bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–02–22
47 papers selected by
Christian Frezza, Universität zu Köln
  1. Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
  2. Adipocyte NADH dehydrogenase reverses circadian and diet-induced metabolic syndrome.
  3. A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity.
  4. Decoding cancer across scales with metabolomics.
  5. BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
  6. DHODH turns cytosolic, yet cells keep growing.
  7. The integrated stress response promotes immune evasion through lipocalin 2.
  8. CypD Dependent mPTP Opening Is Crucial for Oxidized Mitochondrial DNA Release in Ferroptosis.
  9. The Effects of Aging and Anti-Aging Dietary Restriction on Brain Glutathione and Thioredoxin Redox Systems.
  10. The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.
  11. A metabolic safety valve for reductive stress.
  12. Succinate Dehydrogenase-Deficient Cancer Cells Have Increased Susceptibility to Ym155-Induced DNA Damage.
  13. Single-cell epigenetic profiling reveals a tumor-intrinsic interferon response program in ccRCC tied to poor prognosis and BAP1 loss.
  14. 16-h fasting optimizes cancer immunotherapy in mice and humans.
  15. Beyond a degrader: VHL reprograms hypoxic metabolism.
  16. Metabolic crosstalk between cancer and stromal cells: Implications for precision oncology.
  17. Cellular mechanisms of brain lipid metabolism in health and disease.
  18. Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
  19. Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
  20. A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
  21. Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics.
  22. Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
  23. Reduced Versus Oxidized NAD+ Precursors Drive Distinct Transcriptomic, Proteomic, and Metabolic Profiles in Hepatocytes.
  24. Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair.
  25. Large-scale mapping of environmental-genetic interactions illustrates the dynamic nature of cell-cycle and DNA repair regulation.
  26. Generation of a comprehensive epigenomic atlas in clear cell renal cell carcinoma informs kidney cancer progression and heritability.
  27. Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux.
  28. HIF-activated priming of TRAIL-induced cell death determines epigenetic vulnerability in kidney cancer.
  29. A Stable Isotope Tracing Primer for the Mass Spectrometrist.
  30. A switchable role of neuronal BNIP3L/NIX in mitochondrial fate: fission or finish.
  31. The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior.
  32. TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.
  33. Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition in metastatic TNBC.
  34. Human neuromuscular organoids mimic cancer-induced muscle cachexia.
  35. GPX4 Inhibitor Resistance and Metastatic Features in Triple-Negative Breast Cancer.
  36. Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice.
  37. Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation.
  38. Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
  39. Palmitic acid activates c-Myc via dual palmitoylation-dependent pathways to promote colon cancer.
  40. KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
  41. Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
  42. Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.
  43. Oxygen metabolism in descendants of the archaeal-eukaryotic ancestor.
  44. Red blood cells serve as a primary glucose sink to improve glucose tolerance at altitude.
  45. Nucleotide signals coordinate activation and inhibition of bacterial immunity.
  46. Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine Pseudomonas aeruginosa pneumonia.
  47. Nonoxidative pentose phosphate pathway regulates CD8+ T cell immunity by maintaining NADPH homeostasis.
  1. Nat Metab. 2026 Feb 17.
    Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
    Andrea Curtabbi, Sara Natalia Jaroszewicz, Rocío Sanz-Cortés, Rebeca Acín-Pérez, Dimitrios Prymidis, Maksym Cherevatenko, Raquel Martínez-de-Mena, María Jesús Esteban-Amo, Miguel A de la Fuente, Christian Frezza, José Antonio Enríquez.
      Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.
    DOI:  https://doi.org/10.1038/s42255-026-01454-7
  2. Nat Metab. 2026 Feb 18.
    Adipocyte NADH dehydrogenase reverses circadian and diet-induced metabolic syndrome.
    Chelsea Hepler, Nathan J Waldeck, Benjamin J Weidemann, Biliana Marcheva, You-Jia Chen, Jacqueline Hecker, Ziming Zhu, Rino Nozawa, Joseph V Mastroni, Anneke K Thorne, Colleen R Reczek, Jonathan Cedernaes, Kathryn M Ramsey, Clara B Peek, Grant D Barish, Navdeep S Chandel, Joseph Bass.
      Circadian clocks are internal timing systems that enable organisms to anticipate and adapt to daily environmental changes. These rhythms arise from a transcription-translation feedback loop in which CLOCK and BMAL1 regulate the expression of thousands of genes, including their repressors PER and CRY. Disruption of circadian rhythms contributes to obesity, metabolic disease and cancer, yet how the clock maintains metabolic homeostasis remains limited. Here we report that the clock regulates oxidative metabolism in adipocytes through diurnal complex I respiration. Disrupting the clock in male mice via adipocyte-specific genetic deletion or high-fat-diet feeding reduces complex I respiration in adipocytes, leading to suppression of the peroxisome proliferator-activated receptor and insulin signalling pathways. In contrast, restoring complex I function by expressing yeast NDI1 in adipocytes protects against diet-induced and circadian-induced metabolic dysfunction independently of weight gain. These findings reveal that adipocyte circadian disruption impairs metabolic health through mitochondrial complex I dysfunction, establishing clock control of complex I as a key regulator of metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s42255-026-01464-5
  3. Nat Metab. 2026 Feb 16.
    A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity.
    Xingxiu Pan, Subrata Munan, Austin L Zuckerman, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Nirajan Shrestha, Sara Violante, Justin R Cross, Russell P Goodman, Hardik Shah, Valentin Cracan.
      Dihydroxyacetone phosphate (DHAP), glycerol-3-phosphate (Gro3P) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD⁺) are key metabolites of the Gro3P shuttle, which transfers reducing equivalents between the cytosol and mitochondria. Targeted activation of Gro3P biosynthesis has recently emerged as a promising strategy to alleviate reductive stress. However, because Gro3P constitutes the backbone of triglycerides, its accumulation can promote extensive lipogenesis. Here we show that a genetically encoded tool based on a di-domain glycerol-3-phosphate dehydrogenase from the alga Chlamydomonas reinhardtii (CrGPDH) effectively operates both the alternative Gro3P shunt, which regenerates NAD⁺ while converting DHAP to Gro3P, and the glycerol shunt, which converts Gro3P to glycerol and inorganic phosphate, across transformed and primary mammalian cell cultures as well as mouse liver. CrGPDH expression supported proliferation of cancer cells under respiratory chain inhibition or hypoxia, as well as patient-derived fibroblasts with mitochondrial dysfunction. Moreover, CrGPDH decreased triglyceride levels in kidney cancer cell lines and reversed ethanol-induced triglyceride accumulation in mouse liver. Thus, CrGPDH represents a promising xenotopic tool to alleviate redox imbalance and associated impaired lipogenesis in conditions ranging from primary mitochondrial diseases to steatosis.
    DOI:  https://doi.org/10.1038/s42255-025-01450-3
  4. Nat Rev Cancer. 2026 Feb 20.
    Decoding cancer across scales with metabolomics.
    Joe L Rowles, Gary J Patti.
      It is well established that malignant cells alter their metabolism to support proliferation, but the nutrients required to meet the anabolic demands of different cancers located at various anatomical sites throughout the body remain largely unknown. Moreover, the extent to which nutrients are supplied by neighbouring stromal cells or distant tissues, possibly due to metabolic reprogramming, is poorly understood. Metabolomics provides a unique biochemical approach to address these gaps in our knowledge, but cancer studies require careful consideration because it is challenging to identify appropriately matched control samples for comparison. Here, we detail a collection of metabolomics workflows designed to interrogate cancer across three discrete scales. First, we describe experiments to define the nutrient demands of cancer cells themselves. Second, we focus on identifying metabolic relationships between neighbouring cells in the tumour microenvironment. Finally, we highlight strategies to explore the metabolic crosstalk between cancer cells and distant tissues in the tumour macroenvironment. The approaches outlined span cells in culture, animal models and human specimens from patients with cancer. Special emphasis is dedicated to the application of emerging technologies and computational pipelines in the field of mass spectrometry that enable global profiling of metabolites and lipids.
    DOI:  https://doi.org/10.1038/s41568-026-00908-0
  5. Mol Cell. 2026 Feb 13. pii: S1097-2765(26)00032-8. [Epub ahead of print]
    BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
    Brandon Chen, Drew C Stark, Pankaj V Jadhav, Theophilus M Lynn-Nguyen, Benjamin S Halligan, Nicholas J Rossiter, Nicole Sindoni, Myungsun Shin, Joao A Paulo, Matthew Chang, Imhoi Koo, Sergei Koshkin, Sanjana Eyunni, Paolo Ronchi, Michelle T Paulsen, Harrison S Greenbaum, Mariana T Ruckert, Pietro Morlacchi, David A Hanna, Jason Lin, Rachel M Guerra, Tao Liu, David J Pagliarini, Ruma Banerjee, Abhijit Parolia, Mats E Ljungman, Andrew D Patterson, Joseph D Mancias, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.
