bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–09–13
forty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
  2. Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.
  3. ASS1-derived argininosuccinate promotes purine nucleoside synthesis in B cell acute lymphoblastic leukaemia.
  4. Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.
  5. Caloric restriction modulates genome-wide somatic mutation in mice.
  6. Pick and choose.
  7. Adaptive oncogenesis of β-catenin emerges from declining liver tissue integrity.
  8. Childhood proteomic signatures that predict adult cardiometabolic disease.
  9. Mitochondrial Raf1 regulates glutamine catabolism.
  10. Lactate Metabolism: Separating Correlation From Causation.
  11. A single-cell lens into the co-evolution of genotypes and phenotypes in cancer.
  12. Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.
  13. Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
  14. Macrophages tune NK cell IFNγ production through direct lipid transfer.
  15. Mitochondrial Fis1 tunes Rab7A activity via TBC1D15 modulating STING degradation.
  16. Argininosuccinate signalling drives carbon replenishment in B cell acute lymphoblastic leukaemia.
  17. A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
  18. Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia-reperfusion injury in the heart.
  19. B cell responses to CD40 stimulation ignite anti-tumor immunity by activating CD8+ T cell cytotoxicity.
  20. A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.
  21. Deubiquitinases in mitophagy: therapeutic control of mitochondrial quality.
  22. Metabolic regulation of calcium homeostasis via SERCA succination.
  23. Loss of killifish cGAS attenuates age-related signatures but does not affect organismal life span.
  24. Neutrophil elastase-mediated myoepithelial loss is a therapeutic vulnerability in ductal carcinoma in situ progression.
  25. Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
  26. Integrated signatures define mutational processes in prostate cancer.
  27. Linking cellular metabolism to mitochondrial outer membrane potential.
  28. Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction.
  29. Heme as a Versatile Signaling Molecule: Coordinating Mitochondrial Metabolism with Global Cellular Responses.
  30. Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer.
  31. Reflecting on 25 years of cancer research: transformative advances and unmet expectations.
  32. Probing the proteome at cellular scale.
  33. A cancer that swims between hosts.
  34. A guide to understanding tumour evolution through the lens of population genetics.
  35. Pyruvylation expands the redox repertoire of lysine acylation.
  36. Disrupted glucocorticoid rhythms selectively induce severe skeletal muscle insulin resistance and uncouple obesity from hepatic steatosis.
  37. Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.
  38. From heart to BAT: Rethinking mouse models of human BAT.
  39. Dangerous liaisons: interactions between cancer cells and adipocytes as drivers of cancer progression.
  40. Nitric oxide dependent metabolic and genetic dysregulation in metastatic triple-negative breast cancer.
  41. Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.
  42. Telomerase reverse transcriptase as a core regulator of brain health.
  43. Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.
  44. Nucleolar dynamics are determined by the ordered assembly of the ribosome.
  45. A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy.
  1. Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]
    Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
    Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.
      Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.
    Keywords:  BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology
    DOI:  https://doi.org/10.1016/j.cell.2026.08.023
  2. Sci Adv. 2026 Sep 11. 12(37): eaee4935
    Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.
    Julianna G Supplee, Pedro Costa-Pinheiro, Karl Wessendorf-Rodriguez, Stephanie Stransky, Qihua Yang, Christina Demetriadou, Nivitha Murali, Joy Li, Jennifer L Pennise, Mariola M Marcinkiewicz, Simone Sidoli, Nathaniel W Snyder, Christian M Metallo, Ronen Marmorstein, Kathryn E Wellen.
      The cell nucleus is an active metabolic site. Numerous enzymes best known for their roles in cytosolic or mitochondrial pathways also function in the nucleus, where they contribute to gene regulation and DNA replication and repair. Although metabolites can diffuse through nuclear pores, it remains unclear the extent to which the nucleus and cytosol operate as continuous versus distinct metabolic spaces. Both compartments require acetyl-CoA-for example, for histone acetylation and lipid synthesis-and the acetyl-CoA generating enzyme ATP-citrate lyase (ACLY) resides in both locations, but the significance of its dual localization is incompletely understood. Using cell lines in which ACLY is localized to either compartment, we find that ACLY in either location supports fatty acid synthesis and histone acetylation, yet compartment-localized ACLY enables finer control. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and modulates specific transcriptional programs, whereas cytosolic ACLY most efficiently supports lipid biosynthetic fluxes. Thus, local synthesis defines a preferential metabolic fate, providing more precise regulation.
    DOI:  https://doi.org/10.1126/sciadv.aee4935
  3. Nat Metab. 2026 Sep 07.
    ASS1-derived argininosuccinate promotes purine nucleoside synthesis in B cell acute lymphoblastic leukaemia.
    Gen Li, Zhijun He, Mingjie Liu, Junhua Zhao, Haichuan Zhu, Cefan Zhou, Zhenning Wang, Xiaojing He, Jingfeng Tang, Peng Jiang.
      Metabolic remodelling underlies tumour progression. However, how metabolites act as signalling molecules to support cancer cell proliferation remains unclear. Here we show that argininosuccinate (ASA), a key intermediate of the urea cycle, promotes purine nucleoside biosynthesis in tyrosine kinase-driven haematological malignancies. Mechanistically, BCR-ABL phosphorylates argininosuccinate synthase 1 (ASS1), which increases ASA production from citrulline. ASA directly binds cytosolic 5'-nucleotidase II (NT5C2) and enhances its nucleosidase activity. The resulting purine nucleosides serve as a carbon source for glycolysis and the tricarboxylic acid cycle, which supports leukaemia cell proliferation under glucose-replete conditions. Loss of ASS1 or NT5C2 disrupts central carbon metabolism and inhibits leukaemia progression in vivo, which can be rescued with inosine or adenosine supplementation. Collectively, our findings uncover an ASA-NT5C2 signalling axis linking urea cycle dysregulation to purine metabolism, and identify purine nucleosides as a carbon source in tyrosine kinase-driven haematological malignancies.
    DOI:  https://doi.org/10.1038/s42255-026-01586-w
  4. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2537797123
    Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.
    Sneha P Rath, Zhu Li, Arkajit Guha, Fangcong Dong, Ruma Banerjee, Vamsi K Mootha.
      Of the ~1,100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including two genes in vitamin B12 metabolism - the B12 chaperone MMADHC and cytosolic B12-dependent 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC.
    Keywords:  MMADHC; methionine synthase; mitochondria; proton motive force; vitamin B12
    DOI:  https://doi.org/10.1073/pnas.2537797123
  5. Cell. 2026 Sep 09. pii: S0092-8674(26)00940-2. [Epub ahead of print]
    Caloric restriction modulates genome-wide somatic mutation in mice.
    Marta Grońska-Pęski, Victoria Acosta-Rodríguez, Amoolya Srinivasa, Amanda Garrido, Shany Picciotto, Carla B Green, Joseph S Takahashi, Jonathan E Shoag, Gilad D Evrony.
      Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.
    Keywords:  DNA; aging; caloric restriction; diet; genomics; mutation; somatic mutation
    DOI:  https://doi.org/10.1016/j.cell.2026.08.013
  6. Nat Metab. 2026 Sep 11.
    Pick and choose.
