bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–03–29
sixty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Snake postprandial metabolite shows cross-species activation of hypothalamic neurons.
  2. Mitochondrial lactate venting limits oxidative stress.
  3. Discovery of metabolites produced by reactions between central carbon metabolites and cysteine that mark inflammatory macrophages.
  4. The oncogenic control of nucleotide synthesis.
  5. Often forgotten but essential: long-chain acyl-CoAs in metabolic control.
  6. Mitochondrial NADP(H) integrates redox and metabolism.
  7. O-GlcNAcylation regulates PPAR-driven metabolic programming in intestinal stem cells.
  8. The 1p/19q co-deletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas.
  9. Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.
  10. Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?
  11. Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
  12. Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.
  13. Subversion of kynurenine-induced AHR activation in CD8 T cells by kynureninase-expressing antigen-presenting cells.
  14. Immunometabolic gatekeeping: How tissue metabolism conditions tumor immunity.
  15. Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.
  16. Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
  17. Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity.
  18. Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1.
  19. PLIN5 phosphorylation orchestrates mitochondria lipid-droplet coupling to control hepatic lipid flux and steatosis.
  20. Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.
  21. Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
  22. Adaptive crosstalk between polyamine metabolism, translation, and autophagy sustains energy homeostasis in mammals during starvation: a scoping review.
  23. Atlas of one-carbon metabolism in conventional and germ-free mice reveals folate as a key determinant of biochemical pathways.
  24. The pyruvate branch point controls lymphoid cancer cell dissemination.
  25. Midgestation metabolic constraint in purine metabolism drives distinct strategies for placenta and fetal growth.
  26. The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
  27. A structure-selective endonuclease drives uniparental mitochondrial DNA inheritance.
  28. Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
  29. Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.
  30. Cancer Metabolism and Its Historical & Molecular Foundations: An Overview.
  31. UFMylation of Pyruvate Dehydrogenase Regulates Mitochondrial Metabolism.
  32. Pentose phosphate pathway fuels cGAS-STING signalling to boost function of intratumoral conventional dendritic cells.
  33. Suppression of ITPK1 and IPMK activities impairs mTORC1 signaling in pancreatic β-cells and implicates IP 5 in stabilizing activated mTORC1.
  34. Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.
  35. Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states.
  36. Dissecting histological transformation.
  37. Protein domain characterization reveals human MIC60 tolerates loss of helical bundle domain.
  38. SenCat: Cataloging human cell senescence through multiomic profiling of multiple senescent primary cell types.
  39. Cell biology: Killing the prisoner escaping from mitochondria.
  40. Cell-specific isotope labeling identifies myo -inositol transfer between neurons and oligodendroglia to support myelin repair.
  41. Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
  42. Anticipatory metabolic reprogramming distinguishes caloric restriction from fasting-refeeding cycles.
  43. Stress Responses Tied to Metastasis and Immune Evasion.
  44. Hyperinnervation inhibits organ-level regeneration in mammalian skin.
  45. Glioblastoma cells that evade chemoradiotherapy-induced cell death exhibit a bifurcated glycolytic program.
  46. Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
  47. MHC class I on target cells regulates CD4+ T cell-mediated immunity.
  48. RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
  49. Genetic influences on haematopoiesis.
  50. ATM functions as a rheostat of metabolic stress in small-cell lung cancer.
  51. How strong is a mitochondrial targeting signal?
  52. Copper deprivation reprograms antioxidant defense to suppress ferroptosis via SLC7A11.
  53. The pivotal role of metabolism in shaping tumor-associated macrophages phenotype and function.
  54. Systemic Cysteine Elevation Sustains T-Cell Activation to Potentiate PD-1 Blockade.
  55. mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
  56. An enzymatic-metabolic sensing axis in taste cells detects glucose-yielding carbohydrates.
  57. Cancer type-specific variation in patterns of driver alterations across 50,000 tumors.
  58. Dietary interventions in acute kidney injury: From molecular mechanism to clinical trials.
  59. TRIM69 potentiates the cGAS-STING signalling pathway by promoting STING ubiquitination.
  60. PCDHGC3 silencing promotes clear cell renal cell carcinoma metastasis via mTOR/HIF2α activation, lipid metabolism rewiring, and ferroptosis evasion.
  61. Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.
  62. When stress signals to skin: Sympathetic nerves tune immune surveillance.
  63. Biomolecular condensates mediate C-N bond formation.
  64. Simulated Microgravity Recapitulates Aspects of Biological Aging in Humans.
  65. Ribosome Molecular Aging Shapes Translation Dynamics.
  1. Nat Metab. 2026 Mar 27.
    Snake postprandial metabolite shows cross-species activation of hypothalamic neurons.
      
    DOI:  https://doi.org/10.1038/s42255-026-01488-x
  2. Cell Metab. 2026 Mar 24. pii: S1550-4131(26)00093-8. [Epub ahead of print]
    Mitochondrial lactate venting limits oxidative stress.
    Daniela Rauseo, Yasna Contreras-Baeza, Mildreth Salazar, Abigail J Galarza, Sebastián Holtheuer-Gallardo, Hugo Faurand, Natali Cárcamo-Lemus, Raibel Suárez, Joel L Asenjo, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Jan Dernic, Luca Ravotto, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.
      Lactate has been proposed to enter mitochondria and fuel respiration, but this "intracellular lactate shuttle" remains controversial. Using genetically encoded lactate and redox sensors in cultured cells and neurons in vivo, we identify a dynamic lactate pool within the mitochondrial matrix that tracks extracellular and blood lactate and promotes lactylation of mitochondrial proteins. Lactate crosses the inner mitochondrial membrane through a saturable pathway that is partly sensitive to pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC). Despite transport and matrix lactate dehydrogenase activity, lactate does not measurably energize the electron transport chain under the conditions tested. Instead, energized mitochondria can produce lactate from pyruvate, a response enhanced by hypoxia. Blocking MPC causes matrix lactate and H₂O₂ accumulation, revealing a rapid lactate-based "vent" that modulates matrix energy and reactive oxygen species.