    Keywords:  bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.012
  6. Nat Metab. 2026 Feb 17.
    DHODH turns cytosolic, yet cells keep growing.
    Olivia Vidal-Cruchez, Issam Ben-Sahra.
      
    DOI:  https://doi.org/10.1038/s42255-026-01466-3
  7. Nature. 2026 Feb 18.
    The integrated stress response promotes immune evasion through lipocalin 2.
    Jozef P Bossowski, Ray Pillai, John Kilian, Angela Wong Lau, Mari Nakamura, Ali Rashidfarrokhi, Yuan Hao, Ruxuan Li, Katherine Wu, Takamitsu Hattori, Eliezra Glasser, Akiko Koide, Lidong Wang, Andre L Moreira, Cristina Hajdu, Sahith Rajalingam, Sarah E LeBoeuf, Hortense Le, Seungeun Lee, Jin Woo Oh, Cheolyong Joe, Hyemin Kim, Chan-Young Ock, Se-Hoon Lee, Hao Wang, Angana A H Patel, Volkan I Sayin, Aristotelis Tsirigos, Kwok-Kin Wong, Sergei B Koralov, Mario Pende, Francisco J Sánchez-Rivera, Diane M Simeone, Ioannis K Zervantonakis, Shohei Koide, Thales Papagiannakopoulos.
      Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.
    DOI:  https://doi.org/10.1038/s41586-026-10143-0
  8. Adv Sci (Weinh). 2026 Feb 17. e02239
    CypD Dependent mPTP Opening Is Crucial for Oxidized Mitochondrial DNA Release in Ferroptosis.
    Hong Zhou, Wan Fu, Shizuo Liu, Zili Zhang, Hanyan Luo, Qing Zhong.
      Ferroptosis is a type of regulated cell death characterized by the accumulation of lipid peroxides that damage cell membranes specifically. Mitochondrial swelling and dysfunction are hallmarks of ferroptosis; however, what causes mitochondrial swelling and the consequences of mitochondrial swelling in ferroptotic signal transduction remain poorly understood. Our study found that mitochondrial permeability transition pore (mPTP) opening is essential for mitochondrial swelling and ferroptosis activation. During ferroptosis, oxidized mitochondrial DNAs (mtDNAs) are released through the mPTP. These oxidized mtDNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, promoting ferroptosis through activating ferrotinophagy. Consistently, inhibition of mtDNA-repair enhances cellular sensitivity to ferroptosis and therefore synergizes with ferroptosis inducer in suppressing tumorigenesis in mouse xenograft tumor models. This study provides a fundamental understanding of how mPTP engages in ferroptosis by releasing mitochondrial DNAs as crucial messengers to activate ferroptotic signaling.
    Keywords:  cGAS‐STING; ferroptosis; mPTP; mitochondria; mtDNA
    DOI:  https://doi.org/10.1002/advs.202502239
  9. Aging Dis. 2026 Feb 10.
    The Effects of Aging and Anti-Aging Dietary Restriction on Brain Glutathione and Thioredoxin Redox Systems.
    Leah E Jamerson, Patrick C Bradshaw.
      Glutathione (GSH) is a cofactor for several enzymes including glutathione peroxidases (GPXs) that detoxify H2O2 and for glutaredoxins that catalyze protein cysteine deglutathionylation. Aging results in a decreased rate of brain GSH synthesis and an oxidation of brain GSH to glutathione disulfide (GSSG), which increases oxidative damage, but is delayed or reversed by anti-aging dietary restriction (DR). Fasting increases the hepatic synthesis and release of GSH, which is catabolized to its amino acids, possibly increasing their transport to the brain for the re-synthesis of GSH. Brain GSH synthesis is limited by cysteine availability. Some astrocytes may increase GSH synthesis during fasting and DR by increasing metabolic flux through the cysteine and H2S-synthesizing transsulfuration pathway. In contrast to the cytoplasm where the GPX1-GSH pathway for H2O2 detoxification is highly active, the mitochondrial matrix relies largely on peroxiredoxin 3 (PRDX3), which functions together with thioredoxin 2 and thioredoxin reductase 2. In contrast to the cytoplasmic and mitochondrial GSH/GSSG, the ER GSH/GSSG is more oxidized in young organisms and becomes reduced with aging and plays a more fundamental role in buffering protein disulfide bond isomerization than for providing GSH to ER GPXs. Studies addressing the aging and DR-induced redox changes in the cytoplasm, mitochondria, and ER in different neural cell types and brain regions are needed to establish effective therapies for aging-related disorders. This review further covers the brain cell-type and brain region-specific gene expression changes that occur with aging and DR for the major enzymes that maintain the cellular redox state.
    DOI:  https://doi.org/10.14336/AD.2025.1505
  10. FEBS J. 2026 Feb 18.
    The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.
    Michaela Veliova, Caroline M Ferreira, Katrina P Montales, Francisco Villalobos, Alexandra J Brownstein, Rebeca Acín-Pérez, Gabrielly S Ferreira, Anthony E Jones, Linsey Stiles, Ajit S Divakaruni, Marc Liesa, Orian S Shirihai, Marcus F Oliveira.
      Brown adipose tissue (BAT) plays a central role in thermogenesis by coupling fatty acid oxidation to heat production. Efficient BAT thermogenic activity requires enhanced glycolytic flux, which in turn depends on continuous regeneration of cytosolic NAD+ to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle (GPSh), and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh, namely the oxoglutarate carrier (Ogc) and aspartate-glutamate carrier (Aralar1), had no apparent effects on respiratory rates. However, silencing either Ogc or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.
    Keywords:  energy; heat; metabolism; obesity; redox; thermogenesis
    DOI:  https://doi.org/10.1111/febs.70461
  11. Nat Metab. 2026 Feb 16.
    A metabolic safety valve for reductive stress.
    Mahmoud S Yahia, Melanie R McReynolds.
      
    DOI:  https://doi.org/10.1038/s42255-026-01463-6
  12. Endocr Relat Cancer. 2026 Feb 19. pii: ERC-25-0397. [Epub ahead of print]
    Succinate Dehydrogenase-Deficient Cancer Cells Have Increased Susceptibility to Ym155-Induced DNA Damage.
    Qianjin Guo, Sooyeon Lee, Neali Armstrong, Brian Lim, Rebecca C Schugar, David Tomz, Haixia Xu, Anzel Zhen, Leor Needleman, Electron Kebebew, Justin P Annes.
      The hereditary pheochromocytoma and paraganglioma (hPPGL) syndrome, caused by germline succinate dehydrogenase (SDHx) gene mutation, predisposes individuals to pheochromocytomas (Pheo), paragangliomas (PGL), renal cell carcinoma (RCC), and gastrointestinal stromal tumors (GIST). Notably, tumors with succinate dehydrogenase subunit B (SDHB) deficiency demonstrate increased metastatic risk and current systemic treatments remain only palliative. Hence, discovering novel therapeutic avenues to improve SDHB-cancer prognosis is an urgent need. Here we leveraged human SDHB-deficient UOK269 RCC cells (SDHB-KO) and isogenic SDHB-reconstituted control cells (SDHB-WT) to discover SDH-dependent mitochondria-directed cytotoxic agents. Given the reduced ATP-generating capacity of SDHB-KO cells, we hypothesized they would be uniquely sensitive to futile cycle induction with mitochondrial ionophores. Indeed, ionophores exhibited preferential cytotoxicity toward SDHB-KO cells. However, the mitochondria-directed chemotherapeutic compound Ym155 demonstrated more potent and dramatic preferential cytotoxicity towards SDHB-KO cells. Importantly, SDH-dependent cytotoxicity of Ym155 was validated in multiple cell models, including primary human pheochromocytoma cells, a mouse pheochromocytoma (MPC) cell line and primary SDHB-deficient mouse kidney cells. Notably, genetic evidence of Ym155 synthetic lethality with SDHB-deficiency was buttressed in additional cell models using two chemical inhibitors of SDH enzyme activity. Mechanistically, SDH-deficiency sensitized cells to Ym155-induced DNA damage. Strikingly, SDH-dependent Ym155 sensitivity was recapitulated by inhibition of the histone demethylase KDM4, a downstream consequence of SDH deficiency. In summary, accumulation of succinate in SDH-deficient tumors inhibited KDM4 activity, impaired DNA repair and yielded enhanced susceptibility to Ym155-induced reactive oxygen species (ROS) generation. The identified intrinsic susceptibilities of SDHB-deficient cancers have the potential to be therapeutically leveraged.
    Keywords:  DNA damage; Mitochondrial redox imbalance; Pheochromocytomas and Paragangliomas (PPGL); Succinate dehydrogenase; Ym155; renal cell carcinoma; synthetic lethality
    DOI:  https://doi.org/10.1530/ERC-25-0397
  13. Sci Adv. 2026 Feb 20. 12(8): eadv5457
    Single-cell epigenetic profiling reveals a tumor-intrinsic interferon response program in ccRCC tied to poor prognosis and BAP1 loss.