      
    DOI:  https://doi.org/10.1038/s42255-026-01623-8
  7. Nat Commun. 2026 Aug 10. pii: 9565. [Epub ahead of print]17(1):
    Adaptive oncogenesis of β-catenin emerges from declining liver tissue integrity.
    Abhinav Illendula, Charles K Hewett, Yuki Hayata, Lauren S Strathearn, Guoshun He, Laia Carballo-Botinas, Sara Navas-Sanz, Maria Niqui-Capdevila, Avril Garcia-Santos, Rocío Bernabé-Pérez, Alejandra Bustillo-Bustos, Ani Mikoyan, Eleanor Helm, Marina Gonzalez-Sorribes, Nicola de Prisco, Aasthika Das, Yuanguangyan Zhang, David Rossell, Michael Slifker, Naiara Akizu, Beicheng Sun, Joan Font-Burgada.
      Mutations are fundamental to oncogenesis, yet they cannot fully explain cancer progression, as oncogenic mutations frequently accumulate in healthy tissues without immediate malignancy. In the liver, β-catenin mutations are highly prevalent in hepatocellular carcinoma but are widely considered weak or cooperative drivers, raising the question of how their oncogenic potential is contextually regulated. Aging and chronic injury are major determinants of cancer risk. However, how declining tissue integrity reshapes the fitness of cells harboring oncogenic mutations remains poorly understood. Here we show that mutant β-catenin as a single genetic event confers negative fitness in the healthy liver of male mice, where mutant hepatocytes fail to clonally expand and undergo progressive attrition associated with oxidative and endoplasmic reticulum stress. In contrast, as liver tissue integrity declines during chronic injury or aging, cells carrying the same β-catenin mutation clonally expand and promote tumorigenesis, a process linked with activation of the AKT-NRF2 axis. These findings demonstrate that β-catenin mutations acting as single genetic lesions are maladaptive under normal liver homeostasis but become adaptive as tissue integrity deteriorates. This tissue-level shift reshapes the oncogenic fitness landscape, relaxing the constraints that normally prevent tumor initiation.
    DOI:  https://doi.org/10.1038/s41467-026-76373-y
  8. Nat Metab. 2026 Sep 11.
    Childhood proteomic signatures that predict adult cardiometabolic disease.
      
    DOI:  https://doi.org/10.1038/s42255-026-01588-8
  9. Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01053-3. [Epub ahead of print]45(9): 117975
    Mitochondrial Raf1 regulates glutamine catabolism.
    Ronald L Shanderson, Ian D Ferguson, Luca Ducoli, Weili Miao, Suhas Srinivasan, Zurab Siprashvili, Albert M Li, Mary Grace Velasco, Yang Li, Christine N Hoang, Jiangbin Ye, Paul A Khavari.
      Raf kinases are central to mitogenic signaling and cancer, yet the full complement of functionally important Raf-proximal proteins across subcellular compartments remains undefined. Here, proximity-dependent biotinylation (BioID) of Raf1 in Raf1-dependent cancer cells recovered proteins localized to the mitochondrial matrix. Mitochondrial purification and super-resolution microscopy confirmed that a pool of Raf1 resides within mitochondria. There, Raf1 associated with glutaminase (GLS) across diverse human cancers and enabled glutaminolysis, a major source of biosynthetic precursors in tumor cells. These effects required Raf1 kinase activity but were independent of canonical MAP kinase pathway signaling, and matrix-targeted kinase-dead Raf1 impaired both glutaminolysis and in vivo tumorigenesis. Raf1 therefore acts inside mitochondria, where it engages GLS to drive glutamine catabolism and support tumor growth, revealing a non-canonical, metabolic arm of Raf signaling.
    Keywords:  CP: metabolism; MAPK; Raf1; glutaminase; metabolic reprograming
    DOI:  https://doi.org/10.1016/j.celrep.2026.117975
  10. Bioessays. 2026 Sep;48(9): e70181
    Lactate Metabolism: Separating Correlation From Causation.
    Bhavya Blaze, Ahmad A Cluntun.
      Lactate is among the most frequently measured metabolites in physiology and medicine, yet it remains one of the most persistently misunderstood. Long regarded as a metabolic waste product, a marker of anaerobic metabolism, or a direct cause of acidosis and fatigue, lactate remains burdened by misconceptions that obscure its true biological roles. Recent advances in metabolic flux analysis, isotope tracing, hyperpolarized magnetic resonance spectroscopy, and cellular imaging have revised this view and established lactate as a central intermediary in energy metabolism, redox homeostasis, and interorgan metabolic communication. Here, we re-examine common myths surrounding lactate biology and clarify the distinction between correlation and causation in its interpretation. By reframing lactate as a dynamic indicator and, in some contexts, a regulator, of metabolic state rather than a toxic by-product, this review improves experimental reasoning and clinical interpretation across diverse physiological and pathological contexts.
    Keywords:  aerobic glycolysis; clinical biomarkers; correlation versus causation; lactate metabolism; metabolic flux; mitochondrial metabolism; redox homeostasis
    DOI:  https://doi.org/10.1002/bies.70181
  11. Nat Rev Cancer. 2026 Sep 08.
    A single-cell lens into the co-evolution of genotypes and phenotypes in cancer.
    Franco Izzo, Tamara Prieto, Catherine Potenski, Dan A Landau.
      Genetic heterogeneity and clonal outgrowths are observed even in otherwise healthy human tissues, shaping the genetic composition of cell populations in non-malignant disease and during physiological ageing. This clonal mosaicism likely provides the pre-cancerous seeds for malignant transformation. Once a tumour arises, clonal evolution poses a major challenge to achieving cure, as clonal diversification provides an expanded number of substrates upon which therapy can act as a selective pressure, leading to the selection of resistant clones that ultimately fuel disease recurrence. Understanding somatic clonal evolution requires not only mapping genetic diversity but also defining the resulting phenotypes that provide a fitness advantage to mutated clones. This Review discusses multimodal single-cell technologies that enable the measurement of genotypes and additional molecular features from the same cell. These technologies unveil mutant-specific phenotypic traits, often show cell-state specificity in genotype-phenotype effects and can define therapeutic vulnerabilities for precision elimination of disease-propagating mutant cells. Furthermore, the combination of phylogenetic reconstruction with phenotypic measurements allows for the temporal mapping of clonal evolution and phenotypic plasticity. These breakthroughs have created a unique opportunity to define, directly in primary human samples, the mechanisms underlying clonal expansion in both healthy and malignant tissues.
    DOI:  https://doi.org/10.1038/s41568-026-00970-8
  12. Biochim Biophys Acta Mol Cell Res. 2026 Sep 06. pii: S0167-4889(26)00119-9. [Epub ahead of print]1873(8): 120220
    Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.
    Tânia Catarina Medeiros, Gaetano Calabrese.
      Mitochondria are central hubs of cellular metabolism that harbor their own genome (mtDNA), whose maintenance is essential for both cellular and organismal homeostasis. Unlike nuclear DNA, mtDNA replicates continuously throughout the cell cycle, rendering it particularly sensitive to changes in metabolic state. Emerging evidence indicates that mtDNA homeostasis is not governed solely by dedicated replication factors but is tightly coupled to cellular metabolism. In this review, we discuss how metabolic networks shape mtDNA maintenance through three interconnected layers: mitochondrial nucleotide pools, metabolic control of the replication machinery, and stress-response pathways. This conceptual framework underscores the direct role of metabolic state in governing mtDNA replication, stability, and quality control, with significant implications for mitochondrial disease and therapeutic strategies.
