bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–05–03
fifty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
  2. SREBP governs a triglyceride:glycogen metabolic switch in Drosophila.
  3. Good things come in twos.
  4. TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
  5. The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
  6. FXR's double life in bile ducts.
  7. Evolutionary characterization of lung cancer metastasis.
  8. Brain cells refine nitrogen choice with maturity.
  9. A local sympathetic-immune axis inhibits melanoma growth in mice by dictating adrenergic control.
  10. Elevating levels of neuronal MCU in the hippocampus enhances mitochondrial calcium uptake and respiratory efficiency proportional to demand.
  11. Tissue-trained fibroblasts fuel invasion with lipids.
  12. A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAFV600E-Associated Mitochondrial Division in Cancer.
  13. Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.
  14. An anaerobic pathogen rewires host metabolism to fuel oxidative growth in the inflamed gut.
  15. ATM counteracts chromatin-bound cGAS during DNA replication.
  16. MESH1-mediated coenzyme A degradation drives ferroptosis sensitivity and muscle pathology.
  17. Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice.
  18. Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
  19. An unrecognized host response to microbial exposure resets circadian timing.
  20. Replacement-Based Ageing Interventions for Systemic Rejuvenation: Shaping Longevity Science and Clinical Directions.
  21. NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.
  22. SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-XL in Clear Cell Renal Cell Carcinoma.
  23. Citraconate preserves T cell stemness and antitumor immunity.
  24. Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer's brains.
  25. Label free multimodal optical imaging of metabolic heterogeneity in aging by integrating SRS, MPF, FLIM, and SHG.
  26. Postprandial lipid metabolism durably enhances T cell immunity.
  27. Reprogramming of bacterial virulence by lysine acetylation.
  28. Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis with the PDAC Tumor Microenvironment.
  29. DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.
  30. MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth.
  31. SEPHS2 loss reprograms cancer metabolism from oxidative phosphorylation to gluconeogenesis via PCK1 stabilization.
  32. A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity.
  33. Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.
  34. Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.
  35. Loss of Propionyl-CoA Carboxylase Reprograms Hepatic Metabolism by Suppressing Mitochondrial Pyruvate Carboxylation and Fatty Acid Oxidation.
  36. A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8 + T cell antitumor immunity.
  37. Ras promotes macropinocytic nutrient uptake by suppressing the albumin recycling receptor FcRn.
  38. A robust workflow for 3D imaging of human mitochondria using cryo-electron tomography.
  39. Detecting ferroptotic cells using an antibody against hyperoxidized PRDX3.
  40. CXCL-CXCR2 signaling drives cancer-endothelium interactions in SCLC metastatic seeding.
  41. Multiomic screening platform uncovers the impact of histone mutations on chromatin and cell fate.
  42. Tissue-specific fibroblast lipid cues impose the rate of epithelial cancer invasion.
  43. Reprogramming lipid metabolism in pediatric cancers.
  44. LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.
  45. PARP1 suppression drives ROS resistance in aneuploid cancer cells.
  46. Metabolic inequality in microbial communities.
  47. Reactive oxygen species and metabolic checkpoints shape plasmacytoid dendritic cell fate in infection and autoimmunity.
  48. Protocol for measuring mitochondrial respiration in mature human adipocytes using the Seahorse XF analyzer.
  49. Spatial atlas of diabetic kidney disease reveals a B cell-rich subgroup.
  50. Toward life with a 19-amino acid alphabet through generative artificial intelligence design.
  51. Time after time: a quarter century of progress in plant circadian biology.
  52. Tissue tension fosters macrophage-driven lipid peroxidation-induced DNA damage.
  53. Investigating fasting for metabolic health and longevity.
  54. Metabolic regulation of histone acetylation by ACLY supports MDR1 expression in colorectal cancer and highlights a targetable vulnerability.
  55. Rhythmic protein condensation in the circadian regulation of glycogen metabolism.
  56. KDM6 Enzymes are the Mechanistic Targets of Mutant IDH that Dictate Replication Stress Sensitivity.
  57. Clean cut to curtail respiration: OMA1 cleaves AIFM1 to tune stress-induced bioenergetics.
  58. Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
  59. SLC33A1-mediated glutathione transport regulates ER redox balance and function.
  1. Nat Metab. 2026 Apr 29.
    Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
    Milan R Savani, Bingbing Li, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Tracey Shipman, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.
      Stable isotope-tracing assays track few metabolites, yet cells use many nutrients to sustain nitrogen metabolism. Here we create a platform for tracing 30 nitrogen isotope-labelled metabolites in parallel to enable a system-level understanding of cellular nitrogen metabolism. This platform reveals that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine. This link between cell state and pyrimidine synthesis pathway preference persists in murine and human tissues. Mechanistically, we find that S1900 phosphorylation of CAD, the first enzyme of the de novo pathway, is induced by uridine deprivation in differentiated cells and constitutively enriched in primitive cells. Mimicking CAD S1900 phosphorylation in differentiated cells constitutively activates de novo pyrimidine synthesis, while blocking this modification impairs the cellular response to uridine starvation. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.
    DOI:  https://doi.org/10.1038/s42255-026-01520-0
  2. bioRxiv. 2026 Apr 13. pii: 2024.05.13.593915. [Epub ahead of print]
    SREBP governs a triglyceride:glycogen metabolic switch in Drosophila.
    Rupali Ugrankar-Banerjee, Son Tran, Sonakshi Srivastava, Jade Bowerman, Blessy Paul, Lauren G Zacharias, Thomas P Mathews, Ralph J DeBerardinis, W Mike Henne.
      Tissues store nutrients as triglyceride (TG) or glycogen at specific ratios, but how these reserves are sensed and balanced remains poorly understood. Here we show that blockage of de novo lipogenesis (DNL) in the Drosophila fat body (FB) triggers a cell autonomous metabolic switch characterized by severe fat depletion and profound glycogen accumulation that supports animal development. Despite lipid loss, Drosophila develop normally but exhibit shortened lifespans and impaired female fecundity. Mechanistically, we identify SREBP-dependent metabolic rewiring that facilitates a switch from TG to glycogen storage, triggered by fatty acid deficiency when DNL is inhibited, and which is rescued by dietary fatty acids. Fat depleted FBs require glycolysis but exhibit blunted mitochondrial metabolism, and no dependence on lactate utilization. Finally, we identify histone acetyltransferases (HATs) Nej and Tip60, which support SREBP activity, as essential for this metabolic switch. Collectively, we propose that in response to DNL deficiency, the fat-depleted FB undergoes a SREBP-mediated TG-to-glycogen metabolic switch preserving organismal development at the cost of reproductive success.
    Key findings: Fat body-specific FASN1 loss leads to fat-depleted but viable Drosophila that complete their developmental lifecycle by rewiring energy metabolism to store glycogen instead of fat FASN1-deficient larvae functionally rely on glycogen synthesis and glycolysis, but not lactate metabolism, and display blunted TCA metabolismMetabolic screening reveals a SREBP-dependent TG:glycogen metabolic switch in response to blockage of DNL fatty acid biosynthesisHistone acetyltransferases (HATs) Nej and Tip60, and acetyl-CoA synthase, are required for the TG:glycogen metabolic switch.
    DOI:  https://doi.org/10.1101/2024.05.13.593915
  3. Nat Metab. 2026 Apr;8(4): 759
    Good things come in twos.
      
    DOI:  https://doi.org/10.1038/s42255-026-01522-y
  4. Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]
    TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
    Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.
      Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.
    Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2026.04.004
  5. Nat Cell Biol. 2026 Apr 30.
    The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
    Todd Douglas, Pengju Nie, Jiasheng Zhang, Kyrillos S Abdallah, Zhiping Wu, Meghan McReynolds, Kazuhiro Iwai, Junmin Peng, Wendy V Gilbert, Lawrence H Young, Craig M Crews.
      The ribosome has emerged as a signalling hub that can sense metabolic perturbations and coordinate responses that either restore homeostasis or initiate cell death. The range of insults that signal via the ribosome and the mechanisms governing such cell fate decisions remain uncharacterized. Here we identify the atypical E3 ligase HOIL-1 as an unexpected node in the ribosome signalling network that resolves cellular stress. We find that truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice and broadly sensitize cells to nutrient and translational stress. These diverse signals converge on the MAP3K ZAKα, a sentinel of ribotoxic stress. Mechanistically, HOIL-1 promotes ribosome ubiquitination and facilitates cytoprotective ribosome-associated quality control. HOIL-1 loss of function causes glucose starvation to become ribotoxic, leading to ZAKα-dependent ATF4 activation and disulfidptosis driven by the cystine-glutamate antiporter xCT. These data reveal a molecular circuit controlling cell fate during nutrient stress and establish the ribosome as a signalosome that responds to cellular glucose levels.
    DOI:  https://doi.org/10.1038/s41556-026-01936-6
  6. Nat Metab. 2026 Apr 28.
    FXR's double life in bile ducts.
    Shogo Takahashi, Frank J Gonzalez.
      
    DOI:  https://doi.org/10.1038/s42255-026-01528-6
  7. Nature. 2026 Apr 29.
    Evolutionary characterization of lung cancer metastasis.
    TRACERx Consortium
      Limited understanding of the biological processes that govern metastatic dissemination hinders its prevention and treatment1. Here, using 501 longitudinally collected primary and metastatic tumour samples from 24 patients with non-small cell lung cancer (NSCLC) enrolled in the TRACERx lung study and PEACE autopsy programme, we infer tumour evolution from diagnosis to death. With DNA-sequencing data encompassing 70% of the metastases that were radiologically detected before death and paired multi-region sampled primary tumours, we show that the genomes of metastases diverge markedly from those of their ancestral primary tumour, with additional driver alterations and genome doubling events occurring after metastatic dissemination. In 62.5% of patients, multiple primary tumour subclones disseminated, each founding a distinct metastasis. These metastases served as sources of onward spread: more than half of the metastases sampled were seeded by other metastases. The duration that metastases existed in situ influenced their likelihood of seeding further metastases. Most metastatic migrations started and ended in the same anatomical cavity. The few subclones that exited the thorax to seed metastases disseminated widely and were enriched for somatic copy-number alterations, suggesting that chromosomal instability may facilitate extrathoracic spread. This spatial and temporal evolutionary analysis sheds light on the extent of metastatic diversity and seeding in advanced NSCLC-which tends to be underestimated in single metastasis biopsies-and identifies genomic and clinical mediators of metastatic progression.
    DOI:  https://doi.org/10.1038/s41586-026-10428-4
  8. Nat Metab. 2026 Apr 29.
    Brain cells refine nitrogen choice with maturity.
    Andrew J Scott, Costas A Lyssiotis, Daniel R Wahl.
      
    DOI:  https://doi.org/10.1038/s42255-026-01519-7
  9. Neuron. 2026 Apr 29. pii: S0896-6273(26)00285-0. [Epub ahead of print]
    A local sympathetic-immune axis inhibits melanoma growth in mice by dictating adrenergic control.
    Tingting Liu, Daniel Y Kutsovsky, Ethan M Earlie, Liangliang Ji, Michael Iskols, Shakti Ramsamooj, Xavier I Dawkins, Marwa Zerhouni, Alexander Birbrair, Elena Piskounova, Ming O Li, Ashley M Laughney, David J Simon.