    Sabrina Y Camp, Meng Xiao He, Michael S Cuoco, Amanda E Garza, Sherin Xirenayi, Ziad Bakouny, Eddy Saad, Jad El Masri, Erica Pimenta, Kevin Meli, Chris Labaki, Breanna M Titchen, Yun Jee Kang, Jack Horst, Rachel Trowbridge, Erin Shannon, Karla Helvie, Aaron R Thorner, Sébastien Vigneau, Angie Mayorga, Jahnavi Kodali, Hannah Lachmayr, Meredith Bemus, Pengsheng Chen, Haiteng Deng, Jihye Park, Toni K Choueiri, Kevin Bi, Eliezer M Van Allen.
      Transcriptional programs in renal cell carcinoma (RCC) have been linked to tumor heterogeneity and clinical outcomes, but analogous efforts to define chromatin programs shaping disease biology have been limited. Here, we generated single-cell ATAC-seq profiles from patients with RCC and integrated them with three previously published datasets to identify chromatin programs in tumor cells. We identified an interferon response program enriched in BAP1-mutant tumors, and, in bulk ATAC-seq cohorts with linked clinical data, this program was associated with poor prognosis. Mechanistic analyses in isogenic models suggested that BAP1 loss induces a tumor-intrinsic interferon response, with dysregulated endogenous retroviruses as a potential upstream trigger. We further characterized the BAP1 mutation-associated tumor microenvironment across single-cell, bulk, and multiplex immunofluorescence data, identifying features of both inflammation and immune evasion. Together, our findings nominate tumor-intrinsic interferon signaling as a candidate driver of BAP1-associated aggressiveness in RCC and highlight immune evasion pathways as potential therapeutic targets.
    DOI:  https://doi.org/10.1126/sciadv.adv5457
  14. Cell Metab. 2026 Feb 19. pii: S1550-4131(26)00014-8. [Epub ahead of print]
    16-h fasting optimizes cancer immunotherapy in mice and humans.
    Sheng Chen, Tianyi Hu, Kaixiang Zhu, Yue Liu, Yidong Yang, Xiangyuan Li, Jinjie He, Wenyu Cui, Zhexu Chi, Weiwei Yu, Duojiao Chen, Zhen Wang, Jian Zhang, Ruya Sun, Dehang Yang, Siqi Dai, Qianzhou Yu, Quanquan Wang, Qian Xiao, Junbin Qian, Kefeng Ding, Di Wang.
      Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8+ T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8+ clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.
    Keywords:  diet intervention; immune checkpoint therapy; immunometabolism; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.015
  15. Cell Chem Biol. 2026 Feb 19. pii: S2451-9456(26)00031-0. [Epub ahead of print]33(2): 147-149
    Beyond a degrader: VHL reprograms hypoxic metabolism.
    Zhijun He, Peng Jiang.
      The von Hippel-Lindau (VHL) protein is known for degrading hydroxylated proteins in normoxia, but its role under hypoxia remains unclear. In a recent report in Cell Metabolism Li et al.1 demonstrate that mitochondrial VHL remodels amino acid metabolism under chronic hypoxia to support cell growth, independent of hydroxylated protein degradation.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.01.011
  16. Surg Oncol. 2026 Feb 12. pii: S0960-7404(26)00017-4. [Epub ahead of print]65 102366
    Metabolic crosstalk between cancer and stromal cells: Implications for precision oncology.
    Wanwan Yang, Yuwen Ding, Hongzhan Tian.
      Metabolic reprogramming is a hallmark of cancer that extends beyond the boundaries of individual tumor cells to encompass a complex metabolic network within the tumor microenvironment (TME). Cancer cells engage in dynamic metabolic crosstalk with stromal components including fibroblasts, immune cells, endothelial cells, and adipocytes through the exchange of metabolites, signaling molecules, and extracellular vesicles. These interactions coordinate energy production, redox homeostasis, and biosynthetic pathways that sustain tumor growth, angiogenesis, immune evasion, and therapeutic resistance. Cancer-associated fibroblasts (CAFs) supply lactate, amino acids, and lipids that fuel tumor anabolism; immune cells undergo metabolic suppression under nutrient competition and acidic stress; endothelial and adipose cells contribute to angiogenesis and metastatic adaptation through glycolysis and lipid transfer. This metabolic dialogue is governed by key signaling pathways (HIF-1α, mTOR, AMPK, c-Myc, PPAR, NRF2) and modulated by epigenetic mechanisms linking metabolic flux to gene expression. Understanding these multilayered communications provides novel insights into the cooperative and competitive nature of tumor metabolism. Emerging technologies such as spatial metabolomics and single-cell multi-omics are now enabling the identification of patient-specific metabolic dependencies. Targeting metabolic symbiosis rather than isolated pathways represents a promising direction for precision oncology, offering opportunities to disrupt tumor stroma cooperation, overcome therapeutic resistance, and personalize metabolism-based interventions.
    Keywords:  Cancer-associated fibroblasts; Metabolic crosstalk; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.suronc.2026.102366
  17. Nat Cell Biol. 2026 Feb 20.
    Cellular mechanisms of brain lipid metabolism in health and disease.
    Francesco Petrelli, Carlotta Gilardi, Carla Marie Igelbüscher, Diana Panfilova, Alicia Rey, Rosa Chiara Paolicelli, Marlen Knobloch.
      Lipid metabolism has recently regained considerable attention in neuroscience, as disturbances in lipid metabolic pathways have been linked to neurodevelopmental and neurodegenerative diseases. Here we examine brain lipid metabolism from a cellular perspective, focusing on lipid uptake, de novo synthesis, storage, breakdown and intercellular transfer. We cover the recent literature showing how these processes are important during brain development and how they occur in diverse brain cell types, including astrocytes, oligodendrocytes, neural stem and progenitor cells, microglia and neurons in the adult brain. We further discuss the consequences of disrupted lipid metabolism and highlight emerging insights into neuron-glia lipid exchange, as well as the importance of lipid droplets for brain health and disease.
    DOI:  https://doi.org/10.1038/s41556-026-01880-5
  18. Cell Death Discov. 2026 Feb 19.
    Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
    Àngela Llop-Hernández, Sara Verdura, Júlia López, Begoña Martin-Castillo, Javier A Menendez, Elisabet Cuyàs.
      Mitochondria integrate senescence and apoptotic fates, yet it is unclear whether their ability to oxidize different fuels for energy production influences their vulnerability to senolytics in therapy-induced senescence (TIS). Using MitoPlates™ technology, we functionally mapped the mitophenotypes of TIS cancer cells by quantifying electron transport chain (ETC) flux from various NADH/FADH2 substrates. We then related these profiles to the responsiveness of TIS cancer cells to BCL-xL-targeting BH3 senolytics, as well as to inflammatory SASP signaling sensed by an NF-κB/miR-146a reporter. Mechanistically distinct senogenic stressors produced markedly different bioenergetic outputs and substrate diversity, establishing mitochondria as an emergent, stress-encoded property of TIS phenomena. Increased mitochondrial bioenergetic flexibility corresponded with senolytic permissiveness within each cell lineage. However, the magnitude of the senolytic response was largely limited by the pre-senescent bioenergetic configuration of the parental mitochondria, and baseline succinate oxidation served as a functional indicator of this inherited threshold. TIS SASPs were restricted by the secretome of the cell-of-origin, but only the miR146a-positive, fatty acid β-oxidation-related inflammatory SASP states were senolytically responsive. Inflachromene, an inhibitor of the chromatin remodelers HMGB1/2, decoupled mitochondrial bioenergetics from senolytic susceptibility, yielding SASP-null/miR146a-negative senescent cancer cells that were completely resistant to ABT-263/navitoclax and A1331852 despite extensive mitochondrial reprogramming. Thus, the senolytic response is governed by a layered circuit in which mitochondrial bioenergetic heritage establishes the senolytic ceiling, TIS-acquired bioenergetic flexibility fine-tunes the amplitude of the senolytic response, and establishing a mitochondria-inflammatory SASP crosstalk is required for BH3-mediated senolysis. These results support using functional readouts that integrate mitochondrial metabolic flexibility and inflammatory SASP to predict and potentially enhance senolytic efficacy in TIS cancer cells.
    DOI:  https://doi.org/10.1038/s41420-026-02967-6
  19. Dev Cell. 2026 Feb 17. pii: S1534-5807(26)00037-7. [Epub ahead of print]
    Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
    Jyotirekha Das, Saloni K Hombalkar, Alison D Klein, Esraa Nsasra, Muskaan Vasandani, Kay Petruzzi, Dajun Lu, Stephen Ruiz, Orit Kliper-Gross, Jiachen Hu, Michelle Riegman, Xuejun Jiang, Daniel A Heller, Assaf Zaritsky, Michelle S Bradbury, Michael Overholtzer.
