huarong Chen, Wei Kang, Alvin Ho-Kwan Cheung, Cillian H Cheng, Jianming Shen, Yasi Pan, Ying Jiao, Lin Zhu, Tat Wai Chik, Peisi Xie, Xiao Liang, Onno Kranenburg, Zongwei Cai, Jun Yu, Chi Chun Wong.
      The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.
    Keywords:  BCAA; BCAT1; BCAT2; UMP; branched-chain amino acids; colorectal cancer; dietary restriction; metabolic compartmentalization; metastasis; uridine monophosphate
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.007
  41. bioRxiv. 2026 Jan 30. pii: 2026.01.28.702389. [Epub ahead of print]
    AADAT-Driven Metabolic Control of Malate and CoQ 10 Shapes Immune Evasion in Triple-Negative Breast Cancer.
    Megha Chatterjee, Franklin Gu, Susmita Samanta, Uttam Rasaily, Sai Manohar Thota, Dana Varghese, Yunping Qiu, Lynette Ewura Esi Fordwuo, Hugo Villanueva, Mary Kathryn McKenna, Jun Hyoung Park, Weijie Zhang, Lin Tian, Liqun Yu, Badrajee Piyarathna, Yang Gao, Brian Wesley Simons, Sung Yun Jung, Balasubramanyam Karanam, Vasanta Putluri, Nagi Chandandeep, Nada Mohamed, Jaya Ruth Asirvatham, Deborah Jebakumar, Arundati Rao, Carolina Gutierrez, Angela R Omilian, Carl Morrison, Gokul M Das, Christine Ambrosone, Erin H Seeley, Benny Abraham Kaipparettu, Irwin J Kurland, Nagireddy Putluri, Ahmed Elkhanany, Andrew A Davis, Qian Zhu, Xiang H-F Zhang, Arun Sreekumar.
      Compared to other subtypes of breast cancer, triple-negative breast cancers (TNBC) have fewer treatment options and exhibit a worse prognosis. Through integrated transcriptomic, metabolomic, immunohistochemical, spatial, and clinical analyses, we identify the mitochondrial enzyme, α-aminoadipate aminotransferase (AADAT) as a previously unrecognized metabolic immune checkpoint in TNBC. AADAT mRNA and protein were significantly upregulated in human TNBC, and high AADAT expression was associated with reduced intra-tumoral CD8⁺ T-cell density and inferior survival. Genetic silencing of AADAT in orthotopic murine TNBC models curtailed primary tumor growth and distant metastasis in a CD8⁺ T-cell-dependent manner, enhanced effector T-cell activation, and sensitized tumors to dual PD-1/CTLA-4 blockade. Mechanistically, unbiased metabolomics showed increased malate levels after AADAT knockdown. Additionally, 4-hydroxyphenylpyruvate, an essential precursor for coenzyme Q 10 (CoQ 10 ) biosynthesis, decreased following AADAT knockdown, suggesting an impaired mitochondrial electron transport chain. CoQ 10 supplementation restored metabolic balance and reversed malate accumulation caused by AADAT knockdown, indicating that AADAT helps maintain CoQ 10 -supported redox homeostasis, thereby preventing malate buildup and export. Notably, malate addition directly boosted CD8⁺ T-cell oxidative metabolism, increased the NAD⁺/NADH ratio and reactive oxygen species, and augmented TNF-α and IFN-γ production. In vivo, malate supplementation in drinking water phenocopied AADAT knockdown, restored the response to paclitaxel plus anti-PD-1 therapy in multiple independent syngeneic TNBC models with de novo or acquired resistance to immunotherapy, reduced tumor burden, and prolonged survival. In patient cohorts, higher spatially clustered intra-tumoral malate is associated with co-localization of functional CD8⁺ T cells, decreased exhausted T-cell neighborhoods, and superior post-chemotherapy outcomes. These data position AADAT as a central metabolic orchestrator of immune escape in TNBC and nominate oral malate as a readily translatable adjuvant to reverse chemo-immunotherapy resistance in TNBC.