      The nervous system drives tumor growth directly through intra-tumoral axons and indirectly through the systemic action of hormones. Yet contexts where the nervous system inhibits tumor growth are less defined. Here, we performed optical reconstruction of axonal innervation in mouse models of cutaneous melanoma, revealing progressive innervation by sympathetic axons. Local depletion of these axons accelerates while local optogenetic activation slows melanoma growth, together consistent with these axons acting as a physiological growth brake. The sympathetic nervous system is typically associated with driving tumor growth through activation of β-adrenergic receptors (ARs). Here, we find that the initial tumor seeding conditions sensitize melanomas from βAR-driven growth promotion toward α2-AR-driven growth inhibition. Mechanistically, the axonal activation of α2 ARs restricts the number and distribution of pro-tumor myeloid cells, independently of T cell activity. Together, our data reveal context-dependent, bidirectional neural control of tumor progression.
    Keywords:  Adra2a; adrenergic; cancer neuroscience; iDISCO; innervation; melanoma; neuro-immune; nociceptor; pro-tumor macrophage; sympathetic axon
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.016
  10. bioRxiv. 2026 Apr 16. pii: 2026.04.13.718264. [Epub ahead of print]
    Elevating levels of neuronal MCU in the hippocampus enhances mitochondrial calcium uptake and respiratory efficiency proportional to demand.
    Mikel L Cawley, Ryan N Montalvo, Mason L Wheeler, Lucy L Turner, Jessica Pfleger, Zhen Yan, Shannon Farris.
      Mitochondrial calcium signaling integrates energy needs with energy production, amplifying or suppressing mitochondrial respiration in response to activity demand. Neuronal activity is tightly ATPcoupled to increases in mitochondrial calcium uptake, which stimulate the tricarboxylic acid cycle (TCA) and activate calcium-dependent enzymes important for ATP production via oxidative phosphorylation. The mitochondrial calcium uniporter (MCU) is the predominant source of matrix calcium and is differentially expressed across neuronal cell types, suggesting cell-type-specific differences in the coupling of activity-driven calcium levels and mitochondrial respiration. Here, we investigated whether elevating MCU expression enhances mitochondrial calcium uptake and oxidative phosphorylation in the hippocampus. We report that hippocampal mitochondria overexpressing MCU take up calcium at a faster rate without increased sensitivity to calcium overload. By modeling in vivo supply and demand, we found that hippocampal mitochondria overexpressing MCU are more efficient than control mitochondria at responding to increased bioenergetic demand. These findings reveal a role for MCU in modulating mitochondrial calcium uptake and boosting mitochondrial respiration under increasing demand, which contributes to our understanding of how specific cell types may adapt to different bioenergetic demands.
    DOI:  https://doi.org/10.64898/2026.04.13.718264
  11. Nat Metab. 2026 Apr 27.
    Tissue-trained fibroblasts fuel invasion with lipids.
    Gul Muneer, Sara Zanivan.
      
    DOI:  https://doi.org/10.1038/s42255-026-01501-3
  12. Antibodies (Basel). 2026 Apr 20. pii: 38. [Epub ahead of print]15(2):
    A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAFV600E-Associated Mitochondrial Division in Cancer.
    Shanon T Nizard, Yiyang Chen, Madhavika N Serasinghe, Ruben Fernandez-Rodriguez, Kamrin D Shultz, Jesminara Khatun, Anthony Mendoza, Jesse D Gelles, Juan F Henao-Martinez, Ioana Abraham-Enachescu, Md Abdullah Al Noman, Stella G Bayiokos, J Andrew Duty, Shane Meehan, Mihaela Skobe, Jerry Edward Chipuk.
       BACKGROUND/OBJECTIVES: Mitochondria are dynamic organelles that continuously undergo balanced cycles of fusion and division to maintain optimal function. Mitochondrial division is mediated by Dynamin-Related Protein 1 (DRP1), a cytosolic large GTPase whose phosphorylation at serine 616 (DRP1-S616Ⓟ) promotes its translocation to the outer mitochondrial membrane and organelle division. Dysregulated mitochondrial division disrupts cellular homeostasis and contributes to disease pathogenesis, including cancer. Our prior work demonstrated that the oncogene-induced mitogen-activated protein kinase (MAPK) pathway constitutively phosphorylates DRP1 at serine 616, which is essential to cellular transformation and correlates with oncogene status in patient tissues. Similarly, DRP1-S616Ⓟ is subject to pharmacologic control by targeted therapies against oncogenic MAPK signaling.
    METHODS: Building upon this foundation, we developed and characterized a recombinant murine monoclonal antibody (referred to as 3G11) with high specificity for human DRP1-S616Ⓟ, raised against a peptide derived from the human DRP1 sequence.
    RESULTS: Using diverse experimental platforms, we demonstrate the robust utility of 3G11 to detect DRP1-S616Ⓟ in melanoma cell extracts and isolated organelles. Immunofluorescence revealed that pharmacologic inhibition of oncogenic MAPK signaling reduces DRP1-S616Ⓟ levels, which correlates with mitochondrial hyperfusion, while immunohistochemistry showed that elevated DRP1-S616Ⓟ expression in human tissues correlates with BRAFV600E disease.
    CONCLUSIONS: 3G11 is a new recombinant antibody for detecting DRP1-S616Ⓟ and supports studies of mitochondrial division in cancer. Together, these findings establish 3G11 as a specific, versatile, renewable, and cost-effective tool for studying mitochondrial division, with strong potential for clinical applications.
    Keywords:  BRAF; DRP1; cancer; melanoma; mitochondrial dynamics; oncogenes
    DOI:  https://doi.org/10.3390/antib15020038
  13. Immunity. 2026 Apr 29. pii: S1074-7613(26)00144-5. [Epub ahead of print]
    Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.
    Michael Scaglione, Montana Knight, Krittin Trihemasava, Kelly Rome, Anne-Sophie Archambault, Juhee Oh, Erin Tanaka, Elise Hall, Tran Ngoc Van Le, Caleb L Lines, Brian Goldspiel, Hossein Fazelinia, Clemence Queriault, Lucien Turner, Tanay Parnaik, Jimmy Xu, Morgan Brown, Oishi Bardhan, Jessie Axsom, Frederick C Bennett, Lynn A Spruce, Caroline Bartman, Clementina Mesaros, Ramon I Klein Geltink, Crystal S Conn, Will Bailis.
      CD8+ T cells need to function in complex environments with varied nutrient availability, including the tumor microenvironment and inflamed tissues. The mechanisms that allow CD8+ T cells to maintain immune function in these perturbed settings are poorly understood. Here, we show that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reoriented translational programming, which limited nutrient demand and prioritized stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein gamma (CEBPG) jointly established an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial metabolism. Despite diminished energetic capacity under environmental stress, this program sustained central carbon metabolism. This subsequently mitigated cellular dysfunction and potentiated anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers T cell resilience in unfavorable environments, offering potential strategies to enhance immunotherapies.
    Keywords:  ATF4; CD8(+) T cells; CEBPG; GCN2; HRI; T cell exhaustion; T cells; amino acids; anti-tumor immunity; immunometabolism; integrated stress response; mTOR; nutrient stress; polysome profiling; stress adaptation; translation; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.004
  14. Cell. 2026 Apr 30. pii: S0092-8674(26)00401-0. [Epub ahead of print]
    An anaerobic pathogen rewires host metabolism to fuel oxidative growth in the inflamed gut.
    Luisella Spiga, Ryan T Fansler, Yifan Wu, Alexandra Grote, Madison Langford-Butler, Asia K Miller, Maxwell Neal, Owen F Hale, Deepanshu Singla, M Wade Calcutt, Abigail E Rose, Madeline M Bresson, Alexandra C Schrimpe-Rutledge, Brittany Berdy, Simona G Codreanu, Mary Kay Washington, Benjamin P Bratton, Stacy D Sherrod, John A McLean, Karsten Zengler, Cynthia L Sears, Megan G Behringer, Andreas Gnirke, Lili Tao, Jonathan Livny, Danyvid Olivares-Villagómez, Ashlee M Earl, Wenhan Zhu.
      To colonize their host and cause disease, enteric pathogens must deploy their virulence factors to establish distinct nutrient niches. How anaerobic pathogens construct nutrient niches in the densely populated large intestine remains poorly understood. Enterotoxigenic Bacteroides fragilis (ETBF) is a classically anaerobic bacterium implicated in inflammation-associated diseases, including colitis and colorectal cancer. Here, we show that ETBF uses its virulence factor, Bacteroides fragilis toxin (BFT), to generate and adapt to a localized oxidative niche that supports gut colonization. BFT manipulates colonic epithelial signaling and the bile acid recycling pathway, inducing a metabolic shift in the epithelium from oxidative phosphorylation to glycolysis. This shift increases local concentrations of lactate and oxygen, nutrients that support oxidative metabolism in ETBF. These findings reveal an unexpected strategy by which a classically anaerobic pathogen leverages host metabolic remodeling to generate and exploit an oxidative niche in the inflamed gut.
    Keywords:  bile acid recycling; colonocyte metabolism; enterotoxigenic Bacteroides fragilis; obligate anaerobe; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.cell.2026.04.012
  15. Nat Cell Biol. 2026 Apr 29.
    ATM counteracts chromatin-bound cGAS during DNA replication.
    Yunhao Song, Xiaojuan Ran, Yu Xu, Kartik Subramanian, Chao Dai, Mavrakis Konstantinos, Li Lan, Vipin Yadav, Lee Zou.
      Cyclic GMP-AMP synthase (cGAS), a DNA sensor that activates type-I interferon responses, is restrained in the nucleus through chromatin binding, but its impact on DNA metabolism remains unknown. Here we show that chromatin-bound cGAS impedes DNA replication forks unless countered by ATM. Upon ATM loss, chromatin-bound cGAS slows replication forks, increases nascent DNA fragmentation and activates cytosolic cGAS. Remarkably, all these effects are alleviated upon the loss of cGAS chromatin binding, suggesting that ATM enables tolerance to chromatin-bound cGAS. Mechanistically, ATM, backed by ATR, releases cGAS from chromatin by phosphorylating MRE11. ATR inhibition in ATM-deficient cells exacerbates replication stress, causing synthetic lethality and stimulated interferon response. In ATM-deficient cancer cells, cGAS dictates replication stress and ATR inhibitor sensitivity, highlighting its potential as a biomarker for ATR-targeted therapy. Together, our findings uncover a regulatory circuit in which ATM and chromatin-bound cGAS jointly maintain the homeostasis of replication and cGAS signalling in cycling cells.
    DOI:  https://doi.org/10.1038/s41556-026-01931-x
  16. J Clin Invest. 2026 Apr 25. pii: e202212. [Epub ahead of print]
    MESH1-mediated coenzyme A degradation drives ferroptosis sensitivity and muscle pathology.
    Chao-Chieh Lin, Joshua Rose, Alexander A Mestre, Chien-Kuang C Ding, Ssu-Yu Chen, Sze Mun Choy, Kah Yong Goh, Weiyi Jiang, Wen Xing Lee, Qizhou Jiang, Yanting Chen, Tianai Sun, Jianli Wu, Yueqi Chen, Yunju Oh, Pyeonghwa Jeong, Jiyong Hong, Kenon Chua, Michael C Fitzgerald, Guo-Fang Zhang, Hong-Wen Tang, Pei Zhou, Jen-Tsan Chi.