      Ferroptosis is a lipid peroxide-dependent form of cell death that occurs in degenerative conditions and may be leveraged for cancer therapy. Although numerous regulators are known to control its cell-autonomous execution, ferroptosis also has a collective property that involves propagation between cells, and this regulation has remained more obscure. Different modes of ferroptosis induction involving inhibition of the anti-ferroptotic enzyme GPX4 or depletion of glutathione can impact the collective death response differently, but the mechanisms underlying "single-cell" versus "propagative" ferroptosis are not well understood. Here, we discover significant lysosome rupture occurring during propagative ferroptosis and identify glutathione depletion as sufficient to convert GPX4 inhibition from an individual-cell response to a collective response. We find that induction of single-cell ferroptosis involves heterogeneous death profiles, with necrosis and apoptosis occurring in parallel within cell populations. These findings identify factors that control propagation and underscore lysosomes as critical to the execution of ferroptosis.
    Keywords:  GPX4; TFEB; apoptosis; cathepsin; ferroptosis; iron; lipid peroxidation; lysosome; necrosis; propagation
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.014
  20. Cell. 2026 Feb 19. pii: S0092-8674(26)00056-5. [Epub ahead of print]
    A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
    Zhangchuan Xia, Xin Yang, Sviatlana N Samovich, Yulia Y Tyurina, Vladimir A Tyurin, Ning Kon, Jiankang Zhang, Xuejun Jiang, Brent R Stockwell, Jian Jin, Hülya Bayir, Valerian E Kagan, Wei Gu.
      Ferroptosis is a tumor-suppressive mechanism with therapeutic potential. While canonical ferroptosis is usually triggered by inducers, such as erastin and RSL-3, or by glutathione peroxidase (GPX)4 loss, how ferroptosis occurs naturally in vivo without these triggers has been unclear. Building on evidence that p53 can mediate ferroptosis as a natural tumor-suppressive pathway, we describe a noncanonical, in vivo ferroptosis driven by reactive oxygen species (ROS)-induced phosphatidic acid (PA) peroxidation that proceeds without inducers. We identify GPX1 as a key regulator of this ROS-induced ferroptosis by modulating PA peroxidation. GPX1's effects depend on OSBPL8, an endoplasmic reticulum (ER)-membrane-associated oxysterol-binding protein. ROS-driven lipid peroxidation accumulates at the ER before plasma membrane rupture and cell death; GPX1 is recruited to the ER via OSBPL8 and directly reduces oxidized PA. OSBPL8 and GPX1 are overexpressed in cancers; knockdown of either promotes ROS-induced ferroptosis and suppresses tumor growth. Our data link the GPX1-OSBPL8 axis to in vivo ferroptosis and tumor suppression.
    Keywords:  GPX1; GPX4; OSBPL8; ROS; cancer; ferroptosis; lipid peroxidation; p53; phosphatidic acid; phosphatidylethanolamine; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.01.009
  21. Science. 2026 Feb 19. eadx9954
    Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics.
    Grayson E Rodriguez, Yang Zhao, Yoko Nishiga, Frank Peprah, Jiao Shen, Gita C Abhiraman, Masato Ogishi, Chenyu Zhang, Justin Saco, Deepa Waghray, Mamatha Serasanambati, Leonel Torres, Brandon W Simone, Leon Su, Steven C Wilson, Aerin Yang, Qinli Sun, Lora Picton, Robert A Saxton, Vidit Bhandarkar, Madeline J Lee, Elizabeth Andrews, Hua Jiang, Matthias Obenaus, Michelle Yen, Tavus Atajanova, Catherine A Blish, Stefani Spranger, E John Wherry, Amanda Kirane, Antoni Ribas, David H Raulet, Anusha Kalbasi, Stephanie K Dougan, Michael Dougan, Julien Sage, K Christopher Garcia.
      Cytokines dimerize two receptor chains to activate Janus kinases and STAT transcription factors that regulate immune cells but have therapeutic liabilities. We engineered "Trikines" to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs. Trikines co-activated pSTAT5 and pSTAT3 signatures distinct from natural cytokines, by assembling trimeric combinations of Interleukin-2 (IL-2), Interleukin-10 (IL-10), and Interleukin-21 (IL-21) receptors. In pre-clinical models, an IL-2-based-Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without observable toxicity. An IL-10-based Trikine induced immune infiltration into poorly immunogenic tumors, showing efficacy in pre-clinical models of small cell lung cancer and pancreatic cancer. Trikines obviate the need for cell engineering to customize STAT signatures and may hold potential for immunotherapy.
    DOI:  https://doi.org/10.1126/science.adx9954
  22. Adv Sci (Weinh). 2026 Feb 17. e19792
    Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
    Bin-Hsu Mao, Bo-Kai Su, Ying-Jan Wang, Ting-Yuan Tu.
      Metastatic invasiveness emerges from coordinated intrinsic programs and microenvironmental cues that converge on mitochondrial quality control (MQC). Here, we use "context" to denote stage- and site-aware constellations of tumor-intrinsic states (e.g., mtROS tone, mtDNA integrity, epigenetic wiring, cellular stiffness, oncogenic mutations) and extrinsic landscapes (oxygen-nutrient availability, ECM mechanics, stromal/inflammatory signals). These axes jointly shape mitochondrial adaptation by tuning bioenergetics, redox balance, metabolic plasticity, fission-fusion dynamics, mechanosensitive hubs, and Ca2 + homeostasis. As pressures intensify, mitochondrial vulnerabilities-such as mtDNA compromise and mtUPR activation-signal the engagement of mitophagy to preserve organelle fitness under stress. Through these coupled changes in mitochondrial performance and stress responses, context governs EMT/MET plasticity and transitions across migratory, invasive, and proliferative states. Mechanistically, ubiquitin conjugation, via E3 ligases and deubiquitinases, serves as an integrating conduit that links mitochondrial remodeling and mitophagy to cytoskeletal reprogramming and invasive behavior. This ubiquitin-mitochondria interface therefore represents a coherent therapeutic entry point; translational strategies including PROTAC-enabled targeting and selective E3/DUB or mitophagy-pathway modulators may rebalance pathological ubiquitin signaling, restore mitochondrial homeostasis, and constrain tumor dissemination.
    Keywords:  EMT–MET plasticity; extracellular matrix mechanics; hypoxia and nutrient deprivation; mitochondrial ROS; mitochondrial dynamics; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1002/advs.202519792
  23. FASEB J. 2026 Feb 28. 40(4): e71582
    Reduced Versus Oxidized NAD+ Precursors Drive Distinct Transcriptomic, Proteomic, and Metabolic Profiles in Hepatocytes.
    Kasper T Vinten, Bauke V Schomakers, Simone Denis, Michel van Weeghel, Aldo Jongejan, Rob Ofman, Sander R Piersma, Connie R Jimenez, Georges E Janssens, Rubén Zapata-Pérez, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) is a vital molecule, serving as a redox cofactor and the limiting substrate for numerous enzymes. NAD+ decline is a key feature of aging, while supplementation with NAD+ precursors can efficiently counteract aging traits and prevent age-associated conditions in preclinical models. However, clinical translation remains challenging, likely due to the limited NAD+ boosting capacity of classical precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). This has brought attention to their reduced forms, reduced NMN (NMNH) and reduced NR (NRH), which are more potent NAD+ boosters but remain poorly characterized. Here, we performed a comprehensive comparative analysis using RNA sequencing, proteomics, and metabolomics on cultured murine hepatocytes treated with NMN, NMNH, NR, or NRH. Global metabolic profiling revealed that NRH and NMNH induced substantially broader metabolic alterations than NR and NMN, with NRH uniquely suppressing metabolites involved in energy metabolism. The pronounced metabolic effects were reflected at a transcriptional level, with reduced precursors triggering a significantly higher number of differentially expressed genes than oxidized ones. Shared differentially expressed genes between NMNH and NRH revealed upregulation of stress-related glutathione-S-transferases (Gsts) which furthermore were reflected in our proteomic profiling. However, the upregulation of Gsts did not cause a depletion of glutathione or oxiglutathione, suggesting a pseudo-stress response to reduced NAD+ precursors. Together, our data demonstrate that reduced NAD+ precursors are unique and distinct from the market-available NAD+ precursors NR and NMN, not only as more potent NAD+ boosters, but also as compounds influencing a broader range of cellular processes.
    Keywords:  NAD+; NAD+ precursors; comparative analysis; hepatocytes
    DOI:  https://doi.org/10.1096/fj.202501925R
  24. Cell Rep. 2026 Feb 18. pii: S2211-1247(26)00079-3. [Epub ahead of print]45(3): 117001
    Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair.
    Yiting Xu, Maria Fernanda Forni, Abigail Benvie, Nicole Castano, Diane King, Qiushi Sun, Stephan Siebel, Van Anh Tran, Richard G Kibbey, Kathryn Miller-Jensen, Valerie Horsley.