    Keywords:  genetically encoded fluorescent indicator; hypoxia; lactate; lactate dehydrogenase; membrane transport; metabolism; mitochondrial pyruvate carrier; monocarboxylate transporter; pyruvate; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.020
  3. bioRxiv. 2026 Mar 20. pii: 2026.03.18.712640. [Epub ahead of print]
    Discovery of metabolites produced by reactions between central carbon metabolites and cysteine that mark inflammatory macrophages.
    Nicholas L Arp, Felicia Deng, Jorgo Lika, Gretchen L Seim, Paulo Falco Cobra, Carlos Mellado Fritz, Steven V John, Swetha Rathinaraj, Bridget E Shields, Daniel Amador-Noguez, Katherine Henzler-Wildman, Jing Fan.
      Identifying metabolites and metabolic reactions specific to a cellular state, such as inflammatory state in immune cells, is of great interest, as it can provide important biomarkers and point to compounds and reactions of specific biological functions. However, many cell state-specific metabolites remain in the unannotated part of metabolome. Here we identified a series of sulfur-containing metabolites that are actively produced in macrophages upon classical activation, but not in resting state or alternative activation state. Isotopic tracing, in vitro assays and genetic perturbations further revealed that they are formed from reactions between free cysteine and several important intermediates in glycolysis and TCA cycle. Upon classical activation, macrophages specifically upregulate the import of cystine via Slc7a11 , supporting the production of these adducts. Their production dynamically responds to changes in central metabolism, environmental nutrient levels, and is regulated by nitric oxide. Finally, we confirmed these newly identified compounds also present in human samples, and most of them are significantly elevated in inflammatory granuloma annulare lesions. This work elucidated a previously uncharted part of metabolic network that is associated with inflammation and metabolic stress condition, which has important implications and set foundation for many future discoveries.
    DOI:  https://doi.org/10.64898/2026.03.18.712640
  4. Oncogenesis. 2026 Mar 26.
    The oncogenic control of nucleotide synthesis.
    Olivia Vidal-Cruchez, Issam Ben-Sahra.
      Proliferating cancer cells reprogramme metabolism to secure nucleotides and other macromolecules required for biomass accumulation and genome duplication. Beyond serving as DNA/RNA precursors, nucleotides act as energy currencies, second messengers, glycosyl donors, and modulators of cytoskeletal dynamics; sustaining adequate pools is therefore indispensable for tumour growth and progression. Oncogenic lesions, such as loss of TP53 or LKB1, hyperactive PI3K-AKT-mTORC1, and MYC or RAS, coordinate transcriptional programmes, substrate transport, and post-translational control of rate-limiting enzymes to elevate de novo purine and pyrimidine synthesis and shape salvage use. These circuits integrate glycolysis, the pentose-phosphate pathway, folate-dependent one-carbon metabolism, and glutamine/aspartate provisioning to channel carbon and nitrogen into ring assembly. In this review, we organize this landscape into an environment-shaped routing model that explains when tumours favour de novo versus salvage and how therapies reroute flux. We synthesise current mechanisms by which oncogenes and tumour suppressors regulate nucleotide synthesis in cancer and outline therapeutic implications, including inhibitors of pathway enzymes (e.g., DHODH, IMPDH), strategies that restrict precursor availability, and rational combinations with targeted agents or DNA-damaging therapies to exploit replication stress and metabolic vulnerabilities. Together, these insights highlight nucleotide metabolism as a central, drug-responsive nexus linking oncogenic signalling to malignant proliferation.
    DOI:  https://doi.org/10.1038/s41389-026-00608-2
  5. Nat Metab. 2026 Mar 26.
    Often forgotten but essential: long-chain acyl-CoAs in metabolic control.
    Nils J Færgeman.
      
    DOI:  https://doi.org/10.1038/s42255-026-01509-9
  6. Trends Endocrinol Metab. 2026 Mar 25. pii: S1043-2760(25)00267-X. [Epub ahead of print]
    Mitochondrial NADP(H) integrates redox and metabolism.
    Ren Zhang, Kezhong Zhang.
      The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.
    Keywords:  NAD(H); NADK2; NADP(H); fatty acid oxidation; mitochondria; redox
    DOI:  https://doi.org/10.1016/j.tem.2025.12.003
  7. bioRxiv. 2026 Mar 16. pii: 2026.03.13.711696. [Epub ahead of print]
    O-GlcNAcylation regulates PPAR-driven metabolic programming in intestinal stem cells.
    Thomas Hartley McDermott, Dominic R Saiz, Yesenia Barrera Millan, Ngoc Bao Phuong Ho, Matthew Torel, Eric Uher, Caleb Aboagye, Fiona Farnsworth, Gourab Lahiri, Venkataramana Thiriveedi, Jinhua Chi, Haiwei Gu, Charlie Fehl, Benjamin B Bartelle, Miyeko D Mana.
      Diet deeply influences health and disease risk by reshaping cellular metabolism. In the intestine, dietary nutrients directly affect intestinal stem cell (ISC) behavior, yet the regulatory mechanisms linking metabolism to transcriptional control remain poorly defined. Because mitochondria function as central metabolic hubs, we focused on mitochondrial signaling to understand how nutrient utilization governs ISC function. Using the MITO-Tag mouse, we isolated metabolites specifically from ISC mitochondria and found that the sugar-derived metabolite UDP-GlcNAc was reduced in ISCs from mice fed a high-fat diet. Moreover, we identified that reducing O-GlcNAcylation (OGN) rapidly increased stem cell frequency, proliferation, regenerative capacity, and the abundance of PPAR target proteins. Mechanistically, these effects depend on PPAR signaling, as genetic loss of Ppar-d/a blocks the ISC phenotypes induced by reduced OGN. These results reveal an OGN-PPAR signaling axis that translates dietary metabolic cues into transcriptional programs governing fuel utilization and ISC behavior in the intestine. Collectively, our findings highlight that OGN is a previously unrecognized regulator of PPAR signaling in intestinal stem cells.
    DOI:  https://doi.org/10.64898/2026.03.13.711696
  8. Neuro Oncol. 2026 Mar 21. pii: noag063. [Epub ahead of print]
    The 1p/19q co-deletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas.