      Coenzyme A (CoA) facilitates fatty acid synthesis, energy production, gene regulation, and antioxidant function. While CoA biosynthesis is well-characterized, the mechanisms governing CoA degradation remain poorly understood. Here, we identify the Metazoan Homolog of SpoT, MESH1, as a CoA phosphatase that dephosphorylates CoA at the 3' position of the ribose ring to form dephospho-CoA (dp-CoA). Recent studies have shown that CoA, similar to glutathione (GSH), is a cysteine-derived metabolite that protects cells against ferroptosis. Ferroptosis induced by blocking cystine import depletes CoA biosynthesis, while CoA restoration rescues cells from ferroptosis. We found that MESH1 knockdown preserved CoA levels by preventing its degradation, contributing to ferroptosis protection, indicating the bifunctional role of MESH1 in regulating CoA and previously reported NADPH. Mechanistically, MESH1 knockdown elevates CoA levels, maintaining functional mitochondrial thioredoxin system, thereby preventing mitochondrial lipid peroxidation. In Drosophila, we found that dMesh1 overexpression leads to ferroptosis-mediated muscle atrophy, which can be rescued by increasing CoA and NADPH levels. Taken together, these findings establish MESH1 as a key phosphatase that governs ferroptosis sensitivity by coordinating CoA and NADPH homeostasis, unveiling a novel link between CoA degradation, mitochondrial integrity, and muscle health.
    Keywords:  Amino acid metabolism; Cell biology; Molecular biology; Muscle; Muscle biology
    DOI:  https://doi.org/10.1172/JCI202212
  17. Nat Commun. 2026 Apr 27.
    Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice.
    Jie Yao, Su Fang, Miao Lei, Zexian Ou, Chuanfei Zeng, Wanli Peng, Na He, Lian Yang, Bingpeng Guo, Mingmeng Fang, Cuihua Wang, Jie Lv, Shuang Wu, Wei Kevin Zhang, Huimin Huang, Yang Peng, Wei Rao, Zhili Rong, Penghui Yang, Chaoqun Wang, Qian Han, Wenxiang Hu.
      Idiopathic pulmonary fibrosis is a progressive and fatal disorder characterized by abnormal activation of alveolar fibroblasts. However, the metabolic reprogramming of alveolar fibroblasts during lung injury remains unclear. Here we show that uptake of branched-chain amino acids is increased, whereas their catabolism is significantly impaired in fibrotic lung fibroblasts and mouse lung tissues. Branched-chain amino acids promote lung fibroblast activation and bleomycin-induced lung fibrosis. Genetic inactivation of branched-chain amino acid transaminase 2 exacerbates fibrosis, whereas inhibition of the corresponding transporter SLC7A5 or enhancement of catabolism attenuates pulmonary fibrosis in male mice. Mechanistically, ATF4 and PPARγ regulate the expression of SLC7A5 and BCAA catabolic genes, respectively. We identify KDM4A as a key mediator of the epigenetic regulation of fibrotic genes. Notably, dysregulated BCAA metabolism is associated with disease severity in patients, suggesting that targeting BCAA metabolism may serve as a promising therapeutic strategy for idiopathic pulmonary fibrosis.
    DOI:  https://doi.org/10.1038/s41467-026-72273-3
  18. Nat Commun. 2026 Apr 30.
    Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
    Eleonora Centanini, Oliver Pain, Patrick F Chinnery, Alan Hodgkinson.
      Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We then develop tissue-specific genetic scores to predict mtDNA transcript levels and validate them in independent datasets. Applying these scores to 377,439 UK Biobank participants reveals significant associations between predicted mtDNA transcript abundance and multiple common diseases and quantitative traits, many showing marked tissue specificity, including associations with hypertension and Parkinson's disease in biologically relevant tissues. These findings provide genetic evidence that variation in mtDNA transcriptional processes contributes to complex disease biology and highlight mitochondrial RNA processing as a compelling therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-72649-5
  19. bioRxiv. 2026 Apr 14. pii: 2026.04.11.717924. [Epub ahead of print]
    An unrecognized host response to microbial exposure resets circadian timing.
    Devons Mo, Ti Dung Ngoc Lam, Ella Baker, Olivia P Fraser, Jack Dorling, John S O'Neill, Gerben van Ooijen, Antony N Dodd, Carrie L Partch, Priya Crosby, Jacqueline M Kimmey.
      As ubiquitous features of every natural environment, microbes have profoundly shaped eukaryotic biology throughout evolution. Circadian clocks evolved in all domains of life as central regulators that align physiology with environmental cycles, yet whether they respond directly to microbial signals remains unknown. Here, we demonstrate that evolutionarily diverse microbes potently reset mammalian cellular clocks and can drive phase shifts in plants and algae, indicating cross-kingdom effects of microbes on circadian rhythms. In mammals, exposure to soluble bacterial components distinct from canonical innate immune ligands induces acute PER2 upregulation independently of Bmal1 or nascent transcription. A targeted inhibitor screen and biochemical assays implicate p38 MAPK as a modulator of this response. Taken together, this positions bacterial exposure as a previously unrecognized circadian clock input, revealing a new axis of host-microbe interaction that modulates biological timing at the cellular level.
    DOI:  https://doi.org/10.64898/2026.04.11.717924
  20. Aging Cell. 2026 May;25(5): e70516
    Replacement-Based Ageing Interventions for Systemic Rejuvenation: Shaping Longevity Science and Clinical Directions.
    Bjorn Fraser Olaisen, Vadim N Gladyshev, Bohan Zhang, Anthony Atala, Kyle M Loh, Vera Gorbunova, Thomas A Rando, Tony Wyss-Coray, Eric Verdin, Alexander Zhavoronkov, Morten Scheibye-Knudsen, Sierra Lore, Daniela Bakula.
      Biological and synthetic replacement-based ageing interventions hold substantial potential to reverse many forms of age-related damage simultaneously and extend healthy lifespan beyond what can be achieved with conventional therapeutics. In this Perspective, we discuss recent insights, unmet needs, and emerging trajectories that are catalysing research and clinical development of replacement-based treatments and synergistic strategies for multi-targeted damage removal and export at the molecular, organellar, and cellular levels. The first workshop dedicated to replacement as an ageing intervention at the Aging Research & Drug Discovery 2025 conference helped prioritise key challenges, opportunities, and future directions to address the need for preventive replacement and bioengineering technologies capable of inducing systemic and sustained rejuvenation across cells, tissues, and regulatory networks. We propose a roadmap to guide research and innovation integrating replacement and next-generation damage-removal therapeutics to modulate the ageing process in the whole body, restore biological function, and extend healthy lifespan.
    DOI:  https://doi.org/10.1111/acel.70516
  21. Cell Metab. 2026 Apr 29. pii: S1550-4131(26)00142-7. [Epub ahead of print]
    NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.
    Wencao Zhao, Wenkai Zhu, Trace Thome, Ioana Soaita, Jae Woo Jung, Michael C Noji, Jian Li, Huajun Bai, Yansen Xiao, Yifan Yang, Chelsea Thorsheim, Wei Zhou, Yijun Yang, Kristina Li, Jonathan J Edwards, Ivan A Kuznetsov, Boa Kim, Joseph A Baur, Zoltan Arany.
      Angiogenesis requires endothelial cells (ECs) to toggle between quiescence versus proliferation, migration, and invasion. While activation from quiescence is well characterized, mechanisms governing the return from proliferation to quiescence (PtoQ) remain unclear. We show here that metabolic rewiring during PtoQ renders ECs sensitive to oxidative stress, requiring nicotinamide adenine dinucleotide (NAD) turnover for protection. Limiting EC NAD does not affect proliferation or migration but prevents cell-cell contact formation and quiescence acquisition during PtoQ. In vivo and ex vivo, limiting EC NAD permits initial sprouting but impairs vascular stabilization and plexus formation. Mechanistically, NAD suppresses mitochondria-derived hydrogen peroxide (H2O2) during PtoQ. Exogenous H2O2 mimics NAD deficiency, whereas its removal rescues PtoQ. In pathological settings, inhibiting NAD synthesis limits exuberant angiogenesis of retinopathy and tumors. In summary, we unveil metabolic events critical for PtoQ, a poorly studied component of angiogenesis, and point to new ways to suppress pathological angiogenesis.
    Keywords:  H(2)O(2); NAD; NADPH; NAMPT; angiogenesis; endothelial cells; metabolism; quiescence
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.004
  22. Cancer Res. 2026 Apr 30.
    SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-XL in Clear Cell Renal Cell Carcinoma.
    Anusha Uprety, Chandler Judd, Emily D Villella, Rebecca Keller, Ryan Wagner, Keith D Robertson, Jezabel Rodriguez-Blanco, Thibaut Barnoud, Frank M Mason, Thai H Ho, Aguirre A de Cubas.
      SETD2 is frequently mutated or deleted in clear cell renal cell carcinoma (ccRCC). Loss of SETD2 could create synthetic lethal dependencies that confer therapeutic vulnerabilities. Here, we demonstrated that SETD2 deficiency promotes cytoplasmic mitochondrial DNA (mtDNA) leakage, leading to basal activation of cGAS-STING inflammatory signaling and increased apoptotic priming. This inflammatory state upregulated the BH3-only protein NOXA, constrained MCL-1 function, and enforced a synthetic lethal dependency on the anti-apoptotic protein BCL-xL. Pharmacological inhibition of BCL-xL further amplified cGAS-STING signaling in SETD2-deficient cells through sublethal mitochondrial outer membrane permeabilization, resulting in increased mtDNA release and robust NOXA induction. Elevated NOXA neutralized the compensatory MCL-1-mediated survival signaling, triggering apoptosis. In contrast, SETD2 proficient ccRCC cells exhibited minimal cGAS-STING activation and failed to induce NOXA following BCL-xL inhibition, rendering them resistant. Genetic ablation of cGAS, STING, IRF3, or NOXA rescued sensitivity to BCL-xL inhibition, confirming that mtDNA-driven innate immune signaling is required for this dependency. In vivo, BCL-xL inhibition suppressed tumor growth and prolonged survival in SETD2-deficient xenograft models. Collectively, these findings establish a mechanistic link between SETD2 loss, mtDNA-driven innate immune activation, and enforced BCL-xL dependence in ccRCC, revealing a therapeutically targetable vulnerability in SETD2-deficient tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3195
  23. Sci Immunol. 2026 May;11(119): eadz0348
    Citraconate preserves T cell stemness and antitumor immunity.
    Wenhui Li, Minmin Ge, Ziyi Luo, Minju Ni, Kexin Tang, Chenfeng Han, Jiajia Wang, Yifu Ma, Xiaowei Liu, Kaili Ma, Jingxing Yang, Wenjing Li, Cangang Zhang, Qitai Zhao, Guangcan Shao, Jaeoh Park, Yi Zhang, Yonghong Wan, Baojun Zhang, Gang Wang, Mingjing Shen, Qiang Shan, Feng Guo, Ping-Chih Ho, Liyuan Zhang, Lianjun Zhang.