      Tissue repair requires inflammation resolution, but the molecular mechanisms involved in vivo are not fully understood. Here, we show that glutamine metabolism suppresses neutrophil recruitment to abrogate inflammation and drive skin wound repair. Integrated metabolomic and transcriptional profiling identified glutamine metabolism as enriched in macrophages during resolution. Dietary depletion studies and conditional deletion of glutaminase, the enzyme essential for glutamine metabolism, in mouse myeloid cells revealed that macrophages suppress neutrophil recruitment genes during tissue resolution to promote repair. We also found that these genes are upregulated in macrophages in patients with diabetes. Mechanistically, our data reveal that glutamine metabolism in macrophages induces suppressive chromatin remodeling of neutrophil recruitment genes, including Ccl ligands, during resolution of inflammation. These findings highlight the ability of specific metabolites to control cellular communication during tissue repair, with glutamine specifically to suppress neutrophil recruitment to advance inflammation resolution.
    Keywords:  CP: immunology; CP: metabolism; glutamine; immunology; inflammation; macrophages; metabolism; neutrophils; resolution; skin; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.celrep.2026.117001
  25. Mol Cell. 2026 Feb 19. pii: S1097-2765(26)00067-5. [Epub ahead of print]86(4): 757-773.e5
    Large-scale mapping of environmental-genetic interactions illustrates the dynamic nature of cell-cycle and DNA repair regulation.
    Benjamin W Herken, Garrett T Wong, Anna Mäkiniemi, Emma Lundberg, Thomas M Norman, Luke A Gilbert.
      Cells integrate exogenous and endogenous signals to grow, repair, or die. This is likely achieved through dynamic functional associations between genes, but measuring these relationships at scale is non-trivial. Here, we evaluate genetic associations in response to cell-cycle interruption, genotoxic perturbation, and nutrient deprivation using conditional genetic interaction (GI) mapping in human cells. In five maps measuring ∼250,000 GIs or higher-order environmental interactions, we discover widespread rewiring of relationships between genes, complexes, and ontologies across conditions. Specific bioprocesses drive the rewiring signal in each environmental state, as highlighted in our findings that the TIP60 and PP2A complexes radically alter their interaction profiles after inhibition of ATR. This resource reveals numerous genetic relationships for the fields of DNA damage signaling, DNA repair, and cell-cycle control and explores their context specificity. Our work advances a framework for using GI maps to explore environmental rewiring.
    Keywords:  ATR; CRISPRi; DNA repair; cell cycle; genetic interaction; metabolism; rewiring
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.025
  26. Cell Rep. 2026 Feb 12. pii: S2211-1247(26)00046-X. [Epub ahead of print]45(2): 116968
    Generation of a comprehensive epigenomic atlas in clear cell renal cell carcinoma informs kidney cancer progression and heritability.
    Sarah Abou Alaiwi, Elio Adib, Ziwei Zhang, Sandor Spisak, Aurel Prosz, Paulo Cordeiro, Talal El Zarif, Zsófia Márta Sztupinszki, Amin H Nassar, Ji-Heui Seo, Rianna Campbell, John A Steinharter, Mitchell Machiela, Diptavo Dutta, Stephen Chanock, Mark Purdue, Mark Pomerantz, Sabina Signoretti, Zoltan Szallasi, Alexander Gusev, Sylvan C Baca, Toni K Choueiri, Matthew L Freedman.
      By generating 194 epigenomic and transcriptomic datasets from 57 human tissue samples using H3K27ac and HIF2α chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and RNA sequencing, we provide a comprehensive, integrated characterization of clear cell renal cell carcinoma (ccRCC) across normal, tumor, and metastatic states. Our analyses provide several insights into ccRCC biology. First, we demonstrate significant reprogramming of enhancer and HIF2α cistromes as well as chromatin accessibility during the normal-to-tumor transition, whereas localized and metastatic tumors show minimal epigenomic differences. Second, we show reactivation of kidney-specific developmental pathways driving malignancy. Third, we perform a cistrome-wide association study in ccRCC, validating five established RCC risk loci and identifying six novel loci, including a locus at 12q24 linked to SCARB1 that was functionally validated. These datasets provide new perspectives on the role of developmental pathways in ccRCC tumorigenesis, insights into epigenetic mechanisms of ccRCC heritability, and a comprehensive epigenomic atlas for the research community.
    Keywords:  ATAC-seq; CP: cancer; CP: genomics; ChIP-seq; genome-wide association studies; germline risk; kidney cancer; massively parallel sequencing; regulatory elements; renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.celrep.2026.116968
  27. Cell. 2026 Feb 16. pii: S0092-8674(25)01502-8. [Epub ahead of print]
    Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux.
    Mohamad Assi, Ruohong Wang, Emily A Kawaler, Albert S W Sohn, M Zahidunnabi Dewan, Despoina Kalfakakou, Joel Encarnacion-Rosado, Kevin S Kapner, Koelina Ganguly, Joao A Paulo, Diane M Simeone, Andrew J Aguirre, Robert S Banh, Alec C Kimmelman.
      Autophagy, a programmed self-eating process, underlies the progression of multifactorial diseases like pancreatic ductal adenocarcinoma (PDA). Except for nutrient availability, the contribution of microenvironmental factors to autophagy regulation is not well understood. Through integrating functional genomics and tumor-like 3D cultures, we show that human PDA cells regulate their autophagy levels by sensing the extracellular matrix (ECM) via the integrinα3-Hippo-YAP1 axis. The spatial proximity of PDA cells to the ECM shapes their intracellular autophagy levels, leading to heterogeneous biological responses. Specifically, PDA cells with low autophagy levels are proliferative, whereas those with high autophagy levels display better tolerance to chemotherapies. Targeting the ECM-mediated autophagy regulation reduces autophagic heterogeneity, alters PDA growth, and shapes antitumor responses to FDA-approved therapies. In summary, we have characterized a non-metabolic regulation of autophagy through ECM sensing, opening the possibility to investigate and target ECM-specific outputs in diseases.
    Keywords:  autophagy; cancer; extracellular matrix sensing; fibrosis; lysosome
    DOI:  https://doi.org/10.1016/j.cell.2025.12.053
  28. Cell Rep Med. 2026 Feb 18. pii: S2666-3791(26)00047-9. [Epub ahead of print] 102630
    HIF-activated priming of TRAIL-induced cell death determines epigenetic vulnerability in kidney cancer.
    Yong Wang, Yan Xiong, Shuiqiao Liu, Lei Bao, Xing Qiu, Ilia Korboukh, Xiangyang Song, Vanina Toffessi Tcheuyap, Sipeng Wu, Mingyi Chen, James Brugarolas, Jian Jin, Yingfei Wang, Weibo Luo.
      Activation of hypoxia-inducible factors (HIFs) supports cancer cell survival, yet how HIFs govern cell death remains unclear, despite evidence that HIF-1 acts as a tumor suppressor in cell renal cell carcinoma (ccRCC). Here, we report a cell death-priming role for HIF-1/2 in ccRCC. Through cell viability screens with chemical libraries, we identify SGI1027 and its analog MS1129 as HIF-1/2-dependent cell death inducers that specifically kill VHL-deficient ccRCC cells in vitro and patient-derived xenografts in mice. Mechanistically, SGI1027 and MS1129 induce proteasomal degradation of DNMT1/DNMT3A/DNMT3B proteins, leading to the loss of promoter methylation and subsequent upregulation of TRAIL, DR4, and DR5 in ccRCC cells. HIF-1/2 induces procaspase-10 expression serving a commitment point to activate TRAIL-induced apoptosis in VHL-deficient ccRCC following SGI1027 or MS1129 treatment. Notably, recombinant TRAIL protein synergizes with SGI1027 or MS1129 to kill VHL-deficient ccRCC in mice. Collectively, our study unveils an apoptosis induction strategy that involves hijacking HIFs for ccRCC treatment.
    Keywords:  DNMT; HIF; TRAIL; VHL; cell death priming; death receptors; epigenetic vulnerability
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102630
  29. Annu Rev Anal Chem (Palo Alto Calif). 2026 Feb 17.
    A Stable Isotope Tracing Primer for the Mass Spectrometrist.
    Ashley Solmonson, Brandon Faubert, Thomas P Mathews.
      Metabolic function plays a key role in our understanding of both biological and pathophysiological processes. Metabolism is a complex combination of intrinsic processes and environmental cues across a heterogeneous mix of cell types. To investigate metabolism, stable isotope tracing is a versatile approach to assess metabolism across scales, including in cultured cells, animal models, and humans. From the first tracing studies over a century ago, the development and utility of these studies have gone hand-in-hand with technological advances in detecting these labeled atoms, particularly with mass spectrometry. In this review, we describe the instrumentation used to measure isotopically labeled metabolites and approaches to analyze and interpret stable isotope tracing data, and discuss current challenges and opportunities for discovery with these methods.