    Suresh Udutha, Georgios Batsios, Céline Taglang, Anne Marie Gillespie, Pavithra Viswanath.
       BACKGROUND: The 1p/19q co-deletion is a hallmark of oligodendrogliomas. The goal of this study was to exploit the metabolic vulnerabilities induced by the 1p/19q co-deletion for the treatment and imaging of oligodendrogliomas.
    METHODS: We used stable isotope tracing, mass spectrometry, and genetic and pharmacological approaches to interrogate [U-13C]-glucose metabolism in patient-derived oligodendroglioma models (SF10417, BT88, BT54, TS603, NCH612). We examined whether tracing [6,6'-2H]-glucose metabolism using deuterium metabolic imaging (DMI) provided an early readout of treatment response.
    RESULTS: The glycolytic enzyme enolase 1 (ENO1; chromosome 1p36.23) was downregulated in patient-derived oligodendroglioma cells and patient tissue due to the 1p/19q co-deletion and histone hypermethylation. Conversely, inactivation of the CIC transcriptional repressor, driven by activated mitogen-activated protein kinase (MAPK) signaling, upregulated the ENO2 isoform specifically in oligodendrogliomas. Genetic ablation of ENO2 or pharmacological inhibition using POMHEX inhibited proliferation with nanomolar potency but was not cytotoxic to oligodendroglioma cells. Mechanistically, ENO2 loss abrogated [U-13C]-glucose metabolism to lactate but shunted glucose towards biosynthesis of serine and purine nucleotides, an effect that was driven by the rate-limiting enzyme for serine synthesis, phosphoglycerate dehydrogenase (PHGDH). Importantly, combining the PHGDH inhibitor D8 with POMHEX resulted in synthetic lethality in vitro and induced tumor regression in vivo. Furthermore, DMI of lactate production from [6,6'-2H]-glucose provided an early readout of response to combination therapy that preceded MRI-detectable alterations and reflected extended survival.
    CONCLUSIONS: We have identified ENO2 and PHGDH as metabolic vulnerabilities induced by the 1p/19q co-deletion in oligodendrogliomas and [6,6'-2H]-glucose as a non-invasive tracer of early response to therapy.
    Keywords:  ENO2; Oligodendroglioma; PHGDH; deuterium metabolic imaging; serine biosynthesis
    DOI:  https://doi.org/10.1093/neuonc/noag063
  9. Trends Cancer. 2026 Mar 24. pii: S2405-8033(26)00038-5. [Epub ahead of print]
    Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.
    Hendrik A Messal, Larissa Mourao, Lea Dörner, Colinda L G J Scheele, Jacco van Rheenen.
      Understanding tumor initiation is crucial for early interception and prevention. Tumors arise from genetic alterations and microenvironmental changes that together create a niche for malignant growth. Previously, the spatiotemporal dynamics of tumorigenesis were difficult to study. Recent advances in high-resolution intravital microscopy, tissue clearing, and spatial molecular profiling enable direct visualization of mutated cells and clones within their microenvironment in situ. These tools transform tumor initiation from a theoretical construct into a mechanistically dissectible process. Here, we synthesize recent insights into how mutated clones expand or regress, how clonal dynamics drive transformation, and how niche signals shape tumor-initiating cell fate. We highlight key imaging innovations and outline limitations and opportunities for capturing tumor initiation in vivo.
    Keywords:  clonal dynamics; intravital microscopy; spatial transcriptomics; tissue clearing; tumor initiation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.007
  10. Trends Mol Med. 2026 Mar 24. pii: S1471-4914(26)00033-X. [Epub ahead of print]
    Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?
    Ersong Shang, Omar Aftab, Abbienaya Dayanamby, Laura C Greaves.
      Mitochondria, once viewed mainly as cellular powerhouses, are now recognised as key regulators of cancer metabolism, redox balance, and immune interactions. While early models emphasised a switch to aerobic glycolysis, many tumours exhibit metabolic plasticity and retain oxidative phosphorylation capacity. Mitochondrial DNA (mtDNA) mutations are common across cancers, yet their roles in carcinogenesis and therapy response remain unclear. Emerging base-editing technologies now enable modelling of these mutations, allowing the exploration of their impact on tumourigenesis, which may differ depending on mutation type, heteroplasmy, and tissue origin. mtDNA alterations also shape immune responses within the tumour microenvironment and therefore may influence treatment sensitivity. This review integrates recent advances on mtDNA's role in cancer biology and explores therapeutic opportunities for targeting mitochondrial metabolism.
    Keywords:  DNA, mitochondrial; genes, neoplasm; neoplasms; oxidative phosphorylation; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.molmed.2026.02.003
  11. EMBO J. 2026 Mar 24.
    Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
    Mitsuhiro Nishigori, Serina Hirata, Hidetaka Kosako, Takeshi Ichinohe, Hendrik Nolte, Jan Riemer, Thomas Langer, Takumi Koshiba.
      Mitochondrial proteases regulate dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, although only a few of its direct functional targets have been characterized. Using in vitro and in vivo multiproteomic and biochemical approaches, we here demonstrate that the membrane-anchored intermembrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive OMA1 substrate. Under stress conditions, OMA1 cleaves AIFM1 in the IMS with slower kinetics than its conventional substrate, the dynamin-like GTPase OPA1. OMA1-mediated dislocation of cleaved AIFM1 from the mitochondrial inner membrane reduces its interaction with oxidative phosphorylation subunits, thereby decreasing respiratory activity and impairing cell growth. Furthermore, we reveal that under steady-state conditions AIFM1 broadly safeguards the mitochondrial proteome by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. Similar changes to the mitochondrial proteome occur in the lungs of virally infected mice, accompanied by stress-inducible AIFM1 processing. These findings identify OMA1 as a key integrator of mitochondrial stress and cellular energetics through AIFM1 remodeling.
    Keywords:  AIFM1; Mitochondrial Stress; OMA1; OXPHOS Activity; Proteolysis
    DOI:  https://doi.org/10.1038/s44318-026-00734-y
  12. Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00235-4. [Epub ahead of print]45(4): 117157
    Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.