    Statement of Significance: AADAT defines a metabolic-immune axis driving immune evasion and therapy resistance in triple-negative breast cancer. Blocking AADAT or administering oral malate reactivates CD8⁺ T-cell immunity and sensitizes chemo-immunotherapy-resistant tumors to these agents. These findings uncover a readily translatable metabolic vulnerability with potential to improve outcomes for patients with aggressive breast cancer subtypes.
    DOI:  https://doi.org/10.64898/2026.01.28.702389
  42. Nat Cell Biol. 2026 Feb;28(2): 209
    Role of vinculin in metabolism.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41556-026-01891-2
  43. Nat Commun. 2026 Feb 12. 17(1): 1645
    Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
    Veronica Bergo, Pavlos Bousounis, Giang To Vu, Mélodie Douté, Aikaterini Polyzou, Maria-Eleni Lalioti, Bogdan B Grigorash, Lyudmila Tsurkan, Nicholas Morchel, Ward Deboutte, Frédéric Brau, Thomas Manke, Sagar, Hind Medyouf, Dmitry V Bulavin, Nina Cabezas-Wallscheid, Marta Derecka, Eirini Trompouki.
      "Inflammaging", the chronic increase in inflammatory signaling with age, remains poorly understood in hematopoietic aging. Here, we identify the innate immune RNA sensor melanoma differentiation-associated protein 5 (MDA5) as an important factor of hematopoietic stem cell (HSC) aging. Aged Mda5-/- mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged Mda5-/- HSCs retain greater quiescence and superior repopulation capacity in noncompetitive transplants compared to wild-type counterparts. Multiomic analyses- including chromatin accessibility, transcriptomics, and metabolomics-reveal decreased inflammatory signaling, a youthful metabolic profile, and improved proteostasis in Mda5-/- HSCs, through regulation of HSF1 and phospho-EIF2A, key proteostasis regulators. Activation of HSF1 in aged wild-type HSCs partially restores youthful features, supporting a causal role for proteostasis maintenance. Collectively, our findings demonstrate that attenuating MDA5-dependent inflammation preserves HSC function during aging by maintaining metabolic fitness and proteostasis and provide insight into potential therapeutic strategies for mitigating hematopoietic aging.
    DOI:  https://doi.org/10.1038/s41467-026-69424-x
  44. Nat Cell Biol. 2026 Feb 11.
    Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.
    Ayşegül Erdem, Claudia Morganti, Haruhito Totani, Nick van Gastel, Keisuke Ito.
      Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in understanding the metabolic landscape of HSCs, emphasizing how their intrinsic bioenergetic programs facilitate quiescence, self-renewal and differentiation. We also summarize the dynamic metabolic interactions with the bone marrow microenvironment, including stromal cells, osteoblasts, endosteal cells and adipose tissue, highlighting how they support proper HSC fate. In addition, we discuss how alterations in metabolic homeostasis in healthy and aged HSCs are linked to haematological disorders, particularly leukaemogenesis. We discuss metabolic dysregulation in leukaemic cells that maintains malignant persistence by mimicking certain intrinsic-extrinsic key HSC metabolic features, while simultaneously activating distinct metabolic pathways to support their growth and survival. Understanding the complex role of metabolism in HSC biology will be essential to advance regenerative medicine and blood cancer prevention strategies.
    DOI:  https://doi.org/10.1038/s41556-026-01872-5
  45. J Clin Invest. 2026 Feb 12. pii: e189152. [Epub ahead of print]
    Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma.