    DOI:  https://doi.org/10.1146/annurev-anchem-080524-014717
  30. Autophagy. 2026 Feb 19. 1-2
    A switchable role of neuronal BNIP3L/NIX in mitochondrial fate: fission or finish.
    Xinlei Mo, Xingxian Zhang, Xiangnan Zhang.
      BNIP3L/NIX is a mitophagy receptor highly expressed in the brain. Unlike most mitophagy receptors that are recruited to mitochondria only upon stress, BNIP3L constitutively localizes to the mitochondrial outer membrane, suggesting functions beyond stress-induced mitophagy. Here, we identify a non-mitophagic role of BNIP3L in neuronal physiology. Conditional deletion of Bnip3l in glutamatergic neurons of the basolateral amygdala selectively impairs contextual fear memory in mice, a phenotype rescued by both wild-type BNIP3L and a mitophagy-deficient BNIP3L mutant lacking the LC3-interacting region motif. Mechanistically, BNIP3L competitively binds AMP-activated protein kinase (AMPK), thereby relieving AMPK-dependent inhibitory phosphorylation of DNM1L/DRP1 (dynamin 1 like) at Ser637. This interaction promotes rapid mitochondrial fission, supporting synaptic energy availability during memory encoding. Together, these findings reveal a switchable function of BNIP3L in neurons, acting either to acutely regulate mitochondrial dynamics to meet energetic demand or to engage mitophagy when mitochondrial function becomes compromised.
    Keywords:  BNIP3L/NIX; Basolateral amygdala; fear memory; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2634183
  31. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2532796123
    The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior.
    Niaz Mahmood, Cong Loc Dang, Pei You Wu, Ziying Huang, Jung-Hyun Choi, Konstantina Psycharis, Reuben Portugese, Arkady Khoutorsky, Mauro Costa-Mattioli, R Anne McKinney, Nahum Sonenberg.
      The integrated stress response (ISR) plays a crucial role in cognition via bidirectional modulation of the two major forms of synaptic plasticity, long-term potentiation, and long-term depression (LTD). Specifically, inhibition of the ISR blocks metabotropic glutamate receptor-dependent LTD (mGluR-LTD), whereas its activation facilitates this form of synaptic depression. However, the contribution of activating transcription factor 4 (ATF4), the best studied downstream effector of the ISR, to mGluR-LTD remains unknown. Here, we show that pharmacological activation of group I mGluRs in mouse hippocampal slices increases ATF4 protein levels without altering its transcription and concurrently downregulates the expression of oxidative phosphorylation (OXPHOS) proteins. Selective deletion of ATF4 in excitatory neurons impairs mGluR-LTD and prevents the downregulation of OXPHOS proteins. Notably, administration of a small molecule inhibitor of OXPHOS rescues the impaired mGluR-LTD in ATF4-depleted hippocampal slices, indicating that ATF4 regulates this type of synaptic plasticity by modulating mitochondrial function. Moreover, ATF4 deletion in excitatory neurons disrupts object-place learning, an mGluR-LTD-dependent behavior paradigm. Together, these findings reveal a role of ATF4 as a key mediator of protein synthesis-regulated synaptic depression and related behaviors.
    Keywords:  integrated stress response; mGluR-LTD; synaptic plasticity
    DOI:  https://doi.org/10.1073/pnas.2532796123
  32. Nat Commun. 2026 Feb 17.
    TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.
    Liming Meng, Jing Lv, Ying Yi, Xianchun Lan, Chenchao Yan, Lihang Zhu, Jie Yang, Wei Jiang.
      Cell fate determination is closely linked to metabolic state, yet how metabolic remodeling influences human pluripotent stem cells differentiation into three germ layers remains incompletely understood. Here, we reveal that definitive endoderm differentiation from human pluripotent stem cells requires a TGFβ-driven metabolic switch characterized by reduced lactate production and enhanced TCA cycle activity and oxidative phosphorylation, mediated by PDHB. Disruption of glucose utilization or pyruvate entry into the TCA cycle markedly impairs endoderm differentiation, whereas inhibition of lactate production enhances differentiation efficiency. Mechanistically, blockade of glucose metabolism or the TCA cycle reduces intracellular ATP levels, compromising the activity of BAF complex, an ATP-dependent chromatin remodeling complex centered on BRG1. This complex promotes chromatin accessibility and activates endodermal gene programs during differentiation. Together, these findings highlight metabolic reprogramming as a key regulator of human endoderm fate through ATP-dependent control of chromatin remodeling.
    DOI:  https://doi.org/10.1038/s41467-026-69510-0
  33. Nat Cancer. 2026 Feb 18.
    Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition in metastatic TNBC.
    Noah F Greenwald, Iris Nederlof, Cameron Sowers, Daisy Yi Ding, Seongyeol Park, Alex Kong, Kathleen E Houlahan, Sricharan Reddy Varra, Manon de Graaf, Veerle Geurts, Candace C Liu, Jolene S Ranek, Leonie Voorwerk, Michiel de Maaker, Adam Kagel, Erin McCaffrey, Aziz Khan, Christine Yiwen Yeh, Christine Camacho Fullaway, Zumana Khair, Brennan G Simon, Yunhao Bai, Hadeesha Piyadasa, Tyler Risom, Alea Delmastro, Felix J Hartmann, Lise Mangiante, Cristina Sotomayor-Vivas, Sean C Bendall, Ton N Schumacher, Zhicheng Ma, Marc Bosse, Marc J van de Vijver, Robert Tibshirani, Hugo M Horlings, Christina Curtis, Marleen Kok, Michael Angelo.
      Immune checkpoint inhibition (ICI) benefits only a subset of patients with metastatic triple-negative breast cancer and determinants of response remain unclear. We assembled a longitudinal cohort of 103 female patients from the phase 2 TONIC trial, with samples spanning primary tumors, pretreatment metastases and on-treatment metastases during nivolumab therapy. We profiled 37 proteins in 270 tumors using highly multiplexed imaging and developed SpaceCat, an open-source pipeline that extracts more than 800 imaging features per sample, including cell density, diversity, spatial interactions and functional marker expression. Metastatic but not primary tumors contained features predictive of outcome. Spatial metrics such as immune diversity and T cell infiltration at tumor borders were most informative, while ratios of T cells to cancer cells and PDL1 on myeloid cells were also associated with response. Multivariate models stratified patients with the highest performance on treatment (area under the curve = 0.90). Bulk RNA-seq confirmed the predictive value of on-treatment samples. These findings highlight the value of longitudinal profiling to resolve evolving tumor microenvironment dynamics driving ICI response.
    DOI:  https://doi.org/10.1038/s43018-026-01114-5
  34. Cell Rep Methods. 2026 Feb 17. pii: S2667-2375(26)00031-7. [Epub ahead of print] 101331
    Human neuromuscular organoids mimic cancer-induced muscle cachexia.
    Pietro Chiolerio, Beatrice Auletta, Camilla Pezzini, Luigi Sartore, Giorgia Gregolon, Onelia Gagliano, Cecilia Laterza, Valeria Roxana Balmaceda Valdez, Davide Cacchiarelli, Camilla Luni, Carlo Viscomi, Melanie Planque, Sarah-Maria Fendt, Marco Sandri, Roberta Sartori, Anna Urciuolo.
      Cancer cachexia, a devastating metabolic wasting syndrome affecting up to 80% of solid cancer patients, remains incurable despite advances in tumor biology understanding. This study introduces neuromuscular organoids (NMOs) derived from human-induced pluripotent stem cells (hiPSCs) as a platform to investigate cancer-driven muscle cachexia. We found that NMOs respond well to atrophic stimuli and replicate the key features of cancer cachexia when treated with conditioned media derived from cachexia-inducing cancer cells. Specifically, cachectic NMOs showed muscle mass loss, impairment of muscle contraction, alteration of intracellular calcium homeostasis, appearance of mitochondrial dysfunction with a metabolic shift, and enhancement of autophagy. Based on these results, we propose NMOs derived from hiPSCs as an in vitro tool for investigating human muscle cachexia, with potential future avenues of patient-specific modeling and therapeutic screening.
    Keywords:  CP: cancer biology; CP: stem cell; autophagy; cancer cachexia; human induced pluripotent stem cells; in vitro human disease model; metabolic remodeling; mitochondrial dysfunction; neuromuscular junction; neuromuscular organoid; skeletal muscle wasting
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101331
  35. Adv Sci (Weinh). 2026 Feb 17. e23198
    GPX4 Inhibitor Resistance and Metastatic Features in Triple-Negative Breast Cancer.
    Marie Sabatier, Mayher Kaur, Milena Chaufan, Felix-Levin Hormann, Luiza Martins Nascentes Melo, Mario Palma, Jordan Torpey, Yanshan Liang, Alanis Carmona, Cameron Fraser, Midori Flores, Krystina J Szylo, Mahsa Yavari, Sheng Hui, Alpaslan Tasdogan, Sven Heiles, Jessalyn M Ubellacker.