    Jong Woo Kim, Seo Young Jang, Yeon Jin Roh, Yeajin Ju, Ju-Bin Kang, Byung-Sun Park, Ji-Yoon Lee, Min Wook Kim, Byung Jun Jeong, Woosung Jung, Kyoung-Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang-Hee Bae, Tackhoon Kim, Yun Pyo Kang, Hee Min Yoo, Chuna Kim, Scott J Dixon, Dong Wook Choi, Geum-Sook Hwang, Eun-Woo Lee.
      Ferroptosis is a lipid peroxidation-induced cell death mechanism that is regulated by amino acid metabolism. Cystine deprivation induces ferroptosis, but ferroptosis execution requires other amino acids. While methionine contributes to several metabolic pathways, including transsulfuration (TS), its role in ferroptosis remains controversial. Here, we report that methionine is required for ferroptosis triggered by cysteine deprivation. Notably, the TS pathway and methionine cycle in lung cancer cells are largely inactive, and methionine is instead funneled into polyamine synthesis via the methionine salvage route. Methionine depletion provokes metabolic shifts that dampen glutamine catabolism via the glutamine-methionine bi-cycle. Furthermore, methionine depletion alters phospholipid metabolism by promoting ACSL4 degradation, limiting polyunsaturated fatty acid (PUFA) incorporation into phospholipids. The methionine cycle intermediate S-adenosylmethionine (SAM) supplementation is sufficient to restore the perturbed metabolic state and ferroptosis sensitivity. Taken together, the results of this study highlight methionine as a key coordinator of ferroptosis through dynamic metabolic remodeling.
    Keywords:  ACSL4; CP: metabolism; CP: molecular biology; ferroptosis; glutaminolysis; methionine; methionine salvage pathway; phospholipid metabolism; transsulfuration pathway
    DOI:  https://doi.org/10.1016/j.celrep.2026.117157
  13. Cell Rep. 2026 Mar 20. pii: S2211-1247(26)00227-5. [Epub ahead of print]45(4): 117149
    Subversion of kynurenine-induced AHR activation in CD8 T cells by kynureninase-expressing antigen-presenting cells.
    Michael A Giacomantonio, Vishnu Vijay Vijayan, Preethi G Nair, Gopal P Pathak, Barry E Kennedy, Joao A Paulo, Teresa McMillen, Anurag Banerjee, Vishnupriyan Kumar, Mukhayyo Sultonova, Tayah Sommer, Nisha Owens, Unnikrishnan Babukuttan Sheela, Jawairia Atif, Sonya A MacParland, Steven P Gygi, J Patrick Murphy, Shashi Gujar.
      Kynurenine, an intermediate metabolite of tryptophan metabolism, suppresses the antitumor activity of CD8+ T cells by activating the aryl hydrocarbon receptor (AHR). Its role in adaptive immunity is poorly understood. Outside the liver, kynurenine is mainly produced by indoleamine 2,3-dioxygenase 1 (IDO1) and further degraded by kynureninase (KYNU). This report shows that KYNU is predominantly expressed in human and mouse antigen-presenting cells (APCs) in vivo, GM-CSF-differentiated macrophages and dendritic cells in vitro, and alveolar macrophages collected in situ, and is functionally active in breaking down kynurenine into catabolic products without contributing toward de novo NAD+ synthesis. Importantly, while CD8+ T cells uptake kynurenine, they lack active KYNU, leading to AHR-dependent immunosuppression. However, KYNU-expressing APCs can deplete extracellular kynurenine, prevent AHR activation, and restore IFN-γ production in CD8+ T cells. This highlights the importance of KYNU-expressing APCs in combating kynurenine-induced immune suppression against tumors.
    Keywords:  CD8(+) T cells; CP: cancer; CP: metabolism; GM-CSF; IDO1; KYNU; alveolar macrophages; antigen-presenting cells; antitumor immunity; bone marrow; kynureninase; kynurenine pathway; macrophage metabolism; tryptophan catabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117149
  14. Cancer Cell. 2026 Mar 26. pii: S1535-6108(26)00114-5. [Epub ahead of print]
    Immunometabolic gatekeeping: How tissue metabolism conditions tumor immunity.
    Naomi Iris van den Berg, Matouš Elphick, Kevin Mulder, Omar Bouricha, Omid Sadeghi-Alavijeh, Xiao Fu, Samra Turajlic.
      Why the link between immune infiltration and tumor control varies so strongly across tissues remains unresolved. We propose the "immunometabolic gatekeeping" framework, whereby tissue-intrinsic metabolic activity and waste-handling capacity shape anti-tumour immunity. In high-flux tissues, metabolic stress impairs immune surveillance, decoupling infiltration from control and allowing tumor outgrowth. This framework explains cancer paradoxes-including T cell prognostic heterogeneity, hereditary and pediatric tumor tropisms, sex-biased tumor incidence, and cancer-resistant species-and suggests metabolism-aware strategies for cancer prevention and immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.002
  15. J Clin Invest. 2026 Mar 24. pii: e201639. [Epub ahead of print]
    Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.
    Jun Fang, Jeremy M Simon, Tao Wang, Yunpeng Gao, Xianju Bi, Lianxin Hu, Chengheng Liao, Cheng Zhang, Yayoi Adachi, Jin Zhou, Hongyi Liu, Qian Liang, James A Nathan, Ram Mani, James Brugarolas, Qing Zhang.
      Resistance to HIF-2α inhibitors such as Belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1-STAT3 signaling pathway. Using a genome-wide CRISPR screen in VHL-deficient ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1-STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of EPAS1 that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in ccRCC patient samples and functionally validated using CRISPR interference, which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2α-dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1/STAT3 markedly suppressed HIF-2α expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1-STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.
    Keywords:  Cancer; Epigenetics; Genetics; Hypoxia; Oncology
    DOI:  https://doi.org/10.1172/JCI201639
  16. Science. 2026 Mar 26. 391(6792): eadz6830
    Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
    Christopher J Cowley, Sairaj M Sajjath, Luis F Soto-Ugaldi, Mara Steiger, Samantha B Larsen, Thomas Carroll, Douglas Barrows, Alexandra Mattei, Kevin A U Gonzales, Wei Wang, Kevin Li, Alexander Meissner, Helene Kretzmer, Dana Pe'er, Elaine Fuchs.