      Metabolic perturbations in the tumor microenvironment profoundly compromise the stemlike properties and effector functions of CD8 T cells. Deciphering the metabolic circuitry that sustains T cell stemness is critical for reinvigorating tumor-infiltrating lymphocytes and augmenting immunotherapeutic efficacy. Here, we identify citraconate, an itaconate isomer, as a metabolite markedly depleted in CD8 T cells subjected to chronic antigen stimulation or hypoxic conditions. Citraconate supplementation preserves stemlike characteristics, attenuates ferroptosis, and potentiates T cell-mediated antitumor immunity. Mechanistically, citraconate maintains intracellular cyclic adenosine monophosphate (cAMP) concentrations by suppressing phosphodiesterase1A/C (PDE1A/C) expression and preserving mitochondrial integrity, thereby activating protein kinase A (PKA) signaling. This activation transcriptionally represses arachidonate-5-lipoxygenase (ALOX5), consequently reducing arachidonic acid peroxidation. Clinically, diminished ALOX5 or PDE1A expression correlates with reduced T cell exhaustion and improved responses to immune checkpoint blockade (ICB) therapy. Our findings reveal the citraconate-mediated PDE1-cAMP-ALOX5 axis as a potential therapeutic target for enhancing cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciimmunol.adz0348
  24. Nat Cell Biol. 2026 Apr 30.
    Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer's brains.
    Jie Yu, Fengzhi Li, Xing-Jun Chen, Chenye Mou, Di Yao, Zhanying Bi, Xiaoli Chen, Lulu Du, Ziyan Feng, Xinshuang Zhang, Xiaoqian Yu, Lauren G Zacharias, Ralph J DeBerardinis, Li Zhang, Zhen Li, Benyan Luo, Xiao-Ling Hu, Woo-Ping Ge.
      Neurons and glia are distinct in their morphology, development and function, possessing unique transcriptomes and proteomes, but little is known about their metabolomes. The challenge of brain cell metabolic profiling is to obtain a large number of cells for reliable analysis. Here we purified microglia, astrocytes and neurons from mouse brains, identifying >70 metabolites through targeted metabolomics and 9,854 metabolite features via untargeted metabolomics. We systematically characterized cell type-enriched metabolites and metabolic pathways, revealing an enrichment of glutathione (GSH) and polyamine metabolism in microglia. This enrichment was validated in vivo and showed significant decreases with ageing and in an Alzheimer's disease model. Notably, GSH and polyamine metabolism correlated strongly with chemokine-related gene expression. Disrupting the GSH pathway in microglia resulted in downregulation of chemokine-related genes, aberrant morphogenesis and β-amyloid deposition. Our results provide a valuable resource ( https://metabolismocean.org/braincell ) for metabolic studies related to ageing, Alzheimer's disease and other neurological diseases.
    DOI:  https://doi.org/10.1038/s41556-026-01910-2
  25. bioRxiv. 2026 Apr 14. pii: 2026.04.11.717872. [Epub ahead of print]
    Label free multimodal optical imaging of metabolic heterogeneity in aging by integrating SRS, MPF, FLIM, and SHG.
    Hongje Jang, Shuang Wu, Hyehyun Kim, Tong-You Wade Wei, Jian Kang, Anahita Ataran, Fangyuan Gao, Dorota Skowronska-Krawczyk, Kenneth B Margulies, Ali Javaheri, Wei Sun, John Y-J Shyy, Erkin Seker, Lingyan Shi.
      Cellular metabolism is governed by the coordinated organization of macromolecules, including lipids and proteins, together with redox-active cofactors such as NADH and FAD. However, resolving these biochemical features quantitatively and spatially at subcellular resolution remains challenging because no single imaging modality can capture molecular composition, redox state, and tissue architecture simultaneously without labeling. Here, we present MANIFEST ( M ulti-mod A l N onlinear I maging with F luorescence E xcitation and S tatistical T emporal-resolved spectroscopy), a label-free imaging platform that integrates stimulated Raman scattering (SRS), second harmonic generation (SHG), multiphoton fluorescence (MPF), and fluorescence lifetime imaging microscopy (FLIM). The MANIFEST combines chemical imaging of lipids with autofluorescence- and lifetime-based quantification of NADH and FAD metabolism, enabling spatially resolved analysis of metabolic heterogeneity at organelle and tissue-compartment levels. We apply this framework to four distinct aging or disease models: amyloid-beta-treated tri-cultured brain cells, high-fat diet mouse liver, human non-ischemic cardiomyopathy tissue, and aging mouse retina. Across these systems, MANIFEST reveals disease-associated lipid remodeling, redox imbalance, disrupted metabolic zonation, collagen reorganization, and layer-specific metabolic changes. By integrating complementary nonlinear optical modalities into a single label-free platform, MANIFEST provides a generalizable approach for high-resolution metabolic phenotyping in complex biological systems and offers new opportunities for studying disease mechanisms, aging biology, and metabolism-driven tissue pathology.
    DOI:  https://doi.org/10.64898/2026.04.11.717872
  26. Nature. 2026 Apr 29.
    Postprandial lipid metabolism durably enhances T cell immunity.
    Alok Kumar, Dayana B Rivadeneira, Isha Mehta, Bingxian Xie, Rachel Cumberland, Supriya K Joshi, Jitendra S Kanshana, William G Gunn, Victoria Dean, Angelina Parise, Kristin Morder, Erica S Myers, Steven J Mullett, Richard T Cattley, Stacy L Gelhaus, Abigail E Overacre-Delgoffe, Jishnu Das, William F Hawse, Alison B Kohan, Greg M Delgoffe.
      Although intrinsic metabolic pathways have critical roles in T cell function1,2, systemic nutrient availability is in constant flux. Yet, how postprandial metabolism affects T cell fate has been less studied. Here we show that the short-term nutritional state of an individual has marked effects on T cell immunity. Human or murine T cells from fed hosts had higher metabolic capacity than those from fasted hosts, and this increase in capacity persisted after activation and expansion in vitro or in vivo. Triglyceride-rich chylomicrons in serum were drivers of postprandial immunometabolic reprogramming, and chylomicrons primed mTORC1-dependent translation ex vivo and after activation, which markedly enhanced effector function after priming. Human postprandial CAR-T cells manufactured from the same donor showed a therapeutic advantage over T cells collected while individuals were fasted. Thus, postprandial metabolism imparts durable metabolic and functional advantages to T cells, highlighting the importance of considering nutritional status in immunological analysis, vaccination and generation of cellular therapies.
    DOI:  https://doi.org/10.1038/s41586-026-10432-8
  27. Nat Commun. 2026 Apr 27. pii: 3859. [Epub ahead of print]17(1):
    Reprogramming of bacterial virulence by lysine acetylation.
    Ole Schmöker, Britta Girbardt, Sabrina Schulze, Gottfried J Palm, Leona Berndt, Jens Hoppen, Nilüfer Kara, Xenia Schöps, Ruba Al-Abdulla, Klara Garz, Heike Junker, Sophie Wolfgramm, Leif Steil, Christian Hentschker, Katrin Schoknecht, Lea-Maria Mayer, Leonie Speth, Vanessa Lachmayer, Mark Dörr, Stefan Kemnitz, Stefan Müller, Jan-Wilm Lackmann, Marcus Krüger, Kay Hofmann, Uwe T Bornscheuer, Uwe Völker, Elke Krüger, Vera Kozjak-Pavlovic, Michael Lammers.
      Gram-negative bacteria use a plethora of virulence factors to infect eukaryotic cells. CE-clan protease-related virulence factors were reported to act as deubiquitinases/ubiquitin-like specific proteases. Some have an additional acetyl-transferase activity. The molecular mechanisms underlying this dual activity and the physiological consequences are only marginally understood. Here, we report crystal structures for the Simkania negevensis virulence factor SnCE1 in apo-states and in complex with SUMO1. We confirm SnCE1 acting as an efficient deSUMOylase and discover an intrinsic autoacetyltransferase activity. Acetylation impairs SnCE1 tetramer formation structurally being incompatible with SUMO1 binding. We provide a model for regulation of SnCE1-mediated virulence by lysine acetylation modulating autoproteolytic processing and its subcellular distribution in the host cell. SnCE1 localizes to the endoplasmic reticulum in human cells and increases fragmentation of mitochondria. Our data provide mechanistic insights into how lysine acetylation of virulence factors is used to reprogram virulence adjusting it to the host cells' metabolic state.
    DOI:  https://doi.org/10.1038/s41467-026-72244-8
  28. bioRxiv. 2026 Apr 17. pii: 2026.04.14.718544. [Epub ahead of print]
    Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis with the PDAC Tumor Microenvironment.
    Anna S Trimble, Casie S Kubota, Elaine Zhao, Maureen L Ruchhoeft, Jonathan R Weitz, Woncheol Jung, Kristina L Peck, Satoshi Ogawa, Ethan L Ashley, Herve Tiriac, Tae Gyu Oh, Andrew M Lowy, Dannielle D Engle, Christian M Metallo.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy where metabolic homeostasis is maintained by tumor and stromal cells within the tumor microenvironment (TME). To better assess pathways supporting macromolecule biosynthesis in PDAC tumors, we apply 13 C metabolic flux analysis (MFA) to slice cultures of treatment-naïve human tumors and mouse models that retain the native TME. Glycans, lipid headgroups, and very long-chain fatty acids are the most dynamic metabolic pools, while long chain fatty acids, purines, and pyrimidines are predominantly salvaged locally in situ . We use targeted pharmacological modulators to highlight the importance of recycling pathways and metabolic redundancies which mitigate changes in lipid abundances. Finally, we leverage targeted lipid fluxomics and the distinct ganglioside and globoside profiles of tumor and stromal cells, respectively, to demonstrate the role of the lipid kinase PIKfyve in supporting ganglioside homeostasis via sialic acid and ceramide salvage. These data establish application of MFA to slice cultures of PDAC tumors as an effective approach for assessing metabolic mechanisms and therapeutic responses within an intact TME.
    DOI:  https://doi.org/10.64898/2026.04.14.718544
  29. Cell Death Dis. 2026 Apr 28.
    DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.
    Ferial Khalife, Elodie Muzotte, Fatima Naji, Walid Mahfouf, Julien Izotte, Benoît Pinson, Stéphane Claverol, Nivea Amoedo, Hussein Fayyad-Kazan, Lea Dousset, Rodrigue Rossignol, Hamid-Reza Rezvani.
      Dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, has recently emerged as a therapeutic target in various cancers. We have previously identified a pivotal role of DHODH in the initiation of cutaneous squamous cell carcinoma (cSCC), the second most common type of non-melanoma skin cancer. We also showed that pharmacological inhibition of this enzyme suppresses ultraviolet (UV)-induced tumor formation. However, the key mechanisms driving the anticancer activity of DHODH inhibition remain unexplored in cSCC. We investigated the biological consequences of pharmacological and genetic DHODH inhibition in cSCC using xenograft models derived from two human cell lines, A431 and SCC13, implanted in immunodeficient NSG mice. DHODH activity was suppressed pharmacologically with leflunomide (LFN) and the potent DHODH inhibitor PTC299, or genetically via lentiviral shRNA-mediated DHODH silencing (shDHODH). Proteomic and metabolomic analyses were integrated with histopathological, immunohistochemical, and immunoblotting evaluations to delineate the downstream effects of DHODH blockade. Comprehensive proteomic and metabolomic profiling revealed that DHODH inhibition induces a coordinated adaptive program involving keratinization, differentiation, redox homeostasis, and metabolic stress responses. Histological and immunostaining analyses demonstrated marked reductions in Ki67-positive proliferating cells and a corresponding increase in pan-cytokeratin (PanCK) and keratin 10 (Krt10) expression, indicative of enhanced epithelial differentiation. These changes were most pronounced in PTC299-treated and shDHODH xenografts, whereas LFN displayed minimal or no efficacy in SCC13 tumors. DHODH inhibition drives tumor differentiation and suppresses proliferation in cSCC, highlighting metabolic dependency as a potential therapeutic vulnerability. PTC299 exhibited superior antitumor activity and differentiation-inducing capacity compared with LFN. These findings position DHODH as a promising target for bioenergetic vulnerability-based cancer therapy in advanced or treatment-resistant cSCC.
    DOI:  https://doi.org/10.1038/s41419-026-08815-w
  30. Nat Struct Mol Biol. 2026 Apr 29.
    MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth.
    Hector Flores-Romero, Aida Pena-Blanco, Jonas Aufdermauer, Shashank Dadsena, Philip Neubert, Lisa Hohorst, Eileen Cors, Cristiana Zollo, Alvaro Larrañaga-SanMiguel, Jone Zaldunbide, Maria Nenchova, Yasmin Carvalho-Schaefer, Thomas Langer, Georg Häcker, Ana J Garcia-Saez.
      During apoptosis, the BCL-2 family members BAX and BAK oligomerize and form a pore to mediate the decisive step of mitochondrial outer membrane permeabilization. However, the contribution of additional cellular components to apoptotic pore dynamics remains poorly understood. Here we map the protein environment of the apoptotic pore using in situ proximity labeling and identify the mitochondrial carrier homolog protein MTCH2 localizing nearby BAX and BAK assemblies specifically under apoptotic conditions. We show that cells lacking MTCH2 exhibit delayed BAX and BAK oligomerization at the single-particle level, which can be rescued by addition of lysophosphatidic acid. Accordingly, MTCH2 depletion decreases not only apoptosis sensitivity but also sublethal mitochondrial permeabilization during bacterial infection, mitochondrial DNA release into the cytosol and cGAS-STING activation under impaired caspases. Our findings uncover a key role of MTCH2 in promoting BAX and BAK high-order assembly with functional consequences for apoptotic pore growth and downstream responses.
    DOI:  https://doi.org/10.1038/s41594-026-01805-8
  31. Cell Rep. 2026 Apr 25. pii: S2211-1247(26)00375-X. [Epub ahead of print]45(5): 117297
    SEPHS2 loss reprograms cancer metabolism from oxidative phosphorylation to gluconeogenesis via PCK1 stabilization.
    Yihuizhi Zhang, Qinghua Zhang, Bi Wei, Wenzhou Wang, Xinyu Chen, Weijian Ding, Chenguang Li, Yirui Ye, Jiali Xu, Weibo Zhang, Linyue Li, Fengyi Mai, Wenyou He, Xiancai Du, Keyu Zhao, Zining Zhao, Jingnan Huang, Yuchun Niu, Yue Zhang, Lingyun Dai, Baotong Zhang, Siyuan Xia.
      Selenium maintains cellular redox homeostasis primarily through its incorporation into selenoproteins. However, whether and how selenium metabolism modulates oxidative phosphorylation (OXPHOS), a major endogenous source of oxidative stress, has remained unclear. Here, we performed an OXPHOS-focused screen targeting selenium-metabolizing enzymes and identified SEPHS2 as a central hub linking selenium metabolism to OXPHOS. SEPHS2 knockout suppresses OXPHOS while retaining glucose as the primary carbon source of cellular respiration and redirecting glucose metabolism toward gluconeogenesis and the downstream pentose phosphate pathway (PPP). Mechanistically, SEPHS2 loss elevates intracellular NAD+ levels, thereby activating the deacetylase SIRT2 as a cofactor and promoting deacetylation-dependent stabilization of the gluconeogenic enzyme PCK1. Under selenium-limited conditions, SEPHS2 is reduced. SEPHS2 loss promotes tumor spread to the lung and sensitizes tumors to the PPP inhibitor 6-aminonicotinamide. These findings define a selenoprotein biosynthesis-independent role of SEPHS2 in regulating OXPHOS and unveil the PPP as a therapeutic vulnerability in tumors adapting to a selenium-limited microenvironment.
    Keywords:  CP: cancer; CP: metabolism; OXPHOS; PCK1; SEPHS2; cancer metabolism; gluconeogenesis; pentose phosphate pathway; selenium metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117297
  32. Sci Adv. 2026 May;12(18): eaeb2995
    A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity.
    Mayra A Borrero-Landazabal, Vanessa Linke, Tereza Kadavá, Zeshi Li, Piotr Draczkowski, Kacper Kaszuba, Lea Bertgen, Remigiusz A Serwa, Albert J R Heck, Agnieszka Chacinska.
      The translocase of the outer mitochondrial membrane (TOM) is the conserved entry gate for nuclear-encoded proteins. While structurally similar from yeast to humans, the human TOM complex operates in a cellular environment of vastly greater complexity. Here, we present a high-confidence map of the human TOM interactome using a membrane-permeable cross-linker to capture both stable and transient interactors. Alongside extensive overlap with known yeast partners, we uncover a set of human-specific interactors including regulatory factors and TOM-associated proteins. Mapping unique interprotein cross-links reveals conformational flexibility of the receptor TOM20 and enhanced recovery of peripheral components such as TOM70 and several associated quality control factors. Notably, we identify FKBP8 (FK506 binding protein 8) as a human-specific interactor that binds multiple TOM subunits and promotes organization of the complex. Our work redefines the human TOM complex as a dynamic, multifaceted hub coordinating biogenesis, quality control, and signaling. This expanded TOM landscape offers a rich resource for exploring mitochondrial regulation in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.aeb2995
  33. Nat Neurosci. 2026 Apr 30.
    Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.
    Sami Sauma, Stephanie Stransky, Ipek Selcen, Simone Sidoli, Rinat Abzalimov, Ye He, Patrizia Casaccia.
      How it is determined whether postnatal oligodendrocyte progenitor cells (OPCs) will survive, proliferate or differentiate remains unclear. Here we suggest that temporal and brain regional fluctuations of glucose, concomitant with changes in vascularization, modulate OPC population dynamics. We found that regions with high glucose levels exhibited greater OPC proliferation and histone acetylation than regions with low glucose and that this was mediated by the enzyme ATP-citrate lyase (ACLY), which converts glucose-derived citrate to acetyl-CoA. Mice with Acly deletion in OPCs showed a transient hypomyelination phenotype resulting from decreased OPC numbers, whereas their differentiation into oligodendrocytes (OLs) proceeded due to compensatory upregulation of enzymes responsible for extranuclear generation of acetyl-CoA from alternative metabolic substrates. Therefore, OPCs rely on ACLY-dependent nuclear acetyl-CoA from glucose-derived citrate, to regulate proliferation, whereas OLs rely on extranuclear acetyl-CoA from other sources for myelin formation. This suggests a metabolic regulation of OL lineage cell population dynamics.
    DOI:  https://doi.org/10.1038/s41593-026-02263-7
  34. bioRxiv. 2026 Apr 17. pii: 2026.04.16.719038. [Epub ahead of print]
    Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.
    Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.
      Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.
    DOI:  https://doi.org/10.64898/2026.04.16.719038
  35. bioRxiv. 2026 Apr 15. pii: 2026.04.13.718201. [Epub ahead of print]
    Loss of Propionyl-CoA Carboxylase Reprograms Hepatic Metabolism by Suppressing Mitochondrial Pyruvate Carboxylation and Fatty Acid Oxidation.
    Fang Lu, Chorlada Paiboonrungruang, Wentao He, Zhaohui Xiong, Pingchuan Tang, Takhar Kasumov, Xiaoxin Chen, Guo-Fang Zhang.
      Propionic acidemia (PA) is an inborn error of metabolism caused by propionyl-CoA carboxylase (PCC) deficiency due to mutations in either PCCA or PCCB . Without proper management, the disease is associated with high mortality. Even with dietary restriction, patients often develop complications later in life, and the underlying pathological mechanisms remain poorly understood. The liver is the primary organ responsible for propionyl-CoA metabolism, yet the metabolic alterations induced by PCC deficiency in the liver have not been systematically investigated. In this study, we used a hepatocyte model of PA- PCCA null - HepG2 cells-to comprehensively examine metabolic alterations using stable isotope-based metabolic flux analysis. The PCCA knockout recapitulated key metabolic features of PA in HepG2 cells. Furthermore, PCCA deficiency reduced mitochondrial fatty acid oxidation while increasing glucose oxidation through pyruvate dehydrogenase. In contrast, pyruvate anaplerosis via pyruvate carboxylase was markedly reduced in PCCA knockout cells. This reduction in anaplerotic flux impaired the capacity for gluconeogenesis and lipid synthesis, consistent with observations from in vivo studies in Pcca⁻/⁻ (A138T) mice. Additionally, branched-chain keto acid catabolism was reduced in PCCA knockout HepG2 cells. Threonine showed minimal metabolic contribution in this model, further supporting the role of propionate as a major source of propionyl-CoA production. Collectively, these findings highlight the metabolic vulnerabilities associated with PCC deficiency and underscore the increased risk of prolonged fasting in patients with PA, particularly those with severe disease.
    DOI:  https://doi.org/10.64898/2026.04.13.718201
  36. bioRxiv. 2026 Apr 19. pii: 2026.04.15.718788. [Epub ahead of print]
    A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8 + T cell antitumor immunity.
    Wenling Li, Christina M Zarek, Hesuiyuan Wang, Shuheng Gan, Parastoo Sabaiefard, Priscilla Del Valle, Jiwoong Kim, Nicole Poulides, Laura A Coughlin, Jake N Lichterman, Cheng Zhang, Rebecca Suet-Yan Chiu, Tarun Srinivasan, Mauricio J Velasquez, Indu Raman, Vanessa J Maddox, Jeffrey McDonald, Ralf Kittler, Prithvi Raj, Xin V Li, Xiaowei Zhan, Chen Liao, Joao B Xavier, Andrew Y Koh.
      Gut microbiota are critical determinants of effective immune checkpoint therapy (ICT), yet the microbial mediators and host mechanisms that enhance antitumor immunity remain poorly understood. Here, we identify the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as a metabolite associated with immune checkpoint therapy (ICT) response. TDCA administration alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness across multiple murine tumor models. Mechanistically, TDCA directly enhances CD8⁺ T cell-mediated antitumor immunity, increasing cytotoxicity. These effects required signaling through the bile acid receptor TGR5. Together, these findings reveal TDCA as a gut microbial metabolite that restores ICT efficacy after antibiotic disruption by directly augmenting CD8⁺ T cell anti-tumor activity. This work supports metabolite replacement as a therapeutic strategy to mitigate antibiotic-associated loss of cancer immunotherapy response.