    Lisa Werr, Jana Boland, Josephine Petersen, Fiorella Iglesias, Stefanie Höppner, Christoph Bartenhagen, Carolina Rosswog, Anna-Maria Hellmann, Yvonne Kahlert, Nadine Hemstedt, Nadliv Ibruli, Marcel A Dammert, Boris Decarolis, Jan-Michael Werner, Florian Malchers, Kathrin Schramm, Olaf Witt, Klaus Hermann Beiske, Anne Gro Wesenberg Rognlien, Maria Winther Gunnes, Karin Ps Langenberg, Jan Molenaar, Marie Bernkopf, Sabine Taschner-Mandl, Debbie Hughes, Sally L George, Louis Chesler, Johannes H Schulte, Giuseppe Barone, Mario Capasso, Lea F Surrey, Rochelle Bagatell, Julien Masliah-Planchon, Gudrun Schleiermacher, Holger Grüll, Frank Westermann, Anne M Schultheis, Reinhard Büttner, Anton G Henssen, Angelika Eggert, Martin Peifer, Neerav N Shukla, Thorsten Simon, Barbara Hero, H Christian Reinhardt, Roman K Thomas, Matthias Fischer.
      Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We here sought to examine whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome of these patients. Ectopic expression of FGFR1N546K induced constitutive down-stream signaling and interleukin-3-independent growth in Ba/F3 cells, indicating oncogene addicted proliferation. In FGFR1N546K;MYCN transgenic mice, neuroblastoma developed within the first days of life with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1 mutant high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K mutant neuroblastoma cells, and inhibited tumor growth in FGFR1N546K;MYCN transgenic mice and in a chemotherapy-resistant patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma that is associated with failure of current standard chemotherapy, and suggest potential clinical benefit of FGFR-directed therapies in FGFR1 mutant high-risk patients.
    Keywords:  Cancer; Cell biology; Mouse models; Oncology
    DOI:  https://doi.org/10.1172/JCI189152
  46. Cancer Sci. 2026 Feb 13.
    Mitochondrial Transfer in the Tumor Microenvironment.
    Ryo Omae, Takamasa Ishino, Yosuke Togashi.
      Mitochondria are not merely energy-producing organelles but also regulate metabolism, apoptosis, and inflammation. Recent studies have reported that mitochondria can be transferred between cells, and accumulating evidence suggests that this phenomenon is functionally relevant in the tumor context. Mitochondrial transfer is mediated by multiple routes such as tunneling nanotubes and extracellular vesicles. These pathways are regulated by Miro1/2, connexin 43, ICAM-1, VCAM-1, and intracellular reactive oxygen species. Within the tumor microenvironment, mitochondrial transfer from surrounding cells to tumor cells may serve as a mechanism by which tumor cells adapt to hostile metabolic conditions and evade therapeutic pressure. Furthermore, mitochondrial transfer from tumor cells to T cells in the tumor microenvironment reportedly impairs antitumor immunity. Based on these findings, novel therapeutic strategies targeting mitochondrial transfer are under investigation. Future challenges include the development of specific and safe methods to manipulate mitochondrial transfer in vivo. Understanding mitochondrial transfer and its regulation may offer new avenues to overcome resistance and improve cancer outcomes.
    Keywords:  antitumor immunity; cell‐to‐cell interaction; mitochondria; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.70342
  47. Mol Biol Evol. 2026 Feb 10. pii: msag035. [Epub ahead of print]
    Mammalian Mitochondrial DNA Accumulates Insertions and Deletions with Age in Energetically Demanding Tissues.
    Edmundo Torres-González, Barbara Arbeithuber, Nick Stoler, Marzia A Cremona, Omar Shebl, Thomas Ebner, Irene Tiemann-Boege, Francisco Diaz, Francesca Chiaromonte, Kateryna D Makova.