      Tissues harbor memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.
    DOI:  https://doi.org/10.1126/science.adz6830
  17. Sci Immunol. 2026 Mar 27. 11(117): eaeb1459
    Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity.
    Silvia Tiberti, Sara Gennari, Martina Romeo, Ilir Sheraj, Mohamed Faisal Kassir, Juan Fernández-García, Carina B Nava Lauson, Roberta Noberini, Carlotta Catozzi, Tiziano Dallavilla, Mattia Ballerini, Alessia Loffreda, Simona G Codreanu, Stacy D Sherrod, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, John A McLean, Martin H Schaefer, Simona Rodighiero, Tiziana Bonaldi, Sarah-Maria Fendt, Besim Ogretmen, Sara Sdelci, Luigi Nezi, Teresa Manzo.
      Lipid accumulation in the tumor microenvironment is a hallmark of solid tumors, with increased palmitate (PA) availability fostering tumor progression. Although PA's direct effects on cancer cells are well described, its impact on CD8 T cells [cytotoxic T lymphocytes (CTLs)] remains unclear. Here, we show that PA irreversibly impairs CTL mitochondrial metabolism, leading to the loss of effector functions and compromised antitumor immunity. PA-induced mitochondrial dysfunction reduced histone acetylation and chromatin accessibility, suppressing transcription of genes involved in T cell replication and effector programs. We identified sphingosine kinase 2 (SPHK2) as a key mediator of PA-induced dysfunction, with pharmacological inhibition of SPHK2 restoring mitochondrial fitness, rescuing CTL effector function, and promoting antitumor activity. These findings uncover a distinct mechanism by which PA drives immune evasion in tumors and highlight SPHK2 as a potential therapeutic target to enhance T cell-based immunotherapies.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb1459
  18. Cell Metab. 2026 Mar 23. pii: S1550-4131(26)00085-9. [Epub ahead of print]
    Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1.
    Ayaka Sugiura, Katherine L Beier, Channing Chi, Darren R Heintzman, Xiang Ye, Melissa M Wolf, Andrew R Patterson, Jacqueline-Yvonne Cephus, Hanna S Hong, Jeffrey M Perera, Costas A Lyssiotis, Dawn C Newcomb, Jeffrey C Rathmell.
      Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4+ T cell subset requirements for specific AAs remains uncertain. Here, we tested CD4+ T cell AA demands with in vitro and in vivo CRISPR screens and identified subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion in vivo in lung inflammation, SLC38A1 was critical for Th1, but not Th17, cell-driven experimental autoimmune encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing glutamine uptake and disrupting hexosamine biosynthesis and redox regulation. Pharmacological inhibition of SLC38 transporters also delayed Th1-mediated EAE but did not affect lung inflammation. CD4+ T cells thus have subset- and tissue-specific nutrient transporter dependencies that may guide new metabolic approaches for selective immunotherapies.
    Keywords:  Slc38a1; T cell; amino acid transport; glutaminolysis
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.016
  19. Nat Metab. 2026 Mar;8(3): 587-603
    PLIN5 phosphorylation orchestrates mitochondria lipid-droplet coupling to control hepatic lipid flux and steatosis.
    Sun Woo Sophie Kang, Lauryn A Brown, Colin B Miller, Katherine M Barrows, Jihye L Golino, Hanyang Liu, Constance M Cultraro, Daniel Feliciano, Mercedes B Cornelius-Muwanuzi, Kirsten Remmert, Jonathan M Hernandez, Andy D Tran, Michael Kruhlak, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      Steatotic liver disease is common, yet the mechanisms by which hepatocytes cope with surges in dietary fatty acids remain unclear. Here we use single-cell tissue imaging (scPhenomics) and spatial proteomics to map lipid handling across dietary states. Fasting remodeled mitochondria and lipid droplets (LDs), increasing mitochondria-LD contacts, whereas contacts were infrequent in Western diet (WD)-fed male mice. Fasting also elevated perilipin-5 (PLIN5), a mediator of mitochondria-LD tethering. PLIN5 overexpression modulated contact formation in a phosphorylation-dependent manner: the S155A variant enhanced organelle contacts and LD expansion, whereas the S155E variant reduced contacts and yielded fewer, smaller LDs. Overexpression of the S155A variant in WD reduced lipotoxicity. These data reveal an adaptive organelle-interaction program that channels lipids during nutrient stress and is attenuated by an obesogenic diet. Our work establishes scPhenomics for spatially resolved cell-state analysis and identifies PLIN5 phosphorylation as a lever to tune hepatocyte lipid flux, suggesting therapeutic potential for targeting mitochondria-LD coupling.
    DOI:  https://doi.org/10.1038/s42255-026-01476-1
  20. bioRxiv. 2026 Mar 02. pii: 2026.02.28.707294. [Epub ahead of print]
    Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.
    Katia E Niño, Vera Adema, Alyx E Gray, Courtney M Cowan, Wolfgang E Schleicher, Mohsen Hosseini, Sierra N Bennett, Sweta B Patel, Steven Moreira, Etienne Danis, Feiyang Ma, Hsin-Ying Lin, Tracy N Young, Colin A Anderson, Devyani Sharma, Angelica Varesi, Marie-Dominique Filippi, Keisuke Ito, Meelad M Dawlaty, Gang Huang, Julie A Reisz, Stephanie Z Xie, Steven M Chan, Lin Tan, Guillermo Garcia-Manero, Kelly Chien, Irene Gañan Gomez, Angelo D'Alessandro, Simona Colla, Eric M Pietras.