    Keywords:  Integrated stress response (ISR); Metabolism; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Nucleotides; Replication machinery
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120220
  13. J Biol Chem. 2026 Sep 07. pii: S0021-9258(26)02391-4. [Epub ahead of print] 113519
    Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
    Helen A Jordan, Joseph A Tandurella, Vineeth Vengayil, Tanay S Parnaik, Swechha Mainali Pokharel, Kathleen Mulka, Sara Cherry, E John Wherry, Caroline R Bartman.
      During an immune response, metabolism changes dramatically. Metabolites are oxidized to power immune cell functions, serve as building blocks for proliferation, and act as effectors to regulate pathogen or host cells. Though metabolic changes in cultured cells have been studied extensively, metabolism changes in vivo are less understood. Here, we measured metabolomic changes across six mouse tissues in three models of immune activation: CpG-DNA cytokine storm, lymphocytic choriomeningitis virus infection, and polyI:C viral mimetic injection; and carried out metabolomics in cultured macrophages activated with different stimuli. We found most metabolomic changes were exclusive to either inflamed tissues or cultured macrophages, although itaconate was strongly induced in both contexts. We then mechanistically dissected the role of the soluble sialic acid N-glycolylneuraminic acid, which is highly induced in inflamed tissues yet only modestly in cultured macrophages. This metabolite increases in tissues in different models of inflammation, and the analogous human metabolite, N-acetylneuraminic acid, rises in human patients experiencing inflammation. We found that N-glycolylneuraminic acid is produced in CD11b+ myeloid cells by cleavage of protein-bound sialic acid. However, blocking its production did not affect CpG-DNA liver inflammation or LCMV infection in mice. Therefore, these experiments identify soluble sialic acid as a conserved biomarker of inflammation in mice and humans and highlight the differences in metabolism between in vitro and in vivo models of inflammation.
    Keywords:  inflammation; isotopic tracer; macrophage; metabolism; metabolomics; sialic acid
    DOI:  https://doi.org/10.1016/j.jbc.2026.113519
  14. Nat Commun. 2026 Aug 08. pii: 9527. [Epub ahead of print]17(1):
    Macrophages tune NK cell IFNγ production through direct lipid transfer.
    Cathal Keane, Shauna Mayock, Carrie Corkish, Ella Rogerson, Cristhiane Favero de Aguiar, Ya Gao, Sarah Kenny, Lorraine Brennan, Suzanne M Cloonan, David K Finlay.
      Natural killer (NK) cells are critical effectors of innate immunity, but their activity is strongly influenced by metabolic state. While intrinsic NK metabolism has been studied extensively, less is known about how surrounding immune cells shape NK cell function. Here, we identify a direct metabolic communication axis between macrophages and NK cells. Using co-culture and in vivo models, we show that lipopolysaccharide-stimulated macrophages induce lipid accumulation in NK cells that suppresses mTORC1 activity and the production of IFNγ. This lipid accumulation is visualised as increased lipid droplets content in NK cells, generated using fatty acids synthesised within the macrophages. Genetic and pharmacological approaches show that fatty acid transfer from macrophages to NK cells requires cell-cell contact and is associated with CD36 protein transfer via trogocytosis. Blocking fatty acid synthesis specifically in macrophages prevents lipid accumulation in NK cells and restores both mTORC1 activity and IFNγ production. These findings define a previously unrecognized mechanism of macrophage-NK cell cross-regulation, revealing how metabolic exchange constrains NK effector function and establishing a feedback circuit with implications for hyperinflammation and immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-76444-0
  15. Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01072-7. [Epub ahead of print]45(9): 117994
    Mitochondrial Fis1 tunes Rab7A activity via TBC1D15 modulating STING degradation.
    Eunice Dominguez-Martin, Linlin Lei, Jennifer D Petersen, Peng-Peng Zhu, Katherine R Tucker, Richard J Youle.
      The mechanisms governing the final trafficking steps of the cyclic dinucleotide innate immune receptor stimulator of interferon genes (STING) are not fully understood. Here, we identify the mitochondrial protein Fis1 as a regulator of STING endolysosomal degradation. The absence of Fis1 in HeLa cells stabilizes STING, boosting downstream signaling without affecting its initial endoplasmic reticulum (ER)-to-Golgi traffic. Instead, Fis1 loss impairs STING delivery to endolysosomes. Fis1 recruits the Rab7A-GAP TBC1D15 to mitochondria and upon STING activation, TBC1D15 localization shifts to the Golgi. In the absence of Fis1, the interaction between TBC1D15 and Rab7A is disrupted, leading to decreased Rab7A GTPase activity and impaired STING degradation. Our findings reveal a mitochondria-controlled axis where Fis1 tunes Rab7A activity via TBC1D15, which is required to ensure proper STING degradation, directly linking mitochondria to lysosomal trafficking and the termination of innate immune signaling.
    Keywords:  CP: cell biology; CP: immunology; Fis1; Golgi; Rab-GAP; Rab7; STING; TBC1D15; innate immunity; lysosomal degradation; mitochondria; traffic
    DOI:  https://doi.org/10.1016/j.celrep.2026.117994
  16. Nat Metab. 2026 Sep 11.
    Argininosuccinate signalling drives carbon replenishment in B cell acute lymphoblastic leukaemia.
      
    DOI:  https://doi.org/10.1038/s42255-026-01593-x
  17. Sci Adv. 2026 Sep 11. 12(37): eaeg1157
    A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
    Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.
      Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through isoflurane anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. In serum, acylcarnitines and fatty acids were broadly decreased, whereas amino acid metabolites and select nucleotide species were increased. Across multiple organs, isoflurane induced coordinated metabolic remodeling and distinct tissue-specific responses, including glycolytic remodeling in the brain and amino acid accumulation in the pancreas. To address these metabolic disturbances, we established a nonsurgical tail vein catheterization method completed in minutes under brief isoflurane anesthesia that enables multihour tracer infusion in awake, freely moving mice. Using U-13C6-cystine infusion, this method achieved robust cysteine labeling and downstream labeling comparable to jugular infusion while maintaining circulating cystine pools closer to physiological levels. This platform provides a practical approach for in vivo stable isotope tracing under more physiological conditions.
    DOI:  https://doi.org/10.1126/sciadv.aeg1157
  18. Nat Metab. 2026 Sep 08.
    Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia-reperfusion injury in the heart.
    Dan Wu, Tao Chen, Xin Dong, Haoqi Li, Zijie Cheng, Huimin Li, Yufan Chao, Fangling Li, Yun Yin, Fujun Guo, Xinran Xu, Yuxuan Zhang, Kun Ning, Xiaoqing Fu, Yuemin Bian, Fenfen Ma, Julia Ritterhoff, Wang Wang, Qingxun Hu.