      Mitochondrial function can be affected by mutations in mitochondrial DNA (mtDNA). However, detecting de novo mutations in mtDNA has been challenging due to its high copy number, particularly in germline cells, and the low accuracy of conventional next-generation sequencing technologies. Using highly accurate duplex sequencing, we study the frequency of de novo insertion and deletion (indel) mtDNA mutations across multiple age groups in somatic and germline tissues of three mammalian species-mouse, macaque, and human. We demonstrate that, similar to de novo nucleotide substitutions, indels accumulate rapidly with age in somatic tissues with high energetic demand (brain and skeletal muscle) or high proliferation (liver). However, in oocytes, indels accumulate slower with age than nucleotide substitutions (or do not accumulate at all). The increases in indel frequency with age are driven mostly by deletions. Short tandem repeats are highly enriched for indels, implicating DNA replication slippage as a major driver of indel formation in mtDNA. For some species and tissues, indels are depleted at protein-coding sequences, however, indels that are multiples of 3 bp are not overrepresented. omfOurs is the most detailed study of de novo small indels in mtDNA to date. It provides parameters for models of mtDNA evolution, informs molecular mechanisms for a multitude of human genetic diseases, and illuminates the accumulation of indel mutations with age. Such accumulation may have functional consequences, as it affects reproduction later in life and drives the decline of mitochondrial function during aging.
    DOI:  https://doi.org/10.1093/molbev/msag035
  48. Nature. 2026 Feb 13.
    Briefing Chat: Caffeine slows brain ageing, suggests decades of data.
    Benjamin Thompson, Nick Petrić Howe.
      
    Keywords:  Ageing; Nutrition; Technology
    DOI:  https://doi.org/10.1038/d41586-026-00476-1
  49. Nat Aging. 2026 Feb 12.
    Clonal hematopoiesis boosts response to immune checkpoint therapy.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-026-01082-6
  50. Mol Cell. 2026 Feb 06. pii: S1097-2765(26)00030-4. [Epub ahead of print]
    Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses.
    Jie Du, Chaoqun Li, Li Chai, Fabao Zhao, Lin Lv, Zongcheng Yang, Zhiyuan Zhao, Rong Gong, Liu Yang, Meng Wu, Meng Nie, Jihui Jia, Dongwei Kang, Chengjiang Gao, Wei Zhao, Mutian Jia.
      Competition between the host and invading viruses for cellular nutrients determines the outcomes of infectious diseases. Nutrients are increasingly being recognized as regulators that interact with immunological signals, but how immune cells sense specific nutrients to regulate antiviral innate immune responses remains elusive. Here, we establish asparagine (Asn) as an intercellular nutritional checkpoint that is sensed by TANK-binding kinase 1 (TBK1) to drive innate immune responses in human and murine cells. Mechanistically, Asn directly binds to TBK1, which robustly induces TBK1 phase separation and forms liquid-like droplets, promoting TBK1 transautophosphorylation and activation. Moreover, viral infection reduces asparagine synthetase (ASNS) expression to establish an Asn-restricted microenvironment, thereby evading TBK1-triggered host immune defenses. Overall, our results suggest that TBK1 is a natural Asn sensor that links host nutritional homeostasis to antiviral immune responses and reveal that targeting Asn availability is a promising therapeutic strategy for diseases involving dysregulated TBK1 activation.
    Keywords:  IFN responses; TBK1; asparagine; phase separation; virus infection
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.010
  51. Cells. 2026 Jan 28. pii: 254. [Epub ahead of print]15(3):
    Peroxisomes in Aging: Guardians of Cellular Resilience and Function.
    Artuur Vercaemst, Mingming Zhao, Ruizhi Chai, Celien Lismont, Marc Fransen.
      Peroxisomes are multifunctional organelles that play essential roles in lipid metabolism, redox regulation, and cellular signaling. An expanding body of evidence implicates peroxisomal dysfunction as a key contributor to aging and age-related diseases. Aging is accompanied by progressive declines in key peroxisomal functions, including catalase activity, fatty acid β-oxidation, plasmalogen biosynthesis, and the metabolism of bile acids and docosahexaenoic acid, resulting in increased oxidative stress, lipid dysregulation, and alterations in membrane composition. Impaired pexophagy further exacerbates these defects by allowing the accumulation of damaged peroxisomes and compromising cellular homeostasis. Through extensive metabolic and signaling crosstalk with mitochondria, the endoplasmic reticulum, and lysosomes, peroxisomal dysfunction can propagate oxidative and metabolic disturbances throughout the cell. In addition, peroxisome-derived signaling molecules, such as hydrogen peroxide and bioactive lipids, link peroxisomal activity to cellular stress responses and organismal metabolic homeostasis. We propose that aging-associated impairments in peroxisomal protein import, redox regulation, and selective turnover progressively shift peroxisomes from adaptive metabolic signaling hubs toward sources of chronic oxidative and lipid stress. In this context, current studies highlight peroxisomal homeostasis as a potential determinant of healthy aging and point to peroxisomal pathways as emerging targets for intervention in age-related disease.