      The mechanism(s) driving selective expansion of mutant hematopoietic stem and progenitor cells (HSPC) in clonal hematopoiesis (CH) are incompletely understood. Here, we address the role of metabolism in selection for HSPC with loss of function mutations in TET2 . Loss of Tet2 in murine HSPC triggers overexpression of glycolysis and oxidative phosphorylation genes and increased oxidative metabolism via an enlarged mitochondrial network. However, Tet2 -deficient HSPC maintain a normal redox state. Strikingly, compound loss of the rate-limiting pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) triggers increased reactive oxygen species and impairs the fitness of Tet2 -deficient HSPC. We find that aberrant oxidative metabolism is also a feature of HSPC in human CH and clonal cytopenia of unknown significance (CCUS). Overall, our data point to aberrant metabolism as a critical and conserved driver of selection in TET2 -deficient CH and identify the PPP as a crucial compensatory pathway needed to maintain their selective advantage.
    Statement of Significance: This study identifies oxidative metabolism as a critical driver of selection for TET2 -deficient HSPC in clonal hematopoiesis (CH). It also demonstrates that cellular redox state is a vulnerability that impairs their fitness. These insights establish targetable metabolic pathway(s) that could be exploited in the setting of TET2 mutant CH.
    DOI:  https://doi.org/10.64898/2026.02.28.707294
  21. Autophagy. 2026 Mar 22. 1-2
    Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
    Julia A Thayer, Derek P Narendra.
      Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.
    Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2646238
  22. Amino Acids. 2026 Mar 24.
    Adaptive crosstalk between polyamine metabolism, translation, and autophagy sustains energy homeostasis in mammals during starvation: a scoping review.
    Kayhan Karimi, Sigrid C Roberts, Nicola S Carter, Sebastian J Hofer, Reza Karimi.
      Mammalian cells tightly regulate the shift between catabolism and anabolism to maintain energy homeostasis during starvation. Among other adaptations, cells adapt to nutrient restriction by downregulating translation, the most energy consuming cellular process, and inducing autophagy. Polyamines are ubiquitous small polycationic endogenous metabolites indispensable for cellular growth and viability. They regulate both autophagy and translation processes, coordinating an intriguing metabolic hub during cellular adaptation to starvation. Recent studies have highlighted a complex role for polyamines during starvation and a growing body of evidence underscores various nutrients and nutrient-sensing pathways that modulate autophagy through their influence on the mammalian target of rapamycin complex 1 (mTORC1) signaling. mTORC1 is a master regulator of cellular anabolism, including translation. Less explored is how these coordinated systems adapt and respond to starvation. This scoping review explores how changes in polyamine metabolism and related molecules orchestrate the adaptive crosstalk between autophagy, mTORC1, and translation to ensure that the mammalian cell conserves energy to maintain essential cellular functions during starvation. Our review highlights that spermidine and one of its major cellular targets, translation initiation factor 5A (eIF5A), facilitate translation of transcription factor EB (TFEB) to induce autophagy during starvation. Starvation suppresses mTORC1 activity, leading to reduced ribosome biogenesis and translation while promoting autophagy to meet cellular energy demands. We discuss the adaptive mechanisms by which reduced levels of acetyl-CoA, amino acids, EP300, glucose, insulin, and S-adenosylmethionine inhibit mTORC1 and simultaneously induce autophagy. Additionally, we describe the adaptive role that glucagon, Sestrin2, and urea play to inhibit mTORC1 and how eIF5A, glucagon, spermidine, and TFEB induce autophagy.
    Keywords:  Amino acids; Autophagy; Mammals; Spermidine; Translation; mTORC1
    DOI:  https://doi.org/10.1007/s00726-026-03512-6
  23. Nat Metab. 2026 Mar 26.
    Atlas of one-carbon metabolism in conventional and germ-free mice reveals folate as a key determinant of biochemical pathways.
    Jonathan Williams, Woo Sung Kim, Rebecca Danner, Juyeong Cho, Bianca F Silva, David A Harris, Federico E Rey, Snehal N Chaudhari.
      Folates participate in the one-carbon metabolism (OCM) cycle, supporting many biochemical pathways. Existing methods to profile folate are limited in the diversity of vitamers they measure and the samples they profile. Here we present a metabolomics workflow for stable extraction, separation and measurement of folates, along with precursors and products of OCM-associated pathways. We profile these metabolites in 37 mouse tissues to chart an interactive 'OCM atlas' ( https://chaudharilab.com/folate-atlas/ ), revealing vast heterogeneity across organs and an uncharacterized folate derivative. We discover that, in adult mice, the gut microbiota is a consumer of folate and folate polyglutamylation in the host is not regulated by folate availability. Germ-free mice show tissue-specific shifts in methyl donor abundances relative to conventionally raised mice, indicative of altered DNA methylation. Correlation analyses uncover the central roles of folates in potentially modulating other biochemical pathways in tissues, thus linking microbial folate consumption directly to its global impacts on host metabolism.
    DOI:  https://doi.org/10.1038/s42255-026-01489-w
  24. bioRxiv. 2026 Mar 18. pii: 2026.03.16.712182. [Epub ahead of print]
    The pyruvate branch point controls lymphoid cancer cell dissemination.
    Hamidullah Khan, Steven John, Sushmita Roy, Mohd Farhan, Nguyet Minh Hoang, Patrick Buethe, Aman Prasad, Aman Nihal, David T Yang, Lixin Rui, Jing Fan, Stefan M Schieke.
      Cancer cell dissemination critically determines clinical prognosis, yet metabolic dependencies and corresponding therapeutic targets during spread of lymphoid malignancies remain poorly understood. Here we show that the pyruvate branch point operates as a metabolic checkpoint for lymphoid cancer cell migration and disease dissemination through mitochondrial ROS (mROS)/HIF-1a signaling. Isolation of highly migratory mROS hi cells led us to identify selective metabolic requirements of malignant lymphocyte migration and disease dissemination. Highly migratory cells show a reprogrammed metabolic profile characterized by increased glucose uptake and reduced glucose-carbon entry into the TCA cycle. Reprogramming of the TCA cycle with downregulation of citrate synthase provide the mechanistic basis for decreased pyruvate oxidation leading to increased migration and disease dissemination through mROS/HIF-1a signaling. Our findings connect central carbon metabolism and migratory capacity of lymphoid cancer cells and identify the pyruvate branch point as a metabolic switch and potential therapeutic target in lymphoid cancer cell dissemination.