      Exercise promotes physiological cardiomyocyte growth and protects against ischaemia-reperfusion (IR) injury in the heart. The molecular mechanism by which exercise benefits cardiac metabolism and function remains largely unknown. Here, using a genetically encoded fluorescent sensor, we show that exercise increases cytosolic, but not mitochondrial, NADPH levels in cardiomyocytes. This effect is mediated by activation of the pentose phosphate pathway (PPP). Inhibition of PPP activity or depletion of cytosolic NADPH attenuates exercise-induced heart hypertrophy in mice. We observe that NADPH promotes cardiomyocyte growth by inhibiting HDAC3/C/EBPβ pathways. Moreover, exercise-activated PPP/NADPH pathway suppresses acute IR injury and preserves heart function 4 weeks after IR. Among 310 tested Tibetan compounds, the spermidine derivative lyciumspermidine-0527 directly activates the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase, elevates intracellular NADPH levels and alleviates IR injury. Altogether, these results show that PPP-derived NADPH is a critical metabolic checkpoint that regulates exercise-induced physiological cardiomyocyte growth and protects against IR-induced heart injury.
    DOI:  https://doi.org/10.1038/s42255-026-01587-9
  19. Cell Rep. 2026 Sep 10. pii: S2211-1247(26)01035-1. [Epub ahead of print]45(9): 117957
    B cell responses to CD40 stimulation ignite anti-tumor immunity by activating CD8+ T cell cytotoxicity.
    Kendrick Nguyen, Monika Quackenbush, Sara Basbous, Haley Rodriguez, Georgia Lattanzi, Elsie Quansah, Chynna Bowman, Sammy Weiser Novak, Daniela Boassa, Jingting Yu, Taylor Ozbun, Asona Lui, Aatish Thennavan, Peter Watson, April Wehner, Daniel Hollern.
      B cell responses to cancer are critical to patient survival and response to therapy. Yet, the knowledge as to how B cells can elicit anti-tumor immunity remains incomplete. We identify that CD40 pathway activation in B cells in the presence of high tumor mutation burdens activates an anti-tumor B cell response. Significantly, our study shows that CD40-stimulated B cells drive tumor infiltration, organization, and activation of cytotoxic function in CD8+ T cells. These results provide key advances in the mechanistic regulation and function of B cell and CD8+ T cell responses to cancer.
    Keywords:  B cells; Breast cancer; CD40; CD8(+) T cells; CP: cancer; CP: immunology; T cells; cancer; cytotoxic; macrophages; memory B cells
    DOI:  https://doi.org/10.1016/j.celrep.2026.117957
  20. Mol Cancer. 2026 Aug 27. pii: 210. [Epub ahead of print]25(1):
    A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.
    Lucia A Torres-Fernández, Volker Boehm, Joel Kaufmann, Jonas P Becker, Maria Garcia-Marquez, Beaunelle de Bruijn, Agnieszka Rumińska, Christian Müller, Graziella Bosco, Nazanin Alavinejad, Laura Lovric, Johanna I Bihler, Hanna Schulte, Poorya Davoodi, Anna Schöllhorn, Kian R Weihrauch, Laura Kaiser, Olta Ibruli, Fanyu Liu, Ariadne Androulidaki, Nina Wobst, Marcel Schmiel, Justinas Valiulis, Lukas Maas, Joshua D'Rozario, Vignesh Sakthivelu, Bianca Göbel, Marian Touet, Johannes Brägelmann, Katja Höpker, Felix John, Jürgen Wolf, Stefan Knapp, Alexander Quaas, Maria Cartolano, Silvia von Karstedt, Filippo Beleggia, Hans-Georg Rammensee, Cécile Gouttefangeas, Hans A Schlößer, Angelika B Riemer, Hans Christian Reinhardt, Niels H Gehring, Martin Peifer, Roman K Thomas, Julie George.
      Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.
    Keywords:  Cancer genomics; Cancer immunotherapy; Frameshift mutations; Genomic instability; Neoantigen; Nonsense mediated decay (NMD); Proteostasis; RNA surveillance; Small cell lung cancer (SCLC); Tumor mutational burden (TMB)
    DOI:  https://doi.org/10.1186/s12943-026-02750-2
  21. Trends Pharmacol Sci. 2026 Sep 12. pii: S0165-6147(26)00206-3. [Epub ahead of print]
    Deubiquitinases in mitophagy: therapeutic control of mitochondrial quality.
    Yang Xu, Bahareh Behrouz, Andrew Lee, Gang Xin, Nuo Sun.
      Mitochondrial quality control is essential for maintaining cellular and tissue homeostasis. Mitophagy, the selective autophagic removal of damaged mitochondria, is a central component of this process, and defects in mitophagy are increasingly linked to neurodegeneration, cardiovascular disease, cancer, and inherited mitochondrial disorders. Ubiquitin-dependent tagging of outer mitochondrial membrane proteins is a major mechanism for marking damaged mitochondria for clearance; however, recent advances reveal that mitochondrial deubiquitinases (DUBs) shape ubiquitin signaling at damaged mitochondria, thereby influencing the efficiency and selectivity of mitochondrial turnover. Moreover, DUBs are emerging as context-dependent editors of the mitochondrial ubiquitin code that link mitophagy to disease pathogenesis and therapeutic intervention. Here, we synthesize current understanding of mitochondrial DUBs in physiology and disease and discuss emerging pharmacological strategies to guide the development of mitophagy-targeted therapeutics.
    DOI:  https://doi.org/10.1016/j.tips.2026.08.009
  22. Sci Adv. 2026 Sep 11. 12(37): eaeh2771
    Metabolic regulation of calcium homeostasis via SERCA succination.
    Su Jin Ham, Yena Kim, Sehyeon Kim, Sunhoe Bang, Young Hoon Koh, Soung-Hun Roh, Hyung Seo Park, Jongkyeong Chung.
      Although calcium homeostasis is disrupted in metabolic diseases, its metabolic regulation remains unclear. Here, we identify a mechanism by which fumarate suppresses sarco/endoplasmic reticulum (ER) calcium ion-adenosine triphosphatase (SERCA) activity via succination of a conserved cysteine residue, impairing ER calcium uptake and promoting metabolic dysfunction in Drosophila. In mammalian cells, high glucose or fumarate inhibits SERCA activity and increases ER calcium release and cytosolic and mitochondrial calcium levels. Mechanistically, we show that fumarate covalently modifies SERCA2b at Cys875 and that a Cys875Ser mutant resists fumarate-induced inhibition. In Drosophila, knock-in flies with the corresponding Cys875Ser mutation preserve ER calcium homeostasis and are protected from hyperglycemia, glucose intolerance, and reduced survival on a high-sugar diet. These effects are phenocopied by pharmacological fumarate reduction or allosteric SERCA activation. Collectively, these findings suggest that fumarate-mediated SERCA inhibition provides a mechanistic link between glucose metabolism and calcium homeostasis, with potential relevance to metabolic dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.aeh2771
  23. EMBO Rep. 2026 Sep 09.
    Loss of killifish cGAS attenuates age-related signatures but does not affect organismal life span.
    Eugen Ballhysa, Roberto Ripa, Nadine Hochhard, Tin Tin Manh Nguyen, Jennifer Brazzell, Youngjun Park, Baptiste Ferreri, Elena Hoffmann, Raymond Laboy, Joachim David Steiner, Adam Antebi.