    Keywords:  aging; catalase; interorganelle crosstalk; lipid metabolism; metabolic disorders; neurodegeneration; peroxisomes; pexophagy; reactive oxygen species; therapeutic interventions
    DOI:  https://doi.org/10.3390/cells15030254
  52. Cell Rep. 2026 Feb 10. pii: S2211-1247(26)00042-2. [Epub ahead of print]45(2): 116964
    Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death.
    Koyuki Kawamura, Koya Ono, Eikan Mishima, Osamu Hashizume, Marcus Conrad, Hiroaki Miki, Yosuke Funato.
      Mg2+ is an essential cofactor for numerous enzymes, supporting fundamental cellular processes. The phosphatase of regenerating liver (PRL) protein family, frequently upregulated in cancer, inhibits cyclin M (CNNM) Mg2+ efflux transporters. To elucidate the physiological role of PRL in Mg2+ homeostasis at the cellular level, we employed combined genetic knockout and knockdown approaches. PRL deletion led to marked reduction of intracellular Mg2+ levels and triggered extensive cell death. Transcriptomic analysis revealed activation of the NF-κB pathway, and, accordingly, the genetic deletion of NF-κB p65 subunit abrogated cell death. Similarly, CNNM overexpression triggered intracellular Mg2+ decrease, NF-κB activation, and subsequent cell death. Notably, this form of cell death exhibited characteristic morphological features, including actin-driven fiber-like protrusions, distinguishing it from known cell death modalities. Our findings uncover a distinct mode of NF-κB-dependent cell death triggered by intracellular Mg2+ decrease.
    Keywords:  CNNM; CP: cell biology; NF-κB; PRL; actin polymerization; magnesium; regulated cell death
    DOI:  https://doi.org/10.1016/j.celrep.2026.116964
  53. Annu Rev Biophys. 2026 Feb 10.
    Systems Biology of Aging, Metabolism, and Mitochondria.
    Miguel Antonio Aon, Sonia Cortassa.
      Since the beginning of this century, the emergence of systems biology, driven by technological, informatic, and theoretical advances, has led to an unprecedented generation of data and information about biological systems at multiple levels of organization. We now have access not only to components of living systems but also to some of the underlying principles governing their organization within networks. This review focuses on the systems biology of aging, metabolism, and mitochondria, along with the integration of experimental and computational systems biology approaches as applied to multilayered biological networks, spanning from the molecular-subcellular to the whole organism. Sections 2 and 3 provide an overview of the insights gained from systems biology and multi-omics approaches as applied to aging and metabolism. Using the spatiotemporal dynamics of biological networks as a unifying thread, Sections 4 and 5 explore how systems biology and current methods can leverage the understanding of complex biological phenomena through integrated experimental-computational strategies, utilizing iterative, verification-validation loops between experiments and models. Section 6 concludes by highlighting the autonomously dynamic, self-organizing, and self-regulating integrative nature of living systems and the need to address these properties at the emerging convergence of biology, medicine, physics, and powerful computational technologies that include artificial intelligence.
    DOI:  https://doi.org/10.1146/annurev-biophys-021424-011852
  54. Cancer Cell. 2026 Feb 12. pii: S1535-6108(26)00053-X. [Epub ahead of print]
    Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.
    Xiuhui Shi, Alex X Arreola, Zhijun Zhou, Jingxuan Yang, Mingyang Liu, Yang Cai, Yu Ren, Hao Yuan, Qun Chen, Xinjie Chen, Xinyu Yang, Yimei Meng, Jingyi Wang, Wenyi Luo, Michael C Rudolph, Rohan Varshney, Kar-Ming Fung, Chao Xu, Wei R Chen, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li.