    Significance: TDCA is a microbiota-derived metabolite that restores immune checkpoint therapy efficacy after antibiotic disruption by directly enhancing CD8⁺ T-cell-mediated anti-tumor immunity through bile acid receptor TGR5 signaling. Our findings suggest that supplementation with defined microbial metabolites can mitigate antibiotic-associated loss of immunotherapy response without requiring broader microbiome reconstitution.
    DOI:  https://doi.org/10.64898/2026.04.15.718788
  37. EMBO Rep. 2026 Apr 29.
    Ras promotes macropinocytic nutrient uptake by suppressing the albumin recycling receptor FcRn.
    Rafael Paschoal de Campos, Xuxia Wu, Aslihan Inal, Zhao Liu, Craig B Thompson, Wilhelm Palm.
      Macropinocytosis and lysosomal degradation of extracellular protein constitute a nutrient acquisition pathway in Ras-driven cancers. By catabolizing albumin, the most abundant plasma protein, Ras-transformed cells sustain growth in environments where free amino acids are scarce. Under physiological conditions, however, albumin is normally protected from lysosomal degradation by the neonatal Fc receptor (FcRn), which recycles albumin back to the extracellular space. Here, by investigating how cancer cells overcome FcRn-mediated albumin recycling, we identify the Ras-Erk MAPK signaling pathway as a critical regulator of FcRn. Expression of constitutively active Ras variants or stimulation with growth factors represses FcRn transcription through activation of the MAPK pathway, leading to decreased FcRn protein abundance. Conversely, pharmacological inhibition of Ras-MAPK signaling de-represses FcRn expression. Restoring FcRn levels in Ras-transformed cells limits lysosomal albumin degradation and impairs the proliferation of cells that depend on albumin as an essential amino acid source. Thus, oncogenic Ras signaling promotes the nutritional utilization of albumin by suppressing FcRn, thereby supporting cancer cell adaptation to nutrient-poor environments.
    DOI:  https://doi.org/10.1038/s44319-026-00787-4
  38. bioRxiv. 2026 Apr 17. pii: 2026.04.16.717704. [Epub ahead of print]
    A robust workflow for 3D imaging of human mitochondria using cryo-electron tomography.
    Akhil Gargey Iragavarapu, Oleg Artemchuk, Daija Bobe, Anna C Ratliff, Evgeny Pavlov, Halil Aydin.
      Mitochondria are dynamic signaling organelles that transduce metabolic and biochemical cues to facilitate cellular adaptation. Their complex structure and dynamics are essential for integrating metabolic pathways, responding to stressors, and communicating inter- and intra-cellular signals. While optimal mitochondrial activity is frequently linked to cellular and organismal health-influencing processes ranging from metabolism and regulated cell death to differentiation and growth-the mechanistic links between mitochondrial dysfunction and cellular defects leading to human disease remain incompletely understood. Understanding how mitochondrial shape and function are linked is crucial for deciphering the regulatory mechanisms of cell survival and fate. Here, we present a molecular resolution cryo-electron tomography (cryo-ET) imaging and image analysis platform to investigate the structure of isolated human mitochondria under different conditions. We describe optimized protocols for isolating mitochondria from human cells, vitrifying these samples with high-pressure freezing (HPF) using the waffle method, cryo-focused ion beam (cryo-FIB) milling to generate thin sections (lamellae), and imaging with cryo-transmission electron microscopy (cryo-TEM). This is complemented by a robust downstream processing pipeline for tilt-series alignment, tomogram reconstruction, and three-dimensional (3D) segmentation of tomograms using the latest state-of-the-art algorithms. With some variations, this versatile workflow is adaptable to other subcellular compartments for structural studies in isolation or within intact cells. Furthermore, our protocols provide a critical foundation for investigating the in-situ structure of protein machineries that govern key cellular processes.
    DOI:  https://doi.org/10.64898/2026.04.16.717704
  39. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00082-8. [Epub ahead of print]206 95-107
    Detecting ferroptotic cells using an antibody against hyperoxidized PRDX3.
    Peihao Sun, Weinan Yin, Mengmeng Sheng, Yawen Meng, Kaiwen Han, Zhihao Li, Yanchao Xu, Shaojie Cui, Jin Ye.
      Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Although its biological and clinical relevance is increasingly clear, routine and specific detection of ferroptosis remains challenging, especially in tissues and clinical specimens. Indirect measurements of ferroptosis such as lipophilic fluorescent probes (C11-BODIPY581/591), reactive aldehydes (MDA/4-HNE), and pharmacological rescue either lack specificity for ferroptosis, or are impractical for in vivo analysis. Recent work has identified hyperoxidized peroxiredoxin 3 (PRDX3), also known as SO2/3-PRDX3, as a ferroptosis-specific biomarker: Under ferroptotic stress, mitochondrial PRDX3 undergoes selective and irreversible hyperoxidation at its catalytic cysteine residue to generate sulfinic/sulfonic derivatives, a reaction facilitating ferroptosis. Building on this biology, here we outline a method that detects ferroptosis in cells and tissues using 5H7c, a rabbit monoclonal antibody recognizing hyperoxidized but not unmodified PRDX3. The approach offers high specificity, broad sample compatibility (cell lines, animal tissues), and platform flexibility (Western blotting, immunohistochemistry, immunofluorescence).
    Keywords:  Alcoholic liver disease; Cell death detection; Ferroptosis; Hyperoxidized PRDX3; Tissue biomarker
    DOI:  https://doi.org/10.1016/bs.mcb.2026.02.014
  40. bioRxiv. 2026 Apr 19. pii: 2026.04.15.716394. [Epub ahead of print]
    CXCL-CXCR2 signaling drives cancer-endothelium interactions in SCLC metastatic seeding.
    Zhang Yang, Andy Xu, Nicholas Hughes, Chien-Wei Peng, Adrienne Visani, Susrutha Puthanmadhom Narayanan, Xue Wen Ng, Isabella Guppy, Chris Roberts, Yaoxuan You, Monte M Winslow, David W Piston, Jon Park, Zhonglin Lyu, Feng Chen, Li Ding, Rui Tang.
      Small cell lung cancer (SCLC) is a highly metastatic malignancy with tropism to the liver, yet the signals that enable organ-specific metastatic colonization remain largely undefined. During metastasis, disseminated cancer cells first encounter endothelial cells (ECs) at the vascular-tissue interface, positioning cancer-endothelium crosstalk as a key determinant of metastatic success. Defining the signaling pathways underlying this reciprocal communication may uncover actionable vulnerabilities for preventing and treating this lethal disease. Here, we uncover an EC-derived CXCL chemokine program that activates cancer-intrinsic CXCR2-RAC1 signaling as a critical mediator of SCLC liver metastasis. By integrating in vitro and in vivo models, we show that SCLC cells induce robust CXCL chemokine expression from liver ECs, which in turn enhances SCLC migration and reinforces cancer cell-EC interactions. We applied highly quantitative metastatic colony barcode sequencing coupled with individual gene inactivation to demonstrate that CXCR2 is essential for SCLC migration and liver metastatic seeding. Mechanistically, CXCL-CXCR2 signaling activates RAC1-dependent F-actin assembling to drive SCLC motility during CXCL-induced metastatic seeding. Pharmacologic inhibition of CXCR2 or RAC1 suppresses SCLC migration and prevents SCLC liver metastasis. Together, our research defined a chemokine-driven signaling circuit that governs cancer-endothelium communication during the metastatic cascade and nominate the CXCL-CXCR2-RAC1 axis as a promising therapeutic vulnerability for preventing and treating metastatic SCLC.
    DOI:  https://doi.org/10.64898/2026.04.15.716394
  41. bioRxiv. 2026 Apr 17. pii: 2026.04.14.718582. [Epub ahead of print]
    Multiomic screening platform uncovers the impact of histone mutations on chromatin and cell fate.
    Ziyang Ye, Alireza Khademi, Renée L Barbosa, Foster Birnbaum, Margaret R Brown, Colin E Fowler, Arianna Arroyo-Ortega, Daniel Lee, Lijuan Feng, Leah A Gates, Agata L Patriotis, Amy E Keating, Francisco J Sánchez-Rivera, Yadira M Soto-Feliciano.
      Somatic missense mutations in histone genes, often referred to as 'oncohistones', have been identified in diverse types of human cancers. The functional and mechanistic impact of most oncohistones remains unknown. To address this gap, we developed CHANCLA, a modular platform for high-throughput functional screening of oncohistones using multiomic phenotypic readouts. We used CHANCLA to systematically measure the impact of 303 human oncohistones on cellular proliferation, differentiation, histone-specific post-translational modifications, and chromatin accessibility. Integrative multiomic analyses revealed discrete oncohistone molecular classes that promote proliferation, block lineage-specific differentiation, and physically remodel the chromatin landscape by altering specific histone modifications and reducing nucleosome stability. Structural mapping and computational modeling studies uncovered that functionally convergent mutations are clustered at key nucleosome interfaces, particularly H2B-H4, and that chromatin accessibility-promoting mutations are linked to mono-nucleosome destabilization. Leveraging this multiomic resource, we discovered that the H3.3-Q5H mutant histone is a bona fide human oncohistone that accelerates lung adenocarcinoma growth in vivo . Mechanistically, we found that H3 . 3-Q5H expression leads to suppression of promoter-associated H3K4me3 and expansion of repressive H3K27me3 domains, resulting in increased KRAS signaling and gene expression programs associated with epithelial-to-mesenchymal transition. Together, this work provides a multiomic functional atlas of cancer-associated histone mutations, identifies structural and mechanistic principles governing chromatin reprogramming by oncohistones, and establishes CHANCLA as a modular platform for systematic discovery of mechanisms and vulnerabilities associated with these genetic lesions.
    DOI:  https://doi.org/10.64898/2026.04.14.718582
  42. Nat Metab. 2026 Apr 27.
    Tissue-specific fibroblast lipid cues impose the rate of epithelial cancer invasion.
    Timothy Budden, Noah Palombo, Shilpa Gurung, Martha Gutteridge, Charlotte Russell, Jair Marques, Alex von Kriegsheim, Lyutong An, Catherine Harwood, Luisa Motta, Claus Jorgensen, Carlos López-Garcîa, Caroline Gaudy-Marqueste, Kevin Harrington, Malin Pedersen, Ben O'Leary, Antonio Rullan, Amaya Virós.
      Squamous cell carcinomas (SCCs) originate in epithelial tissues of older individuals who have been exposed to environmental carcinogens. Despite overlapping clinical hallmarks, SCCs from different anatomic sites have different prognoses. Here we show that fibroblasts confer site-specific cues that determine SCC proliferation and invasion. Oral and lung fibroblasts have distinct lipid metabolism, transferring unique lipids to SCC cells that promote epithelial-to-mesenchymal transition, and oral and lung SCC invasion. Whereas oral fibroblasts transfer sphingomyelins, which activate the ceramide-sphingosine-1-phosphate-STAT3 pathway and promote oral SCC invasion, lung fibroblasts transfer triglycerides to lung SCCs, thereby triggering cholesterol synthesis and invasion, which is associated with poor survival. By contrast, dermal fibroblasts are lipid poor, and cutaneous SCC is less invasive. Our data indicate that targeting fibroblast lipid synthesis and SCC lipid uptake or breakdown inhibits oral and lung epithelial cancer invasion.