      The cGAS/STING pathway is a central innate immune signaling pathway responsive to cytosolic DNA. Chronic activation of this pathway promotes numerous age-related pathologies, but its impact on lifespan remains unknown. Here we engineer a cGAS knockout (KO) in the turquoise killifish Nothobranchius furzeri to assess effects on physiology and aging. In cultured fibroblasts, cGAS deficiency results in elevated DNA damage but reduces radiation-induced senescence and enhances cellular proliferation. In vivo, cGAS KO attenuates DNA damage-induced transcriptional responses in young fish, and blunts age-associated transcriptional changes in old fish, consistent with dampening of senescence and aging. Accordingly, old cGAS KO animals exhibit lower levels of senescence-associated β-galactosidase activity and higher levels of cell proliferation, without detectable differences in immune infiltration. Despite these attenuated aging signatures, lifespan is not extended. Together, these findings reveal that while cGAS loss alleviates senescence and age-related signatures, additional mechanisms constrain longevity.
    DOI:  https://doi.org/10.1038/s44319-026-00917-y
  24. Cell Rep Med. 2026 Sep 11. pii: S2666-3791(26)00467-2. [Epub ahead of print] 103050
    Neutrophil elastase-mediated myoepithelial loss is a therapeutic vulnerability in ductal carcinoma in situ progression.
    Tarek Taifour, Yu Gu, Adéline Massé, Xiwei Meng, Clarisse Dane Echavez, Dongmei Zuo, Virginie Sanguin-Gendreau, Anne Blouin, Adda-Lee Graham-Paquin, Miranda Addie, Emilie Solymoss, Bin Xiao, Hailey Proud, Sherif Samer Attalla, Alice Jisoo Nam, Vasilios Papavasiliou, Hellen Kuasne, Peter M Siegel, Khandan Keyomarsi, Luke McCaffrey, Morag Park, William J Muller.
      Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in breast cancer progression, yet the mechanisms governing this transition remain poorly defined. Here, we identify neutrophils as a key immunological driver of DCIS progression. Across two independent breast cancer mouse models, neutrophil depletion or genetic deletion of their tumor-derived chemoattractant chitinase-3 like 1 (Chi3l1) preserves the myoepithelial barrier, halts DCIS-to-IDC transition, and suppresses lung metastasis. Mechanistically, tumor-infiltrating neutrophils release neutrophil elastase (NE) that degrades the basement membrane extracellular matrix, leading to erosion of the myoepithelial layer by anoikis. Pharmacological NE inhibition restores myoepithelial integrity and blocks DCIS progression and metastasis. Consistently, elevated NE levels in human breast cancer samples are associated with myoepithelial disruption, DCIS progression, and metastasis. Together, these findings identify neutrophils as key mediators of myoepithelial barrier disruption and highlight NE as a potential therapeutic target for high-risk DCIS.
    Keywords:  DCIS; breast cancer progression; ductal carcinoma in situ; extracellular matrix; invasive transition; metastasis; myoepithelial layer; neutrophil elastase; neutrophils; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103050
  25. JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]
    Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
    Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.
      Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.
    Keywords:  Endocrinology; Muscle biology; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.210523
  26. Nature. 2026 Sep 09.
    Integrated signatures define mutational processes in prostate cancer.
    Pan Prostate Cancer Group (PPCG)
      Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology1. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion-deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the mutational processes in 85% of primary prostate cancer genomes. IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress. Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency, the latter being enriched in patients of African ancestry. Extending to the metastatic setting, we found that IMFs predicted sensitivity to androgen receptor pathway inhibitors. Taken together, our study delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.
    DOI:  https://doi.org/10.1038/s41586-026-10468-w
  27. Mitochondrion. 2026 Sep 10. pii: S1567-7249(26)00108-X. [Epub ahead of print] 102218
    Linking cellular metabolism to mitochondrial outer membrane potential.
    Kaitlin Abrantes, Bethel G Beyene, Nina A Bautista, Wendy Fitzgerald, Tatiana K Rostovtseva, Sergey M Bezrukov, Megha Rajendran.
      The voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane (MOM) responds to transmembrane voltage through intrinsic gating and voltage-dependent interactions with cytosolic proteins, such as α-synuclein and β-tubulin. Despite this characteristic voltage sensitivity found in vitro, the existence of a substantial MOM potential (ΔΨMOM) in vivo remains controversial. Using pH sensors targeted to the cytosol and the intermembrane space (IMS), we measured the difference in proton concentration across the MOM and calculated a ΔΨMOM of ~33 mV, positive from the IMS side in HeLa cells; in contrast, HEK-293 cells lacked substantial ΔΨMOM. Hexokinase 2 (HK2) is known to be overexpressed in cancer cells. Consistent with the previously proposed role of VDAC- HK complexation in ΔΨMOM generation, we observed lower HK2 expression in HEK-293 cells than in HeLa cells. In addition, by studying pH changes in the IMS and cytosol in response to changes in glucose and glucose-6-phosphate concentrations in HeLa cells, we establish a relationship between ΔΨMOM and metabolic activity in cancer cells. Thus, our results demonstrate the metabolism-dependent generation of ΔΨMOM and provide strong evidence that VDAC regulation by voltage, observed in in vitro studies, is highly relevant to cell physiology.
    Keywords:  Hexokinase; VDAC; Voltage-dependent anion channel; pH sensors
    DOI:  https://doi.org/10.1016/j.mito.2026.102218
  28. Cell Metab. 2026 Sep 10. pii: S1550-4131(26)00339-6. [Epub ahead of print]
    Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction.
    Selim Chaib, Larissa G P Langhi Prata, Masayoshi Suda, Andres Sola, Thomas J Mitchell, Zacharias P Anastasiadis, Hawley E Kunz, Jia Nie, Stella G Victorelli, Ricardo Lozano Flores, Moritz Weigl, Shimpei Kawamoto, Ken Uemura, Hyungsoo Kim, Binsheng Wang, Christina L Inman, Tamar Pirtskhalava, Nino Giorgadze, Ailing Xue, Kurt O Johnson, Jair M Espindola-Netto, Sonja Suvakov, Jennet Hatamova, Erik S Parker, Davyn Benitto Hartono, Vagisha Kulshreshtha, Jose Alberto Lopez-Dominguez, Aaron M Deisinger, Allyson K Palmer, Yi Zhu, Megan M Weivoda, Anne Gingery, Robert Hromas, Vesna D Garovic, João F Passos, David B Allison, Eiji Hara, Michael D Jensen, Nicolas Musi, Stefan G Tullius, Ze'ev A Ronai, Manuel Serrano, Ming Xu, Ian R Lanza, Yuji Ikeno, Tamara Tchkonia, James L Kirkland.
      Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.
    Keywords:  PD-1; PD-L1; PD-L2; aging; cellular senescence; immune-related adverse events; immunotherapy; irAE; sPD-L2; senolytics
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.014
  29. J Biol Chem. 2026 Sep 07. pii: S0021-9258(26)02390-2. [Epub ahead of print] 113518
    Heme as a Versatile Signaling Molecule: Coordinating Mitochondrial Metabolism with Global Cellular Responses.
    Iva Chitrakar, Breann L Brown.