      Cancer-induced cachexia and anorexia are debilitating complications across many cancers, yet effective treatments remain limited due to a poor understanding of the underlying mechanisms. Here, we identify an uncharacterized tumor-immune-neural circuit driving these syndromes, centered on growth and differentiation factor 15 (GDF15). Using genetically engineered mouse models, we find that loss of GDF15 protects against appetite loss, muscle wasting, and fat loss in pancreatic, lung, and skin cancers. Single-cell RNA sequencing reveals macrophages as a major source of GDF15, induced by tumor-derived colony-stimulating factor 1 (CSF1). GDF15 acts via the central nervous system to enhance β-adrenergic signaling in the tumor microenvironment, thereby amplifying cachexia. The disruption of this feedforward loop with GDF15-neutralizing antibody, anti-CSF1R antibody, or Rearranged during Transfection (RET) inhibitor markedly reduces both cachexia and anorexia. These findings reveal a non-cell-autonomous mechanism linking tumor signals, macrophage-derived GDF15, and neural pathways, highlighting the tumor-immune-neural triad as a promising therapeutic target.
    Keywords:  adipose loss; body composition; energy expenditure; hormone; metabolic stress; muscle atrophy; norepinephrine; sympathetic nerve; tumor immune microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.014
  55. Cancer Res. 2026 Feb 09.
    FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.
    Moumita Banerjee, Yekaterina Y Zaytseva, Ellen M Reusch, Dana L Napier, Sumati Hasani, Piotr Rychahou, Tadahide Izumi, Dennis A Cheek, Jing Li, Robert M Flight, Hunter N B Moseley, Heidi L Weiss, William McCulloch, B Mark Evers, Tianyan Gao.
      Altered lipid metabolism is a potential targetable metabolic vulnerability in colorectal cancer (CRC). Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Here, by using samples from a window trial of TVB-2640 treatment in CRC patients, we found that FASN inhibition induced DNA damage but impaired the DNA damage response (DDR). In colon cancer cell lines and patient-derived organoids, FASN inhibition potentiated chemotherapy-induced double-strand DNA breaks (DSBs) and apoptotic cell death by altering histone acetylation levels. In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation. Mechanistically, FASN inhibition attenuated activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to -H2AX foci in an acetylation-dependent manner. Moreover, FASN inhibition mediated DNA repair deficiency induced synthetic lethality with PARP inhibition in CRC cells. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1917
  56. Nature. 2026 Feb 11.
    Robust partitioning of cell contents by physical instabilities and biological clocks.
      
    Keywords:  Cell biology; Developmental biology
    DOI:  https://doi.org/10.1038/d41586-026-00021-0
  57. Mol Cell. 2026 Feb 11. pii: S1097-2765(26)00062-6. [Epub ahead of print]
    RAD51 succinylation regulates homologous recombination and contributes to the chemosensitivity in cancer.
    Zhe Wang, Mingpeng Jin, Linhui Zhai, Bingsong Huang, Xuan Jin, Xuanhe Wang, Ala Eddine Boudemia, Xiaoning Yang, Zhiting Wei, Yiming He, Jie Yang, Yunxuan Li, Xin Ding, Rui Li, Xuan Zhou, Wen Zheng, Yaobing Ouyang, Qianwen Wang, Yifei Song, Zhikai Zeng, Yu Li, Lu Lu, Jiaqi Liu, Yunhui Li, Lei Li, Ke Li, Chun-Long Chen, Zhenkun Lou, Minjia Tan, Jinhuan Wu, Yuping Chen, Jian Yuan.