    DOI:  https://doi.org/10.1038/s42255-026-01514-y
  43. Oncogenesis. 2026 Apr 30.
    Reprogramming lipid metabolism in pediatric cancers.
    Vinzent L Lindemann, Nazek Noureddine, Raphael J Morscher.
      Metabolic reprogramming is a defining feature of malignant transformation and cancer cell growth. Pediatric cancers arise from genetic disruptions hijacking developmental programs by aberrant transcriptional networks. This coordinated rewiring shapes lipid metabolism through activation of biosynthetic pathways, membrane remodeling, and metabolic flexibility. This review synthesizes recent advances in the understanding of lipid metabolism reprogramming across pediatric cancers, examining four key areas: (1) transcriptional drivers that activate fatty acid and cholesterol synthesis; (2) lipid catabolism sustaining ATP, acetyl-CoA and NADPH pools under metabolic stress; (3) ferroptosis evasion through desaturation pathways and membrane remodeling; and (4) tissue-specific metabolic adaptations enabling metastasis to the bone marrow and cerebrospinal fluid. Despite extensive preclinical evidence identifying targetable vulnerabilities - including dependencies on FASN, SCD, and HMGCR - clinical impact remains to be proven. We discuss challenges of introducing therapies targeting lipid metabolism to the clinic and argue that the future lies in a better understanding of lipid flux and patient-specific dependencies.
    DOI:  https://doi.org/10.1038/s41389-026-00617-1
  44. Sci Adv. 2026 May;12(18): eaed8013
    LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.
    Zengfu Shang, Jui-Chung Chiang, Ching-Cheng Hsu, Ciara Newman, Anthony J Davis, Yuanyuan Zhang.
      Replication stress (RS) and altered metabolism are two hallmarks of cancer, yet how metabolic perturbations contribute to RS remains poorly understood. Lipotransferase 1 (LIPT1) catalyzes the covalent attachment of lipoic acid to mitochondrial 2-ketoacid dehydrogenases, sustaining flux through the tricarboxylic acid (TCA) cycle. Loss of LIPT1 causes accumulation of 2-hydroxyglutarate (2-HG), which is known to inhibit α-ketoglutarate (α-KG)-dependent histone demethylases and promotes heterochromatin formation. Here, we show that 2-HG-driven heterochromatin impedes replication fork progression, causing fork stalling and RS in LIPT1-deficient cancer cells. To bypass stalled forks, PrimPol-mediated repriming resumes DNA synthesis but leaves behind single-stranded DNA (ssDNA), which requires poly(adenosine 5'-diphosphate-ribose) polymerase 1 (PARP1) for repair. Furthermore, nascent DNA at reprimed forks undergoes MRE11-dependent degradation, further destabilizing replication fork integrity. Consequently, LIPT1 deficiency promotes replication and genome instability, and therapeutic vulnerability to PARP inhibitor. Together, these findings reveal a mechanistic link between mitochondrial lipoylation and replication fork stability, uncovering a metabolic basis for genome instability in cancer.
    DOI:  https://doi.org/10.1126/sciadv.aed8013
  45. Mol Cell. 2026 Apr 30. pii: S1097-2765(26)00240-6. [Epub ahead of print]
    PARP1 suppression drives ROS resistance in aneuploid cancer cells.
    Pan Cheng, Angela Mermerian-Baghdassarian, Yufeng Wang, Ze Chen, Helberth M Quysbertf, Pradeep Singh Cheema, Joseph C Mays, Xin Zhao, Lizabeth Katsnelson, Sally Mei, Rohini Shrivastava, Mirna Bulatovic, Jiehui Deng, Markus Schober, Kwok-Kin Wong, Teresa Davoli.
      Aneuploidy is common in cancer and has been implicated in promoting tumor progression, yet the underlying mechanisms remain poorly understood. By generating models of aneuploidy, we found that aneuploidy confers resistance to reactive oxygen species (ROS)-mediated cell death, independent of the specific chromosomes gained or lost. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1) is suppressed in aneuploid cells, which inhibits PARP1-mediated cell death (parthanatos). We validated aneuploidy-associated PARP1 suppression across 15 cell models and human tumors, with pronounced effects in metastatic tumors. Importantly, PARP1 downregulation promotes tumor metastasis while PARP1 upregulation suppresses it. Through a genome-wide CRISPR screen and functional validation, we identified the transcription factor CCAAT/enhancer-binding protein beta (CEBPB) as a mediator of PARP1 downregulation and ROS resistance in aneuploid cells. Lysosomal dysfunction serves as the upstream activator of CEBPB in aneuploid cells. We propose that aneuploidy-driven CEBPB activation suppresses PARP1, fostering ROS resistance and cancer progression.
    Keywords:  PARP1; aneuploidy; cancer; cell death; oxidative stress
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.006
  46. bioRxiv. 2026 Apr 17. pii: 2026.04.14.718602. [Epub ahead of print]
    Metabolic inequality in microbial communities.
    Emmi A Mueller, Jay T Lennon.
      How metabolic activity is distributed among individuals determines the scaling of cellular physiology to higher levels of biological organization. Yet the mechanisms that generate this heterogeneity and shape its distribution remain largely unresolved. We quantified single-cell metabolism in microbial communities spanning aquatic, terrestrial, and host-associated ecosystems. Across more than one million cells, metabolic activity followed a long-tailed distribution best described by a lognormal model, with a small subset of individuals contributing disproportionately to community metabolism. In some cases, the most active 20% of cells accounted for over 90% of metabolic output, although this pattern became less pronounced in more productive environments. To assess the consequences of metabolic inequality, we developed a model linking single-cell activity to community respiration. Because respiration responds nonlinearly to enzyme activity, variation among cells does not translate proportionally into ecosystem-level fluxes. As a result, ignoring metabolic heterogeneity can bias estimates of community respiration by up to 60%. Our findings reveal a general pattern of metabolic inequality across microbial communities in disparate habitats. Accounting for this structure is critical for understanding how microorganisms shape ecosystem processes and for improving predictions of large-scale biogeochemical dynamics.
    Significance: Inequality is a common feature of social, economic, and physical systems. It also arises in nature, where a small fraction of individuals accounts for an outsized share of biological output, including reproduction, immunity, and diversity. Here, we show that metabolic activity in microbial communities follows a characteristic long-tailed distribution that consistently emerges across diverse ecosystems, including lakes, soils, ocean plankton, marine sediments, and mammalian guts. Rather than a 'rich-get-richer' dynamic, metabolism becomes more evenly distributed among individuals in more productive environments. An explicit representation of metabolic inequality can improve predictions of how microbial communities, and the processes they support, respond to environmental change.
    DOI:  https://doi.org/10.64898/2026.04.14.718602
  47. Redox Biol. 2026 Apr 22. pii: S2213-2317(26)00183-7. [Epub ahead of print]93 104185
    Reactive oxygen species and metabolic checkpoints shape plasmacytoid dendritic cell fate in infection and autoimmunity.
    Lena Rueschpler, Sebastian Schloer.
      Plasmacytoid dendritic cells (pDCs) are innate immune sentinels uniquely specialised in the rapid and potent production of type I interferons (IFN-I) during viral infection. While this capacity is essential for antiviral defence, sustained pDC activation is a central feature of numerous autoimmune and inflammatory disorders. Although the molecular pathways governing nucleic acid sensing and IFN-I induction have been extensively characterised, the metabolic and redox mechanisms that support, and limit pDC function remain incompletely understood. Emerging studies reveal that pDC activity is tightly linked to a specialised redox-metabolic programme involving mitochondrial respiration, reactive oxygen species (ROS), and endolysosomal signalling networks. In this review, we integrate current evidence to propose that pDCs operate within a tightly regulated redox window that permits effective acute antiviral responses but renders them vulnerable to metabolic stress and dysregulation upon chronic stimulation. We examine how mitochondrial fitness, NAD+ homeostasis, ROS dynamics, and endolysosomal redox control collectively influence pDC activation, resolution of inflammation, and pathogenic persistence. By reframing pDC biology through a redox-metabolic perspective, we highlight new conceptual insights into IFN-I-driven disease and identify potential therapeutic strategies to selectively modulate pathogenic pDC responses.
    Keywords:  Autoimmunity; Immunometabolism; Interferons; Mitochondria; NAD(+); Plasmacytoid dendritic cells; Redox signalling; Viral infection
    DOI:  https://doi.org/10.1016/j.redox.2026.104185
  48. STAR Protoc. 2026 Apr 25. pii: S2666-1667(26)00173-5. [Epub ahead of print]7(2): 104520
    Protocol for measuring mitochondrial respiration in mature human adipocytes using the Seahorse XF analyzer.
    Helen Broghammer, Claudia Gebhardt, John T Heiker.
      Primary mature human adipocytes are an important tool bridging basic research and clinical medicine by reflecting human biological diversity. Here, we present a protocol for measuring the oxygen consumption rate of mature adipocytes. We describe the steps for isolation of adipocytes from adipose tissue samples, Matrigel embedding, and Seahorse analysis, as well as normalization and data analysis. This protocol enables the investigation of the metabolic function of primary mature human adipocytes in response to drugs or genetic modifications.
    Keywords:  Cell Biology; Cell culture; Cell isolation; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2026.104520
  49. Nature. 2026 Apr 29.
    Spatial atlas of diabetic kidney disease reveals a B cell-rich subgroup.
    TRIDENT consortium
      Diabetic kidney disease (DKD), the leading cause of kidney failure, is marked by clinical and molecular heterogeneity, making therapeutic development exceedingly difficult1. Here we used Xenium and CosMx single-cell spatial transcriptomics, integrated with single-nucleus RNA sequencing, to build a cross-platform kidney atlas that makes tissue architecture computable for prognosis, non-invasive detection and patient selection. Using this atlas, we defined reproducible tissue niches and injury-linked microenvironments and uncovered a profibrotic context that expands with disease and tracks with worse kidney function. Within this architecture, we identified a B cell-predominant, tertiary lymphoid structure-like immune microenvironment that defines a distinct DKD subset with accelerated progression to renal end-points. We developed tissue biomarkers and a matched plasma protein panel that capture this biology, stratify patients in a population biobank and improve risk prediction beyond clinical models-supporting their potential for biomarker-guided selection in future B cell-targeted DKD trials.
    DOI:  https://doi.org/10.1038/s41586-026-10363-4
  50. Science. 2026 Apr 30. 392(6797): eaeb5171
    Toward life with a 19-amino acid alphabet through generative artificial intelligence design.
    Liyuan Liu, Charlotte Rochereau, Simon Kozlov, Guillaume Urtecho, Xiaonan Liu, Jiahui Zhao, Jasmine Wang, Yiming Huang, Yiming Qu, Zetian Zhang, Tomasz Blazejewski, Avi Swartz, Sergey Ovchinnikov, Harris H Wang.