    DOI:  https://doi.org/10.64898/2026.03.16.712182
  25. bioRxiv. 2026 Mar 18. pii: 2026.03.18.712680. [Epub ahead of print]
    Midgestation metabolic constraint in purine metabolism drives distinct strategies for placenta and fetal growth.
    Weizhi Xu, Nancy De La Cruz, Andrea Woods, Dmitry Lokshtanov, Shihong Gao, Nawal Khan, Sylvia Wright, Maria E Florian-Rodriguez, Donald D McIntire, Elaine L Duryea, David B Nelson, Catherine Y Spong, Christina L Herrera, Jacob H Hanna, Sanjay Srivatsan, Alejandro Aguilera-Castrejon, Ashley Solmonson.
      Purine nucleotides are essential for mammalian development 1,2 . Purine monophosphates support cell signaling and proliferation and are synthesized by cells through either de novo synthesis or a salvage pathway 3 . We previously identified a midgestational metabolic transition in mice (gestational days gd10.5-11.5) characterized by changes in purine metabolism 4 . Midgestation is a period of rapid growth for placenta and embryo, yet it remains unclear how the placental tissues expand without directly competing with the embryo for biosynthetic resources. Here, we show that this midgestational metabolic transition is associated with a marked reduction in embryonic expression of purine salvage enzymes, which constrains embryonic metabolism and leads to different strategies for purine synthesis between the placenta and embryo. Midgestation embryos are unable to engage the purine salvage pathway even when de novo purine synthesis is blocked either in vivo or in ex utero embryo culture, whereas placental tissue and trophoblasts retain the capacity to use either pathway. Disruption of de novo purine synthesis in mice causes reduced embryonic growth, impaired axial elongation, and abnormal brain and placental development, which are only partially rescued by supplementation with purine salvage precursors. In human placenta, trophoblast stem cells readily switch between the de novo and salvage pathways based on nutrient availability, and syncytiotrophoblasts (STB) preferentially rely on the salvage pathway. We identified guanosine monophosphate (GMP) as a metabolic checkpoint regulating STB differentiation, with insufficient GMP levels causing degradation of the small GTPase Rheb and failure of mTOR activation. Supplementation of purine salvage substrates restored GMP synthesis and STB differentiation in humans, but not mice. Further, in vivo measurements in humans revealed that maternal circulating hypoxanthine decreases during pregnancy and is further reduced in women with clinically small placentas, highlighting the role of hypoxanthine in supporting placental growth. These results uncover compartmentalized purine salvage between the embryo and placenta as a mechanism that limits competition for biosynthetic resources and enables coordinated growth during mammalian development.
    DOI:  https://doi.org/10.64898/2026.03.18.712680
  26. Cell. 2026 Mar 20. pii: S0092-8674(26)00116-9. [Epub ahead of print]
    The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
    Ngee Kiat Chua, Tania J González-Robles, Cameron J Reddington, Jane Dudley-Fraser, Richard W Birkinshaw, Jiru Han, Ashleigh Solano, Soon Wei Wong, Tomasz Kochańczyk, Joshua J Peter, Mark A Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Alex Garnham, Hannah Huckstep, Matthew E Ritchie, Ingrid Wertz, Sarah Hymowitz, Sharad Kumar, Ron C Conaway, Gilbert G Privé, Alex N Bullock, Jeffrey J Babon, Rachel E Klevit, Sonja Lorenz, Alessio Ciulli, Eric S Fischer, Nicolas H Thomä, Radosław P Nowak, Brenda A Schulman, Michael Rapé, Katrin Rittinger, Julia K Pagan, Melanie Bahlo, Joel P Mackay, Peter D Mace, Christopher D Lima, Ronald T Hay, David Komander, Bernhard C Lechtenberg, Claudio A P Joazeiro, Michele Pagano, Kay Hofmann, Rebecca Feltham.
      To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.
    DOI:  https://doi.org/10.1016/j.cell.2026.01.029
  27. bioRxiv. 2026 Mar 20. pii: 2026.03.19.713005. [Epub ahead of print]
    A structure-selective endonuclease drives uniparental mitochondrial DNA inheritance.
    Mayu Shimomura, Hwa Young Yun, Philip C Zuzarte, Jared T Simpson, Haley D M Wyatt, Thomas R Hurd.
      Maternal inheritance of mitochondrial DNA (mtDNA) is a near-universal feature of eukaryotes 1 , yet the mechanisms that ensure this by preventing paternal mtDNA inheritance have remained unclear. In both Drosophila and humans, mtDNA is actively eliminated from sperm during spermatogenesis, producing mature sperm whose mitochondria lack their genomes 2-5 . Here we identify Hotaru, a previously uncharacterized, testis-specific GIY-YIG endonuclease, as a central player in this process. We find that Hotaru is expressed in elongated spermatids, localizes to the mitochondrial matrix, and is required for paternal mtDNA elimination. In hotaru mutants, sperm retain mtDNA at levels comparable to those present before the elimination process. Genetic and biochemical analyses show that Hotaru selectively recognizes and cleaves cruciform DNA structures within the mtDNA control region. Together, these findings identify a dedicated nuclease that enforces mitochondrial genome elimination in the animal male germline and reveal that an unexpected structural feature of mtDNA serves as the molecular determinant of its destruction. By recognizing DNA structure rather than specific sequence motifs, this mechanism is inherently robust to the high mutation rate of mitochondrial genomes.
    DOI:  https://doi.org/10.64898/2026.03.19.713005
  28. Nat Commun. 2026 Mar 24.
    Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
    Giulio Di Minin, Anna B Rüegg, Kevin Halter, Tobias Fuhrer, Tatjana Kleele, Nicola Zamboni, Anton Wutz.