      Genomic instability and metabolic reprogramming are core hallmarks of cancer, yet how they are mechanistically interconnected remains unclear. Here, we demonstrate that succinyl-coenzyme A (CoA), a tricarboxylic acid (TCA) cycle metabolite and protein succinylation donor, modulates homologous recombination (HR) by regulating RAD51 succinylation. OXCT1 succinylates RAD51 at K285, whereas HDAC11 removes this modification. RAD51 succinylation disrupts BRCA2 interaction, impairs RAD51 foci formation, and suppresses HR. Upon DNA damage, ATM-dependent phosphorylation of HDAC11 enhances the interaction with RAD51, promoting RAD51 desuccinylation and inhibiting HR. In breast cancer models, elevated RAD51 succinylation correlates with reduced HR capacity and increased sensitivity to the PARP inhibitor olaparib, whereas diminished succinylation confers resistance. Moreover, a cell-penetrating peptide that disrupts the RAD51-HDAC11 interaction increases RAD51 succinylation and synergizes with chemotherapy. Collectively, our findings uncover a metabolic-epigenetic mechanism linking protein succinylation to HR and genomic stability and identify RAD51 succinylation as a predictive biomarker and therapeutic target in cancer.
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.020
  58. Nat Commun. 2026 Feb 12. 17(1): 1493
    Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
    Sathish Babu Vasamsetti, Samreen Sadaf, Mohammad A Uddin, Jixing Shen, Ebin Johny, Awishi Mondal, Jonathan Florentin, Liqun Lei, Aleef Mannan, Krithika Sudhakar Rao, John Sembrat, Mauricio Rojas, Ian Sipula, Jake Kastroll, Michael J Jurczak, Sruti Shiva, Robert M O'Doherty, Vijay Yechoor, Partha Dutta.
      How cellular metabolism facilitates tissue-resident macrophage maintenance remains elusive. Here we show that visceral adipose tissue (VAT)-resident macrophages, unlike monocyte-derived macrophages, are enriched with mitochondrial-specific antioxidant enzymes restraining inflammation and promoting VAT homeostasis and insulin sensitivity. Additionally, VAT resident macrophages express high levels of plasminogen activator inhibitor type 2, encoded by SerpinB2, which is involved in the blood coagulation cascade. SerpinB2 promotes adipose resident macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing the release of pro-apoptotic cytochrome c from the mitochondria into the cytoplasm via antioxidant glutathione production. Chronic inflammation, such as obesity, diminishes SerpinB2 expression in VAT macrophages in patients and mice, leading to the decline of this macrophage subset. Mechanistically, interferon-γ elevation in diabetes induces Ikaros, a transcriptional suppressor, which binds to the SerpinB2 promoter and decreases SerpinB2 expression. Congruently, selective depletion of the IFN-γ receptor in myeloid cells or supplementation of macrophage-specific SerpinB2 deficient mice with N-acetylcysteine, a glutathione precursor, restores VAT resident macrophage survival, decreases adipocyte size, and improves glucose tolerance and insulin sensitivity. Our data thus reveal an unexpected function of SerpinB2 in the regulation of mitochondrial function and survival of tissue-resident macrophages.
    DOI:  https://doi.org/10.1038/s41467-026-69196-4
  59. bioRxiv. 2026 Jan 30. pii: 2026.01.27.702131. [Epub ahead of print]
    A genetically encoded ionic-stress sensor reveals protons as a sleep driver.
    Zhijian Ji, Junqiang Liu, Bingying Wang, Shuaian Wei, Yanchang Bian, Wenjie Zeng, Chan-I Chung, Zhimin Ma, Jianxiu Zhang, Xiaokun Shu, Dengke K Ma.