      Because all known living organisms are made from at least 20 canonical amino acids, the feasibility of life using a more simplified alphabet remains unclear. In this work, we leveraged computational design and synthetic biology to explore building a cell from a 19-amino acid alphabet. Initial analyses suggested that isoleucine (Ile) may be dispensable, which we confirmed by directly replacing Ile residues in essential proteins in Escherichia coli. Critically, protein language models and structure-based models were necessary to redesign functional Ile-less proteins in most cases. We systematically replaced all 382 Ile residues from the ribosome and combined 21 redesigned subunits at a native genomic locus to produce a viable, evolutionarily stable cell. This work provides a roadmap to create the first 19-amino acid organism since early evolution.
    DOI:  https://doi.org/10.1126/science.aeb5171
  51. NPJ Biol Timing Sleep. 2026 Apr 28. pii: 16. [Epub ahead of print]3(1):
    Time after time: a quarter century of progress in plant circadian biology.
    Stacey L Harmer.
      The past 25 years have seen remarkable progress in plant circadian biology. This perspective highlights major advances in our understanding of the oscillator network, the processes it regulates, and circadian variation across tissues and cell types. Genomic and systems approaches uncovered pervasive circadian control of physiology, development, and fitness, including photoperiodic and domestication traits. Emerging tools now position the field to engineer clocks for agricultural resilience in a changing climate.
    DOI:  https://doi.org/10.1038/s44323-026-00076-2
  52. Cancer Cell. 2026 Apr 30. pii: S1535-6108(26)00176-5. [Epub ahead of print]
    Tissue tension fosters macrophage-driven lipid peroxidation-induced DNA damage.
    Mary-Kate Hayward, Jason J Northey, Valentina Opazo-Mellado, Connor Stashko, Ori Maller, Alastair J Ironside, Xuchu Que, Jonathon N Lakins, E Shelley Hwang, Joseph L Witztum, Hugo Gonzalez, Valerie M Weaver.
      Inflammation can induce mutagenic DNA damage to enhance cancer risk and progression. Inflammation also increases fibrosis and stromal stiffening that promotes malignancy, and tissues with higher cancer risk are often stiffer. Despite this connection, how stromal stiffness contributes to inflammatory-mediated DNA damage in tumorigenesis remains unclear. Here, we show that tissue tension engages macrophages to generate lipid peroxidation-induced DNA damage, contributing to mutational burden that may promote malignant progression. We identify that fibrotic breast tumors display higher mutational burdens. Mechanistically, tissue tension increases epithelial STAT3 to drive chemokine-mediated macrophage recruitment. Stiffness promotes reactive oxygen species-induced lipid peroxidation in recruited macrophages, generating aldehydes that damage DNA and enhance progression. Notably, high mammographically dense breast tissues-associated with increased cancer risk-are stiffer and inflamed and display elevated lipid aldehydes and DNA damage. This work links fibrosis and inflammation to tension-mediated cancer initiation and progression.
    Keywords:  DNA damage; breast cancer; extracellular matrix; inflammation; lipid peroxidation; macrophages; stromal stiffness; tissue fibrosis; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.022
  53. Biogerontology. 2026 Apr 27. pii: 93. [Epub ahead of print]27(3):
    Investigating fasting for metabolic health and longevity.
    Matthew L Steinhauser, Pouneh K Fazeli.
      Humans have evolved adaptive mechanisms that enable survival even with zero calories for periods of months or longer. Intermittent 'low-dose' exposure to the metabolic stress of fasting may also activate pathways that promote metabolic health and longevity, although such benefits have not been proven in humans. Here we present our perspective of the current rationale and evidence base to support fasting for gain in metabolic health. In the absence of individual level risk factors for potential harm, such as frailty, osteoporosis or osteopenia, or a current/historical eating disorder, a trial of intermittent fasting or time-restricted eating to promote weight loss and metabolic health is reasonable for the motivated patient who is overweight or obese. We conclude, however, that the current state of evidence is limited and not sufficient to justify widespread adoption of fasting practices, nor is it sufficient to exclude the possibility that fasting holds a key to a longer life. We provide a template for the types of studies that will be required to optimize fasting protocols and establish therapeutic proof of concept. In our opinion, incorporation of mechanistic and multi-omics endpoints will be critical to understand potential mechanisms of benefit in humans; pathways that could ultimately be targeted with a fasting mimetic drug to obviate the need for long-term adherence to onerous dietary restriction.
    Keywords:  Caloric restriction; Fasting; Longevity; Obesity; Starvation; Time restricted eating
    DOI:  https://doi.org/10.1007/s10522-026-10438-9
  54. Neoplasia. 2026 Apr 30. pii: S1476-5586(26)00044-8. [Epub ahead of print]77 101314
    Metabolic regulation of histone acetylation by ACLY supports MDR1 expression in colorectal cancer and highlights a targetable vulnerability.
    Ana García-Bautista, Aiora Cenigaonandia-Campillo, Anxo Rio-Vilariño, Lara Sanz-Criado, Marta Selva-Giménez, Raquel Perez-Antolín, Arancha Cebrián, Laura García-García, María Jesús Fernández-Aceñero, Natalia Baños-Herraiz, Lorena Mozas-Vivar, Estrella Núñez-Delicado, Jesús García-Foncillas, Óscar Aguilera.
      Chemoresistance remains a major cause of treatment failure in colorectal cancer (CRC), yet the metabolic mechanisms sustaining efflux-mediated drug resistance are not fully defined. Here, we identify ATP-citrate lyase (ACLY) as a metabolic regulator linking citrate-dependent acetyl-CoA production to epigenetic control of MDR1/ABCB1 expression. Using genetic and pharmacologic approaches, we show that ACLY catalytic activity contributes to the maintenance of histone acetylation at H3K9 and H4K16 and supports MDR1 transcription in CRC cells. Consistently, ACLY overexpression enhances, whereas its inhibition reduces, MDR1 expression and associated resistance-related transcriptional programs. In human CRC specimens, ACLY and MDR1 levels positively correlate, with a stronger association observed in advanced-stage tumors, supporting clinical relevance of this metabolic-epigenetic axis. Metabolic tracing with 13C-glucose suggests that perturbation of citrate flux influences ACLY-associated pathways and acetyl-CoA availability. In this context, vitamin C treatment reduces citrate-derived acetyl-CoA and ACLY phosphorylation and is associated with global histone deacetylation and decreased MDR1 expression in vitro and in KRAS-mutant patient-derived xenografts. Together, these findings highlight ACLY-dependent acetyl-CoA production as a potential metabolic vulnerability linked to epigenetic regulation of drug efflux programs in CRC. Targeting this metabolic-chromatin axis may represent a strategy to modulate MDR1-associated chemoresistance.
    Keywords:  ACLY; Ascorbate; Cancer; Chemoresistance; Epigenetic; KRAS; MDR-1; Metabolism
    DOI:  https://doi.org/10.1016/j.neo.2026.101314
  55. iScience. 2026 May 15. 29(5): 115605
    Rhythmic protein condensation in the circadian regulation of glycogen metabolism.
    Lily A Burton, Gopal K Pattanayak, Michael J Rust.
      Circadian rhythms are endogenously generated daily cycles in physiology that are closely tied to metabolism and can be found in all kingdoms of life. Because of their genetic simplicity, cyanobacteria provide a unique opportunity to uncover rhythmic mechanisms. In cyanobacteria, glycogen storage is highly rhythmic. Using a combination of mass spectrometry and live cell imaging, we find that the glycogen synthase enzyme (GlgA), is rhythmically condensed. The appearance of condensed foci of GlgA corresponds to inhibition of glycogen synthesis during morning hours, allowing storage to be coordinated with the demand for energy at dusk. Through mutational analysis, we show that the condensation status of GlgA is dictated by the state of the circadian clock rather than the amount of glycogen in the cell. These results reveal a model of circadian control of glycogen metabolism achieved through rhythmic spatial reorganization of a key enzyme.
    Keywords:  Chronobiology; Developmental biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115605
  56. bioRxiv. 2026 Apr 17. pii: 2026.04.14.715350. [Epub ahead of print]
    KDM6 Enzymes are the Mechanistic Targets of Mutant IDH that Dictate Replication Stress Sensitivity.
    Alexander C-Y Tsai, Mathew D Lin, Vinesh T Puliyappadamba, Dorothy M Junginger, Victoria G Donovan, Eleanor G Kaplan, Laura M Drepanos, Hiroaki Wakimoto, Daniel P Cahill, Julie A Losman, Kent W Mouw, Kalil G Abdullah, John G Doench, Duane Nash, Daniel Vitt, Christian Gege, Hella Kohlhof, Samuel K McBrayer, William G Kaelin, Diana D Shi.
      Cancer-associated isocitrate dehydrogenase (IDH) mutations sensitize gliomas to replication stress, although the underlying mechanisms are unclear. IDH-mutant enzymes synthesize ( R )-2-hydroxyglutarate (R2HG), which broadly inhibits 2-oxoglutarate-dependent enzymes. We performed forward genetic screens targeting all 2-oxoglutarate-dependent enzymes and discovered that KDM6 histone demethylases play a vital role in protecting cells from replication stress. Genetic or R2HG-mediated repression of KDM6 catalytic activity sensitized glioma cells to disparate replication stress-inducing drugs, including Ataxia-telangiectasia and Rad3-related (ATR) and dihydroorotate dehydrogenase (DHODH) inhibitors. This liability is generalizable because KDM6A loss-of-function mutations commonly observed in urothelial carcinomas sensitized bladder cancer cells to DHODH inhibition, thereby phenocopying IDH mutations in glioma. To exploit these oncogene-induced replication stress vulnerabilities, we developed an effective, on-target, and well-tolerated DHODH inhibitor, GLIO-1, that is poised for clinical translation. Collectively, we reveal KDM6 activity as a fundamental determinant of replication stress sensitivity and nominate pan-cancer, mechanism-based biomarkers of ATR and DHODH inhibitor efficacy.
    STATEMENT OF SIGNIFICANCE: We discovered that the KDM6 enzymes are the mechanistic targets of R2HG that mediate mutant IDH-induced replication stress hypersensitivity. We report a promising new DHODH inhibitor, GLIO-1, and nominate KDM6 and IDH mutations as predictive biomarkers for the antitumor effects of GLIO-1 and other replication stress inducers.
    DOI:  https://doi.org/10.64898/2026.04.14.715350
  57. EMBO J. 2026 Apr 30.
    Clean cut to curtail respiration: OMA1 cleaves AIFM1 to tune stress-induced bioenergetics.
    Muhammad Irfan Afridi, Agnieszka Chacinska.
      
    DOI:  https://doi.org/10.1038/s44318-026-00787-z
  58. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2518812123
    Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
    Miriam S Götz, Dan J Hayman, Gracie Adams, Fumiaki Obata, Mirre J P Simons.
      Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress-responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway), is prolongevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in longevity in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed that dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signaling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown may upregulate proteostasis and DNA repair pathways. Our work reveals that ATF4 may exhibit a dual, dose-, and context-dependent role in aging. Chronic dATF4 activation is detrimental in flies, while chronic suppression is prolongevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.
    Keywords:  aging; borrelidin; integrated stress response; tRNA; transcriptomics
    DOI:  https://doi.org/10.1073/pnas.2518812123
  59. Nat Cell Biol. 2026 May 01.
    SLC33A1-mediated glutathione transport regulates ER redox balance and function.
      
    DOI:  https://doi.org/10.1038/s41556-026-01929-5
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