      Heme is an essential iron-containing cofactor that supports diverse biological processes, including oxygen transport, mitochondrial respiration, and xenobiotic metabolism. Beyond these canonical functions, accumulating evidence has established heme as a dynamic signaling molecule that couples mitochondrial metabolic state to cellular stress responses, gene expression, and metabolic adaptation. Heme biosynthesis is compartmentalized between mitochondria and the cytosol, requiring tightly coordinated synthesis, trafficking, sensing, and degradation to maintain cellular homeostasis and prevent heme toxicity. In this review, we examine mechanisms by which heme regulates mitochondrial protein quality control, respiratory chain assembly, and metabolic feedback to coordinate organellar function with cellular energy demands. We further discuss how heme is trafficked to extramitochondrial compartments, where it modulates cytoplasmic stress signaling, iron homeostasis, transcriptional networks, and metabolic programs through interactions with proteins, including the BACH1 transcription factor, REV-ERB nuclear receptors, and the glycolytic enzyme GAPDH. We also highlight ongoing debates surrounding mitochondrial heme trafficking and identify critical unanswered questions regarding the identity of intracellular heme chaperones and mitochondrial heme sensors. Finally, we discuss how dysregulation of heme synthesis, trafficking, sensing, and degradation contributes to diverse pathologies. Collectively, recent advances establish heme as a central regulator of mitochondrial communication and cellular homeostasis, underscoring the therapeutic potential of targeting heme signaling pathways in human disease.
    Keywords:  heme; iron; mitochondria; oxidative stress; porphyrin; unfolded protein response
    DOI:  https://doi.org/10.1016/j.jbc.2026.113518
  30. Nat Commun. 2026 Sep 09. pii: 9646. [Epub ahead of print]17(1):
    Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer.
    Pan Prostate Cancer Group (PPCG)
      The inactivation of tumour suppressor genes is a key step in cancer development, and is usually achieved by homozygous loss. In prostate cancer, however, large genomic regions are often hemizygously lost, which complicates the identification of putative tumour suppressors in these regions. Here, we develop Epi2Hit, an integrative computational method that leverages whole genome sequencing, epigenomic profiling and gene expression to identify biallelic inactivation of tumour suppressor genes involving DNA methylation of promoter and enhancer regions of one allele and genomic loss of the other allele. We apply Epi2Hit to a cohort of 2,021 prostate cancers to discover tumour suppressor genes. In particular, we identify epigenetic biallelic inactivation of ZFHX3 at a recurrence level similar to TP53. Biallelic inactivation of ZFHX3, a transcriptional repressor, leads to upregulation of oncogenes, including MYC and a shorter time to metastasis. Finally, we provide evidence that epigenetic silencing as 2nd hit is particularly enriched in regions with nearby essential genes, precluding homozygous loss.
    DOI:  https://doi.org/10.1038/s41467-026-72182-5
  31. Nat Rev Cancer. 2026 Sep 08.
    Reflecting on 25 years of cancer research: transformative advances and unmet expectations.
    Allan Balmain, René Bernards, Hans Clevers, Karen H Vousden, Paul Workman, Marinka Zitnik.
      
    DOI:  https://doi.org/10.1038/s41568-026-00974-4
  32. Nature. 2026 Sep;657(8131): 562-564
    Probing the proteome at cellular scale.
    Michael Eisenstein.
      
    Keywords:  Biological techniques; Cell biology; Proteomics; Technology
    DOI:  https://doi.org/10.1038/d41586-026-02805-w
  33. Nat Genet. 2026 Sep;58(9): 2078
    A cancer that swims between hosts.
    Hui Hua.
      
    DOI:  https://doi.org/10.1038/s41588-026-02760-2
  34. Nat Rev Cancer. 2026 Sep 09.
    A guide to understanding tumour evolution through the lens of population genetics.
    Giulio Caravagna, Trevor A Graham, Andrea Sottoriva.
      Every cancer carries the history of its own evolution, hidden in its genome. Modern DNA sequencing can catalogue millions of mutations and profile tumours across space and time, but sequencing alone struggles to answer the questions that matter most: when did key adaptations emerge, how strongly were they selected, why do some tumours relapse whereas others do not, and how will the cancer evolve next? The reason is fundamental: sequencing is a snapshot, whereas evolution is a dynamic process. Bridging this gap requires moving beyond descriptive cancer genomics towards quantitative evolutionary inference. In this Review, we argue that population genetics provides the mathematical framework needed to extract evolutionary dynamics from cancer genomes. We show how models of mutation, selection and drift transform allele frequencies from descriptive measurements into quantitative estimates of clonal fitness and evolutionary timings. We discuss how these principles extend to epigenetic inheritance, plasticity and ecological interactions within the tumour ecosystem, and examine the assumptions and limitations for their application to modern sequencing data. By reframing cancer genomes as quantitative records of evolutionary processes rather than catalogues of mutations, researchers have used population genetics to provide a foundation for understanding - and ultimately predicting - the trajectories of cancer evolution.
    DOI:  https://doi.org/10.1038/s41568-026-00973-5
  35. Trends Biochem Sci. 2026 Sep 07. pii: S0968-0004(26)00253-7. [Epub ahead of print]
    Pyruvylation expands the redox repertoire of lysine acylation.
    Jun Seo Park, Sung Joong Lee.
      Song et al. establish lysine pyruvylation (Kpy) as an acylation response to glycolytic flux and pyruvate availability, detect pyruvyl-CoA, implicate histone acetyltransferase 1 and p300 as writers and sirtuin 3 as an eraser, and link promoter-associated histone Kpy to transcriptional regulation, defining a distinct C3 acylation alongside lactylation at the redox-coupled pyruvate-lactate node.
    Keywords:  acylation; epigenetics; lactate dehydrogenase; post-translational modification; pyruvylation
    DOI:  https://doi.org/10.1016/j.tibs.2026.08.008
  36. Cell Rep. 2026 Sep 08. pii: S2211-1247(26)01004-1. [Epub ahead of print]45(9): 117926
    Disrupted glucocorticoid rhythms selectively induce severe skeletal muscle insulin resistance and uncouple obesity from hepatic steatosis.
    Agnieszka Agas, Sanjeev Sharma, Anthony Narciso, Lucas Paulo Jacinto Saavedra, Jijo Wilson, Jack Lungstrum, Lucie Yammine, Anna S Arzeno, Louise Lantier, Erin Kilkenny, Ahsan Uddin, Carolina E Echeverria, Katherine R Ferrick, Isaac Nathoo, Jonathan Gao, Edmund D Kapelczak, Rashel Jacobo, Roma Patel, Tara TeSlaa, Marcus D Goncalves, Timothy E McGraw, Mary N Teruel.
      Disruption of circadian glucocorticoid (GC) rhythms is associated with chronic stress and obesity, yet its metabolic signature remains poorly defined. Using a physiological mouse model, we show that the liver is largely protected from pathological steatosis despite profound obesity and hyperinsulinemia. We identify a unique redistribution of insulin resistance: rhythm disruption does not globally impair insulin action as occurs in diet-induced obesity. Instead, skeletal muscle develops severe insulin resistance while adipose and hepatic tissues remain functionally insulin responsive. This preserved sensitivity allows the adipose tissue to act as a metabolic reservoir, utilizing sustained hyperinsulinemia to sequester lipids and shield the liver from toxic fatty-acid flux. These findings reveal that GC-rhythm disruption uncouples obesity from hepatic steatosis by redistributing insulin action from skeletal muscle to adipose tissue and liver. Thus, GC-rhythm disruption and high-fat diet are independent and additive drivers of adiposity with divergent hepatic effects.