      Leveraging ferroptosis as a cancer therapy has faced challenges due to the limited bioavailability and systemic toxicities of small-molecule ferroptosis modulators. Small molecule inhibitors such as RSL3 and ML210 trigger ferroptosis by targeting glutathione peroxidase 4 (GPX4), a key enzyme that neutralizes lipid peroxides. While many studies have focused on targeting primary tumors, much less is known about the extent to which GPX4-inhibitor resistance may contribute to metastasis. To address this, we cultured triple-negative breast cancer cell lines with GPX4 inhibitors to generate cell lines (M231, 4T1) that were resistant to GPX4 inhibitors (GPX4i). Tumors derived from GPX4i-resistant cells compared to parental cells had unique metabolic and lipidomic profiles, were associated with a shift toward an epithelial-like state (decreased vimentin, increased EpCAM expression), formed decreased spontaneous metastases from primary tumors, but had no differences in overall metastatic burden upon intravenous injection. Collectively, these data demonstrate that long-term maintenance with GPX4-inhibitors in vitro leads to altered metastatic profiles in vivo.
    Keywords:  ferroptosis; lipid peroxidation; metastases; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202523198
  36. J Clin Invest. 2026 Feb 19. pii: e196819. [Epub ahead of print]
    Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice.
    Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang Lin, Jiwon Hwang, Xinxin Chen, Alan C Rupp, Abigail J Tomlinson, Andrew J Scott, Zhen Zhao, Daniel R Wahl, Martin Myers, Costas A Lyssiotis, Ling Qi.
      Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice (Sel1LSynCre) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age-mirroring core clinical features observed in affected patients-despite preserved neuronal numbers and only modest ER stress. Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulted from induction of the integrated stress response (ISR). Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing new insight into the molecular basis of ERAD-related neurodevelopmental disease.
    Keywords:  Cell biology; Cell stress; Metabolomics; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/JCI196819
  37. Nat Genet. 2026 Feb 16.
    Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation.
    Tessa M Popay, Ami Pant, Femke Munting, Melodi Tastemel, Morgan E Black, Nicholas Haghani, Jesse R Dixon.
      The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here we utilized acute depletion of NIPBL to characterize cohesin-mediated loop extrusion in vivo. We find that many chromatin loops are rapidly diminished upon loss of NIBPL, but some cohesin-dependent chromatin loops persist for multiple hours. These persistent loops required NIPBL for their establishment during mitotic exit, were associated with distinct chromatin states and were preferentially dependent on STAG1 for their persistence. Furthermore, by depleting NIPBL from multiple cell types, we find that NIPBL specifically regulates cell identity genes by supporting a unique local genome conformation defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.
    DOI:  https://doi.org/10.1038/s41588-026-02516-y
  38. Cell Metab. 2026 Feb 17. pii: S1550-4131(26)00012-4. [Epub ahead of print]
    Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
    Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Maria Milà-Guasch, Jorge Alvarez Luis, Pilar Villacampa, Elena Eyre, Jordi Altirriba, Sabrina Genßler, Markus Haake, Christine Schuberth-Wagner, Xavier Remesar, Antonio Zorzano, Pablo M Garcia-Rovés, Francesc Ventura, Josep Vidal, Claude Knauf, Rubén Nogueiras, Tamas L Horvath, Katrien De Bock, Mariona Graupera, Marc Claret.
      Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of Mfn2 in ECs (Mfn2iΔEC), but not of Mfn1iΔEC, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions in vivo. Notably, Mfn2iΔEC mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2iΔEC mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.
    Keywords:  GDF15; aging; diabetes; endothelial cells; mitochondria; mitofusin; mitohormesis; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.012
  39. Cell Discov. 2026 Feb 17. 12(1): 12
    Palmitic acid activates c-Myc via dual palmitoylation-dependent pathways to promote colon cancer.
    Wenxin Du, Jianing Zhang, Yuexin Wang, Minjun Li, Ji Cao, Bo Yang, Qiaojun He, Xuejing Shao, Meidan Ying.
      c-Myc is broadly hyperactivated in colon cancer, yet the mechanisms sustaining its transcriptional activation remain elusive. Here we identify palmitic acid (PA) as a metabolite cue that activates c-Myc via dual palmitoylation-dependent pathways operating across tumor initiation and progression. In colitis models, PA-rich diets exacerbate inflammation and enrich MYC target programs without increasing Myc mRNA. Mechanistically, the palmitoyltransferase ZDHHC9, upregulated by IL-1β, directly palmitoylates c-Myc at C171, enhancing c-Myc/MAX dimerization and transcriptional activity; genetic or pharmacologic inhibition diminishes c-Myc palmitoylation and target gene expression. During tumor progression, c-Myc transactivates FATP2, increasing PA uptake and reinforcing c-Myc palmitoylation, thereby establishing a feedforward loop and metabolic addiction to PA. Functionally, PA accelerates xenograft growth, whereas targeting ZDHHC9 and FATP2 inhibits c-Myc function to suppress tumor burden. These findings uncover metabolite-driven control of c-Myc through palmitoylation and highlight ZDHHC9/FATP2 as actionable vulnerabilities for colon cancer treatment.
    DOI:  https://doi.org/10.1038/s41421-026-00869-6
  40. EMBO Mol Med. 2026 Feb 18.
    KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    Ruilin Wu, Negar Khosraviani, Ann Mansur, Emilie Boudreau, Gabrielle E Largoza, Suejean Park, Dakota Gustafson, Sneha Raju, Crizza Ching, Amira Klip, Thomas Wälchli, Kathryn L Howe, Ivan Radovanovic, Joshua D Wythe, Jason E Fish.
      Somatic activating KRAS mutations in endothelial cells are the predominant cause of sporadic brain arteriovenous malformations (bAVMs) and also occur in sporadic extracranial AVMs. We found that KRASG12V expression in the endothelium increased angiogenesis, which was accompanied by enhanced glucose uptake and glycolytic flux. Mechanistically, this increase in glycolysis was facilitated by enhanced membrane localization of glucose transporters (e.g., GLUT1) and induction of hexokinase-2 (HK2) expression. Importantly, RNA-sequencing and proteomics revealed that HK2 appeared to be the only glycolytic component elevated. Analysis of single-cell RNA-sequencing data and immunofluorescence staining confirmed that HK2 was elevated in mouse and human bAVMs. Critically, either pharmacologic inhibition of glycolytic flux or knockdown of HK2 suppressed sprouting angiogenesis in cultured KRASG12V endothelial cells. Glycolysis inhibition also reversed arteriovenous shunts and potentiated the effect of MEK inhibition in a KRAS-mutant zebrafish model. Finally, combined glycolysis and MEK inhibition suppressed angiogenesis in patient-derived bAVM primary endothelial cells. Together, our findings show that KRAS-driven reprogramming of endothelial metabolism represents a potential therapeutic vulnerability for sporadic AVMs.
    Keywords:  Arteriovenous Malformations; Endothelial Glycolysis; KRAS Signaling; Metabolic Regulation; Targeted Therapeutics
    DOI:  https://doi.org/10.1038/s44321-026-00383-y
  41. Nat Metab. 2026 Feb 20.
    Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
    Caroline A M Weiss, Lauryn A Brown, Lucas Miranda, Paolo Pellizzoni, Sophia Steigerwald, Kirsten Remmert, Jonathan M Hernandez, Karsten Borgwardt, David E Kleiner, Shani Ben-Moshe, Florian A Rosenberger, Natalie Porat-Shliom, Matthias Mann.
      Understanding protein distribution patterns across tissue architecture is crucial for deciphering organ function in health and disease. Here we show the application of single-cell Deep Visual Proteomics to perform spatially resolved proteome analysis of individual cells in native liver tissue. We built a robust framework comprising strategic cell selection and continuous protein gradient mapping, allowing the investigation of larger clinical cohorts. We generated a comprehensive spatial map of the human hepatic proteome by analysing hundreds of isolated hepatocytes from 18 individuals. Among the 2,500 proteins identified per cell, about half exhibited zonated expression patterns. Cross-species comparison with male mice revealed conserved metabolic functions and human-specific features of liver zonation. Analysis of samples with disrupted liver architecture demonstrated widespread loss of protein zonation, with pericentral proteins being particularly susceptible. Our study provides a comprehensive and open-access resource of human liver organization while establishing a broadly applicable framework for spatial proteomics analyses along tissue gradients.
    DOI:  https://doi.org/10.1038/s42255-026-01459-2
  42. bioRxiv. 2025 Dec 03. pii: 2025.12.01.691597. [Epub ahead of print]
    Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.
    Matias Fabregat, Rachel J Fenske, Julia K Hansen, Cameron J Kaminsky, Jevin Lortie, Alexander Nassar, Kayla Kressin, Annie Jen, Lucia Cilloni, Katherine Overmeyer, Caroline M Alexander, John W Garrett, Perry J Pickhardt, Joshua J Coon, Costas A Lyssiotis, Marina Pasca di Magliano, Lingjun Li, Adam J Kuchnia, Andrea Galmozzi.
      Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.
    DOI:  https://doi.org/10.64898/2025.12.01.691597
  43. Nature. 2026 Feb 18.
    Oxygen metabolism in descendants of the archaeal-eukaryotic ancestor.
    Kathryn E Appler, James P Lingford, Xianzhe Gong, Kassiani Panagiotou, Pedro Leão, Marguerite V Langwig, Chris Greening, Thijs J G Ettema, Valerie De Anda, Brett J Baker.
      Asgard archaea were pivotal in the origin of complex cellular life1. Heimdallarchaeia (a class within the phylum Asgardarchaeota) are inferred to be the closest relatives of eukaryotes. Limited sampling of these archaea constrains our understanding of their ecology and evolution2,3, including their role in eukaryogenesis. Here we use massive DNA sequencing of marine sediments to obtain 404 Asgardarchaeota metagenome-assembled genomes, including 136 new Heimdallarchaeia and several novel lineages. Analyses of their global distribution revealed they are widespread in marine environments, and many are enriched in variably oxygenated coastal sediments. Detailed metabolic reconstructions and structural predictions suggest that Heimdallarchaeia form metabolic guilds that are distinct from other Asgardarchaeota. These archaea encode hallmark proteins of an aerobic lifestyle, including electron transport chain complex (IV), haem biosynthesis and reactive oxygen species detoxification. Heimdallarchaeia also encode novel clades of respiratory membrane-bound hydrogenases with additional Complex I-like subunits, which potentially increase proton-motive force generation and ATP synthesis. Thus, we propose an updated Heimdallarchaeia-centric model of eukaryogenesis in which hydrogen production and aerobic respiration may have been present in the Asgard-eukaryotic ancestor. This expanded catalogue of Asgard archaeal genomic diversity suggests that bioenergetic factors influenced eukaryogenesis and constitutes a valuable resource for investigations into the origins and evolution of cellular complexity.
    DOI:  https://doi.org/10.1038/s41586-026-10128-z
  44. Cell Metab. 2026 Feb 19. pii: S1550-4131(26)00018-5. [Epub ahead of print]
    Red blood cells serve as a primary glucose sink to improve glucose tolerance at altitude.
    Yolanda Martí-Mateos, Zohreh Safari, Shaun Bevers, Ayush D Midha, Will R Flanigan, Tej Joshi, Helen Huynh, Brandon R Desousa, Skyler Y Blume, Alan H Baik, Stephen Rogers, Aaron V Issaian, Allan Doctor, Angelo D'Alessandro, Isha H Jain.
      High-altitude conditions improve glucose tolerance and reduce diabetes risk, but the physiological mechanism is not well understood. Using mouse models, we found that hypoxia alone robustly improved glucose tolerance and that the effect persisted for weeks after returning to normal oxygen levels. PET/CT imaging suggested a significant, unknown glucose sink beyond major internal organs. We hypothesized that hypoxia-induced red blood cells (RBCs) serve as this sink. Manipulating RBC numbers through phlebotomy or transfusion directly altered blood glucose, establishing RBCs as necessary and sufficient for this effect. In chronic hypoxia, RBCs showed a sustained ∼3-fold increase in glucose uptake and ∼2-fold increase in GLUT1 protein abundance, specifically in newly synthesized RBCs, which ultimately contributes to increased glycolytic flux toward 2,3-diphosphoglycerate (2,3-DPG). Mechanistically, acute hypoxia displaces GAPDH from inhibitory band 3 binding through competitive interactions with deoxyhemoglobin, thereby boosting glycolytic flux and driving 2,3-DPG production. We also found that hypoxia or our small-molecule hypoxia mimetic, HypoxyStat, rescued hyperglycemia in mouse models of type 1 and type 2 diabetes. Our findings identify RBCs as key regulators of systemic glucose metabolism, highlighting a novel therapeutic approach for hyperglycemic disorders.
    Keywords:  altitude; diabetes; glucose; hypoxia; oxygen; red blood cells
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.019
  45. Nature. 2026 Feb 18.
    Nucleotide signals coordinate activation and inhibition of bacterial immunity.
    Sonomi Yamaguchi, Samantha G Fernandez, Douglas R Wassarman, Marlen Lüders, Frank Schwede, Philip J Kranzusch.
      The cellular nucleotide pool is a major focal point of the host immune response to viral infection. Immune effector proteins that disrupt the nucleotide pool enable animal and bacterial cells to broadly restrict diverse viruses, but reduced nucleotide availability induces cellular toxicity and can limit host fitness1-5. Here we identify Clover, a bacterial anti-phage defence system that overcomes this trade-off by encoding a deoxynucleoside triphosphohydrolase enzyme (CloA) that dynamically responds to both an activating phage cue and an inhibitory nucleotide immune signal produced by a partnering regulatory enzyme (CloB). Analysis of phage restriction by Clover in cells and reconstitution of enzymatic function in vitro demonstrate that CloA is a dGTPase that responds to viral enzymes that increase cellular levels of dTTP. To restrain CloA activation in the absence of infection, we show that CloB synthesizes a dTTP-related inhibitory nucleotide signal, p3diT (5'-triphosphothymidyl-3'5'-thymidine), that binds to CloA and suppresses activation. Cryo-electron microscopy structures of CloA in activated and suppressed states reveal how dTTP and p3diT control distinct allosteric sites and regulate effector function. Our results define how nucleotide signals coordinate both activation and inhibition of antiviral immunity and explain how cells balance defence and immune-mediated toxicity.
    DOI:  https://doi.org/10.1038/s41586-026-10135-0
  46. Nat Commun. 2026 Feb 20.
    Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine Pseudomonas aeruginosa pneumonia.
    Rong Chen, Ran Zeng, Mengmeng Shi, Guoliang Zhang, Feiyang Wang, Qingyuan Yang, Yanshan Jiang, Yuxuan Zhang, Yanan Li, Jieming Qu.
      Metabolic reprogramming in immune cells can determine the outcome of pathogen infection. For Pseudomonas aeruginosa, a clinically challenging pathogen, it remains unclear whether the host can exploit this strategy to combat bacterial invasion. Here, we identify phosphoglycerate dehydrogenase as a key mediator of macrophage inflammation during Pseudomonas aeruginosa infection. Pharmacological and genetic inhibition of phosphoglycerate dehydrogenase suppress macrophage hyperactivation and the production of pro-inflammatory cytokines. In a murine model of Pseudomonas aeruginosa pneumonia, myeloid-specific deletion of phosphoglycerate dehydrogenase improves survival, alleviates lung injury, and reduces bacterial load. Similarly, dietary restriction of L-serine improves prognosis in infected mice. Mechanistically, phosphoglycerate dehydrogenase fuels L-serine synthesis to augment one-carbon metabolism, which strengthens the direct interaction between histone H3 lysine 27 trimethylation and dual-specificity phosphatase 4. This cascade ultimately promotes extracellular signal-regulated kinase 1/2 phosphorylation. Our study uncovers a metabolism-epigenetics crosstalk that amplifies macrophage inflammation, proposing metabolic modulation as a therapeutic strategy for bacterial pneumonia.
    DOI:  https://doi.org/10.1038/s41467-026-69539-1
  47. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2526325123
    Nonoxidative pentose phosphate pathway regulates CD8+ T cell immunity by maintaining NADPH homeostasis.
    Jingyu Feng, Qian Zhang, Li Luo, Zhichao Gu, Wen Liu, Jingsong Xu, Mengxin Qi, Zhongji Meng, Lin Li, Liangliang Lin, Zhuoshun Yang, Huafeng Zhang.
      NADPH is essential for cellular biosynthesis and redox balance in CD8+ T cells. Here, we demonstrate that the nonoxidative pentose phosphate pathway (non-oxPPP), mediated by transketolase (TKT) and transaldolase (TALDO1), is critical for CD8+ T cell activation, proliferation, and memory formation by maintaining NADPH homeostasis. Metabolomic profiling and isotopic tracing revealed upregulated non-oxPPP flux in effector (Teff) and memory (Tm) CD8+ T cells, enabling a pentose cycle that amplifies NADPH yield and sustains metabolic fitness for T cell immunity. Genetic knockdown or pharmacological inhibition of Tkt or Taldo1 impaired NADPH production, leading to ribose-5-phosphate (R5P) accumulation, oxidative stress, reduced lipid synthesis, mitochondrial dysfunction, and compromised Teff cell proliferation, cytokine production, and antitumor efficacy. Conversely, enhancing non-oxPPP activity promoted Tm differentiation, persistence, and recall responses. Targeting the non-oxPPP represents a promising strategy to enhance cancer immunotherapy and vaccine efficacy by bolstering T cell effector and memory responses.
    Keywords:  CD8+ T cell; NADPH; memory T cell; nonoxidative pentose phosphate pathway
    DOI:  https://doi.org/10.1073/pnas.2526325123
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