      Dynamic ionic changes are hallmarks of physiological and behavioral state transitions, including sleep in animals. Although biosensors for specific cellular ions are widely available, real-time monitoring of overall ionic strength in living organisms remains challenging. Here, we present a g enetically e ncoded n uclear translocation ionic s ensor (GENTIS) that enables direct visualization of ionic stress in vivo . Using GENTIS in C. elegans , we uncover rhythmic elevations in ionic strength during larval molting transitions that coincide with the lethargus sleep. Cytosolic proton ionic increase through inhibition of v-ATPase is sufficient to induce GENTIS nuclear translocation and evoke behavioral quiescence, characterized by reduced feeding and activation of sleep-active neurons. Apical membrane v-ATPases undergo disassembly during lethargus and under sleep-inducing stress conditions, leading to proton accumulation. Notably, this proton-mediated sleep is suppressed by proton buffering with ammonium. Together, these findings establish GENTIS as a powerful tool for tracking ionic strength dynamics in living organisms and support protons as a physiological driver of sleep.
    DOI:  https://doi.org/10.64898/2026.01.27.702131
  60. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00036-7. [Epub ahead of print]45(2): 116958
    A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
    Ying Wang, Xinwan Su, Yu Chen, Yijian Chen, Chengyu Shi, Fangzhou Liu, Yuqi Ye, Panyi Sun, Manman Tan, Meng Yu, Ya Wang, Shanshan Xie, Jian Liu, Qingfeng Yan, Qiming Sun, Dante Neculai, Wei Liu, Jianzhong Shao, Yang Liu, Weiqiang Lin, Aifu Lin.
      Mitochondrial genetic diseases arise from mitochondrial DNA (mtDNA) defects, which gene therapy tools may rectify. However, delivering single-guide RNAs (sgRNAs) into mitochondria remains a challenge limiting CRISPR-mediated mtDNA therapy. Here, through network analysis of mitochondrion-localized long noncoding RNAs (lncRNAs) and RNA-binding proteins (RBPs), we found that lncRNA RP11-46H11.3 translocates into mitochondria via binding mitochondria-associated RBPs using its key RNA recognition motifs (RRMs); its derived 30 nt ST2-RNA mitochondrial targeting sequence (RMTS) showed the highest mitochondrial localization efficiency. We engineered the RMTS-CRISPR tool by fusing ST2-RMTS to sgRNA, verifying its ability to target and cleave mtDNA. Strikingly, our results demonstrated that RMTS-CRISPR could achieve heteroplasmic mtDNA shifting efficiencies of up to 26.37% in m.3243A>G mutant cell models and 26.79% in vivo, offering a technological approach for the correction of heterogeneous mtDNA mutations. Taken together, our findings reveal a CRISPR-based mitochondrial gene intervention strategy that may have applications in mitochondrial disorders.
    Keywords:  CP: genomics; CRISPR-Cas system; RNA recognition motif; mitochondrial DNA; mitochondrial disorder; organelle-associated RNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.116958
  61. bioRxiv. 2026 Jan 30. pii: 2026.01.28.702329. [Epub ahead of print]
    Methionine metabolism and the NOP2 methyltransferase are essential for MYC-Driven liver tumorigenesis.
    Sensen Lin, Charles Berdan, Moriah Sandy, Xinjun Lu, Vijay Ramani, Daniel K Nomura, Xin Chen, Joyce Lee, Andrei Goga.
      Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in developed nations. 1,2 The MYC oncogene or its paralogs are frequently amplified or overexpressed in subtypes of cancer associated with stem cell-like features and worse clinical outcomes, 3,4 including in liver cancer. 5 Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent, with markedly diminished tumor growth when mice are fed a methionine low diet. While RAS-driven liver cancer was resistant to a low methionine diet. S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues cell proliferation following methionine depletion, suggesting that methylation processes are especially critical in the context of MYC high tumor cells. Heavy isotope methionine tracing in MYC high cells identified increased levels of m5C nucleotides. We found NOP2, an rRNA m5C-methyltransferase, was regulated by both MYC overexpression and methionine abundance linking the two processes. Methionine depletion reduced methylation of multiple 28S rRNA residues as did NOP2 knockdown. Depletion of NOP2 selectively inhibited MYC liver cancer cell proliferation and in vivo tumor growth. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and the rRNA methyltransferase NOP2 may serve as a new therapeutic target in liver cancer.
    DOI:  https://doi.org/10.64898/2026.01.28.702329
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