    Keywords:  CP: metabolism; adipose tissue; circadian rhythm; fatty liver; glucocorticoids; high-fat diet; hyperinsulinemia; insulin resistance; lipolysis; obesity; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117926
  37. Oncogene. 2026 Sep 11.
    Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.
    Weidong Yu, Bo Wang, Fanhao Meng, Xiaojun Ren, Danyi Zhou, Huanxin Wei, Zhengquan Yang, Hongwei Sun, Minghua Jiang, Tao Xia, Wei Cui, Hezhi Fang.
      Pancreatic ductal adenocarcinoma (PDAC) cells rely on fatty acid oxidation (FAO) for proliferation; however, the regulatory mechanisms governing this dependency and their clinical implications remain unclear. Here, we report that PDAC patients exhibit decreased plasma levels of propionyl-CoA intermediates, alongside accelerated propionyl-CoA catabolic activity within both human PDAC tumors and Pdx1-Cre/KrasG12D/+/Trp53R172H/+ (KPC) mouse tumors. Specifically, PDAC cells upregulate propionyl-CoA carboxylase (PCC) to accelerate propionyl-CoA catabolism, thereby establishing a metabolic signature distinct from that of healthy tissues. Mechanistically, PCC is essential for PDAC growth, not by fueling the TCA cycle, but by preventing toxic propionyl-CoA accumulation. We further demonstrate that elevated propionyl-CoA leads to the propionylation-induced inactivation of the mitochondrial fatty acid oxidation (FAO) enzyme ACAA2 at Lysine 137, thereby blocking the FAO flux required for tumor proliferation. Moreover, high PCCA expression in patient PDAC tumors is significantly associated with decreased lipid accumulation, and PDAC cells with high PCC levels are more sensitive to etomoxir-induced cell proliferation arrest. These findings establish the PCC-ACAA2 axis as a critical metabolic vulnerability and a promising target for diagnostic and therapeutic interventions in PDAC.
    DOI:  https://doi.org/10.1038/s41388-026-03979-3
  38. Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01045-4. [Epub ahead of print]45(9): 117967
    From heart to BAT: Rethinking mouse models of human BAT.
    Yingzi Shi, Siegfried Ussar.
      Ran et al. identify a heart-associated origin of mouse supraclavicular brown adipose tissue (BAT). Their findings challenge the dominance of interscapular BAT in mouse research and suggest that anatomically corresponding depots may better inform translation to human thermogenic fat.
    DOI:  https://doi.org/10.1016/j.celrep.2026.117967
  39. Genes Dev. 2026 Sep 09.
    Dangerous liaisons: interactions between cancer cells and adipocytes as drivers of cancer progression.
    Carolina Dehesa Caballero, Almut Schulze.
      Metabolic plasticity and flexibility are key characteristics that allow cancer cells to adapt and thrive in different environments. Specifically, cancer cells can dynamically change the routing of metabolic pathways in response to environmental changes and adapt their metabolic activity depending on local nutrient availability. The tumor microenvironment (TME) plays crucial roles in cancer development and progression. It is now widely accepted that different stromal cells, as well as soluble factors, including metabolites, derived from the TME support cancer cell proliferation and survival and drive migration, invasion, and the formation of metastases. Some cancer types grow in the proximity of adipose tissue (AT), which is mostly composed of mature adipocytes, a specialized cell type responsible for the storage and controlled release of lipids. In response to specific stimuli released by cancer cells, adipocytes can transform into cancer-associated adipocytes (CAAs). CAAs release signaling molecules, and provide fatty acids to cancer cells and other cell types in the TME, which can then utilize these fatty acids as fuel. The interaction between cancer cells and adipocytes creates a dynamic cross-talk that promotes disease progression through multiple mechanisms. In this review, we aim to provide an overview of the main factors in the CAA-cancer cell cross-talk, with a focus on the metabolic consequences of this interaction.
    Keywords:  EMT; cancer-associated adipocytes; fatty acid transport; lipid droplets; metabolic flexibility and plasticity; metastasis; oxidative stress
    DOI:  https://doi.org/10.1101/gad.353813.126
  40. J Biol Chem. 2026 Sep 08. pii: S0021-9258(26)02398-7. [Epub ahead of print] 113526
    Nitric oxide dependent metabolic and genetic dysregulation in metastatic triple-negative breast cancer.
    Jennifer N Daw, Pricila K Moly, Su Chung, Sarah Young, Nhi Van, Sara Centuori, David G Besselsen, Nathan Ellis, Ronald L Heimark, William R Montfort.
      Chronic inflammation drives many diseases, including cancer, where inflammation is associated with metastasis, the cause of death in 90% of cancer fatalities. Tumor inflammation drives inducible nitric oxide synthase (NOS2) and cyclooxygenase 2 (COX2) expression, each of which is associated with poor outcomes in cancer. Here, we knocked out the NOS2 gene in the murine triple-negative breast cancer allograft tumor model 4T1 and examined metastatic spread from primary mammary tumors to lung in BALB/c mice with intact immune systems. Remarkably, while the parental 4T1 tumors were highly metastatic, metastasis from 4T1 NOS2-/- tumors was nearly eliminated. In cell culture, we find that nitric oxide (NO) from NOS2 induces a glycolytic phenotype, epitrascriptomic dysregulation, and prostaglandin E2 synthesis by stimulating COX2. Cytokine addition led to DNA damage, presumably from NO. Human colorectal cancer cell line DLD1 yielded similar results. RNA sequencing of 4T1 cells revealed a NOS2-dependent reduction in mRNAs associated with regulation of chromosome and DNA replication, including cell cycle checkpoints, as well as mRNAs associated with RNA demethylation, including tRNA demethylation. Immunoprofiling of the tumor microenvironment revealed immunosuppressed primary tumors that were low in cytotoxic T cells and high in myeloid derived suppressor cells expressing interferon gamma, which induces NOS2 expression. Taken together, these data suggest high NOS2 in tumor cells may drive metastasis through a broad accumulation of cancer-associated factors - including metabolic dysregulation, genetic dysregulation, and an increase in inflammatory prostaglandins - all of which contribute to aggressive cancers.
    Keywords:  Inflammation; epigenetics; immunosuppression; metabolism; nitric oxide
    DOI:  https://doi.org/10.1016/j.jbc.2026.113526
  41. J Inherit Metab Dis. 2026 Sep;49(5): e70244
    Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.
    Barbara Siri, Diego Martinelli, Rosalba Carrozzo, Sara Boenzi, Sara Cairoli, Cristiano Rizzo, Teresa Giovanniello, Johannes Häberle, Carlo Dionisi-Vici.
      ATP synthase defects, including TMEM70 and MT-ATP6 deficiencies, cause severe mitochondrial encephalo-(cardio)-myopathies complicated by acute metabolic decompensations (AMDs) often associated with hyperammonaemia. However, detailed biochemical characterisation of these events remains limited. The aim of the study was to evaluate the metabolic profiles associated with TMEM70 and MT-ATP6 deficiencies during AMDs in comparison to stable metabolic conditions, assessing frequency and severity of hyperammonaemia, and exploring the mechanisms linking impaired mitochondrial ATP production to the urea cycle by in vivo ureagenesis studies, using [15N] ammonium chloride as stable isotope and assessed by high-resolution mass-spectrometry coupled with liquid chromatography. We retrospectively analysed clinical and biochemical profiles from two genetically confirmed cohorts. Patients with TMEM70 deficiency experienced more frequent AMDs, often with hyperammonaemia and requiring extracorporeal detoxification, while the MT-ATP6 cohort had more prominent neurological symptoms and a lower incidence of hyperammonaemia. Biochemically, both groups showed elevated lactate, alanine and glutamine, with orotic aciduria and abnormalities in purine/pyrimidine metabolism. Plasma citrulline levels were divergent in the two cohorts, with a consistent reduction in patients with MT-ATP6 deficiency and normal or borderline elevated levels in the TMEM70 cohort. In vivo stable isotope studies pointed to the differential impact of TMEM70 and MT-ATP6 deficiency on ureagenesis and on the enrichment of individual urea cycle-related amino acids. This study reveals that TMEM70 and MT-ATP6 deficiencies share features of mitochondrial dysfunction but present distinct metabolic profiles, highlighting a different impact on the urea cycle and its related metabolites, and providing novel insights on our understanding of mitochondrial pathophysiology.
    Keywords:  ATP synthase defects; MT‐ATP6; TMEM70‐related encephalo‐(cardio)‐myopathy; acute metabolic decompensation; urea cycle
    DOI:  https://doi.org/10.1002/jimd.70244
  42. Trends Mol Med. 2026 Sep 11. pii: S1471-4914(26)00200-5. [Epub ahead of print]
    Telomerase reverse transcriptase as a core regulator of brain health.
    Hong Seok Shim, Ronald A DePinho.
      Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase, the holoenzyme whose activity maintains telomeres. Beyond this canonical role, emerging evidence indicates that TERT participates in nontelomeric programs with broad relevance to brain health. TERT can function as a transcriptional co-regulator of genes linked to neuronal viability, synaptic plasticity, and neurodegeneration. During aging and in neurodegenerative states, the TERT locus becomes epigenetically repressed, resulting in altered gene expression programs relevant to neuronal resilience. Genetic and pharmacologic restoration of physiological TERT levels reverses multiple aging phenotypes and mitigates molecular and pathological features associated with neurodegenerative disorders, including Alzheimer's disease. In this opinion article, we synthesize emerging evidence that positions TERT as a central coordinator of brain health and disease.
    Keywords:  TERT; aging; brain; gene regulation; neurodegeneration; telomerase
    DOI:  https://doi.org/10.1016/j.molmed.2026.08.003
  43. Cell Death Differ. 2026 Sep 08.
    Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.
    Matea Rob, Farah H Siddiqi, Junrui He, Yoshinori Tanaka, David C Rubinsztein.
      Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic aggregate-prone proteins, which are characteristic pathological hallmarks of neurodegenerative diseases. As we previously found that microglia secreted factors impair neuronal autophagy and identified CCL3, CCL4 and CCL5 as causative chemokines, we screened the microglial secretome for soluble factors and neuronal cytokine receptors to identify candidates impacting autophagy in neuronal models. Against our expectations of identifying negative regulators, we found that two receptor-ligand pairs, CXCR3-CXCL10 and CXCR5-CXCL13, stimulated autophagy across several neuronal models, both in vitro (SH-SY5Y, i3Neurons) and in vivo. Mechanistically, CXCL10 and CXCL13 promoted autophagy through a shared mechanism: cognate receptor stimulation led to downstream activation of JNK, which in turn phosphorylates BCL-XL, promoting its disassociation from BECN1. The freed BECN1 interacts with VPS34 to form the autophagy initiation complex, enhancing autophagosome formation and flux. These findings reveal chemokine signalling as a targetable pathway for neuronal autophagy induction in neurodegeneration.
    DOI:  https://doi.org/10.1038/s41418-026-01865-9
  44. J Cell Biol. 2026 Nov 02. pii: e202605096. [Epub ahead of print]225(11):
    Nucleolar dynamics are determined by the ordered assembly of the ribosome.
    Jessica Sheu-Gruttadauria, Xiaowei Yan, Nico Stuurman, Riley O Ogrean, Sabrina Lin, Stephen N Floor, Ronald D Vale.
      Ribosome biogenesis occurs in the nucleolus, a biomolecular condensate whose material properties are thought to be important for function. However, the molecular basis of nucleolar dynamics and their relationship to ribosome assembly remain incompletely understood. We present a platform for high-throughput FRAP (HiT-FRAP) and use it to screen hundreds of genes for their impact on dynamics of the nucleolar scaffold nucleophosmin (NPM1). We find that NPM1 dynamics and nucleolar morphology are sensitive to ribosome assembly state: accumulation of early pre-ribosomal intermediates slows NPM1 dynamics and compacts the condensate, while accumulation of abortive late precursors accelerates dynamics and disrupts condensate integrity. These opposing biophysical states correlate with the strength of NPM1-pre-ribosome interactions. Importantly, mutations in the NPM1 intrinsically disordered region that alter pre-ribosome binding directly tune nucleolar dynamics. These results establish that ribosomal precursor assembly state determines nucleolar material properties through the strength of scaffold-pre-ribosome interactions and introduce HiT-FRAP as a platform for interrogating condensate dynamics broadly.
    DOI:  https://doi.org/10.1083/jcb.202605096
  45. Cell Rep Med. 2026 Sep 10. pii: S2666-3791(26)00444-1. [Epub ahead of print] 103027
    A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy.
    Rajesh Kumar, Parth Desai, Rajaa El Meskini, Chirayu Mohindroo, Alexandra Ágnes Benő, Devon Atkinson, Michael Nirula, Laura Bassel, Nobuyuki Takahashi, Kelly L Sovacool, Anna Meinhardt, Mohit Arora, Kanak Parmar, Darryl Nausome, Samantha Nichols, Linda Sciuto, Shannon Swift, Kolos Nemes, Ajit Kumar Sharma, Nathan Pate, Arun Rajan, Elliot Levy, Michael Kassin, Christopher Febres Aldana, Vishal Koparde, Melissa Galloux, Roshan Shreshta, Zoe Weaver Ohler, Lorinc Pongor, Anish Thomas.
      Small-cell lung cancer (SCLC) is an aggressive malignancy with substantial tumor heterogeneity and limited clinically actionable biomarkers beyond established features such as liver metastases. We profile tumor-intrinsic chromatin accessibility in a patient-derived xenograft biobank and identify three recurrent chromatin programs: neuroendocrine, marked by ASCL1/NEUROD1 activity; immunogenic, marked by IRF-associated activity; and stem-like, marked by TEAD/OCT activity. These programs are reproduced at the cohort level across bulk and single-cell transcriptomic datasets comprising more than 800 tumors, including 300 extensive-stage samples. In patients treated with chemoimmunotherapy, the stem-like program is associated with inferior survival, including a median overall survival of 7.41 months versus 15.9 and 12.6 months for immunogenic and neuroendocrine groups, respectively. This association remains significant after adjustment for liver metastases, brain metastases, and elevated lactate dehydrogenase. These findings support a high-risk stem-like SCLC chromatin program for prospective biomarker refinement and therapeutic investigation.
    Keywords:  ATAC-seq; PDX; biomarker; chemoimmunotherapy; chromatin accessibility; multi-omics; plasticity; regulatory programs; small-cell lung cancer; stem-like tumor state
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103027
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