      A hallmark of mammals is a diploid genome. Despite constraints from dosage compensation and imprinting, haploid embryonic stem cells can be established. However, rapid diploidization is observed in such cultures from mice, rats, and humans, limiting their use and indicating counterselection of a haploid genome. Here, we use metabolic profiling to discover that diploidization is triggered by an imbalance that arises from a smaller cytoplasmic volume and increased mitochondrial density. Reduced respiration causes a change in redox potential, leading to increased NADPH. Conversely, we demonstrate that NADPH oxidation in the mitochondria is sufficient to stabilize the haploid genome. We further show that the redox change leads to reduced AURORA kinase activation on chromosomes, connecting metabolic state to mitotic regulation. Our data, therefore, identify a mitochondrial metabolic imbalance as the root cause of diploidization and connect redox dysregulation to karyotypic instability.
    DOI:  https://doi.org/10.1038/s41467-026-70939-6
  29. Cell Stem Cell. 2026 Mar 23. pii: S1934-5909(26)00081-0. [Epub ahead of print]
    Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.
    Ashley N Kamimae-Lanning, Jill M Brown, Matthias Günther, Franziska Esau, Holly Russell, Lise Larcher, Frédéric Langevin, Tomoya Isobe, Nicola K Wilson, Felix A Dingler, Rebecca L Cordell, Meng Wang, Christopher L Millington, Nina Claudino, Ewa Gogola, Matthew Nicholls, Verena Körber, Berthold Göttgens, Marella F T R de Bruijn, Juan I Garaycoechea, Jean Soulier, Thomas Höfer, Ketan J Patel.
      DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial for embryonic HSC emergence and throughout life. Despite severe deficiencies in HSCs, these mice produced blood for many months. To determine what enables this, we employed an unbiased method for detecting clones, which exploits somatic variant data. This revealed initial polyclonal hematopoiesis that diminishes to monoclonal hematopoiesis, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to the last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.
    Keywords:  Fanconi anemia; HSC attrition; bone marrow failure; clonal hematopoiesis; endogenous DNA damage; formaldehyde; neutral drift; somatic evolution; stem cell aging
    DOI:  https://doi.org/10.1016/j.stem.2026.02.011
  30. Drugs Drug Candidates. 2026 Mar;5(1):
    Cancer Metabolism and Its Historical & Molecular Foundations: An Overview.
    Rami A Al-Horani.
      Cancer metabolism is a cornerstone of tumor biology, characterized by profound alterations in cellular energy production and biosynthetic pathways that drive malignancy. The seminal discovery of the "Warburg effect", the preference of cancer cells for aerobic glycolysis even under oxygen-rich conditions, provided the first major insight into this field. Historically, this observation was attributed to defective mitochondria, but modern research has revealed a far more complex picture of metabolic reprogramming that is actively driven by oncogenes, tumor suppressor genes, and the tumor microenvironment (TME). This review advances a unifying framework for understanding cancer metabolism as a dynamic ecosystem defined by three interconnected adaptations: metabolic plasticity, oncometabolite-driven epigenetic remodeling, and immune-metabolic crosstalk. These adaptations extend beyond glycolysis to encompass glutamine metabolism, lipid synthesis, amino acid utilization, and mitochondrial dynamics, all coordinated to fuel rapid proliferation, promote survival, and enable metastasis. By examining the drivers, consequences, and therapeutic barriers within this framework, we highlight emerging strategies for precision intervention. Although understanding the mechanistic basis of these pathways has unveiled new therapeutic avenues, clinical translation has been limited by metabolic redundancy, microenvironmental buffering, and patient heterogeneity. Strategies such as metabolic inhibitors, dietary interventions, and immuno-metabolic combinations offer promising prospects for disrupting tumor growth when guided by biomarker-driven patient selection and emerging technologies, including spatial metabolomics and AI-driven network modeling.
    Keywords:  TME; Warburg effect; aerobic glycolysis; epigenetic regulation; metabolic reprogramming; mitochondrial dynamics; targeted therapy
    DOI:  https://doi.org/10.3390/ddc5010017
  31. bioRxiv. 2026 Mar 18. pii: 2026.03.18.712693. [Epub ahead of print]
    UFMylation of Pyruvate Dehydrogenase Regulates Mitochondrial Metabolism.
    Phong T Nguyen, Zheng Wu, Dohun Kim, Tamaratare Ogu, Siyu Yin, Varun Sondhi, Feng Cai, Trevor S Tippetts, Annie Jen, Evgenia Shishkova, Ling Cai, Dennis Dumesnil, Margaret Cervantes, Hongli Chen, Prashant Mishra, Joshua J Coon, Gerta Hoxhaj, Min Ni, Ralph J DeBerardinis.
      The ubiquitin-fold modifier 1 (UFM1) post-translational modification (PTM), or UFMylation, regulates protein homeostasis and is essential for human development. Yet the roles of the de-UFMylase, UFM1-specific peptidase 2 (UFSP2), which removes UFM1 from UFMylated proteins, remain poorly characterized. Here, we demonstrate that UFMylation and UFSP2 regulate mitochondrial metabolism. Quantitative proteomics in UFSP2-deficient cells revealed the accumulation of many proteins previously unknown to be impacted by UFMylation. These included components of the mitochondrial ribosome, electron transport chain (ETC), and pyruvate dehydrogenase (PDH) complex. Functional analyses demonstrated that excessive UFMylation in UFSP2-deficient cells increases mitochondrial respiration, glucose oxidation in the tricarboxylic acid (TCA) cycle, and PDH enzymatic activity. We identified dihydrolipoamide S-acetyltransferase (DLAT), the E2 component of PDH, as a direct UFMylation substrate, with lysine 118 (K118) as the primary conjugation site. Mutating K118 to arginine (K118R) abolished DLAT UFMylation and reduced pyruvate oxidation, identifying this modification as an activator of PDH. These findings reveal a UFMylation-based regulatory mechanism that controls mitochondrial function by inducing utilization of pyruvate as a TCA cycle fuel.
    DOI:  https://doi.org/10.64898/2026.03.18.712693
  32. Nat Commun. 2026 Mar 23.
    Pentose phosphate pathway fuels cGAS-STING signalling to boost function of intratumoral conventional dendritic cells.
    Ben Liu, Zhonglei Geng, Yujie Huang, Yaqing Yuan, Tongchang Xu, Yi Zhu, Jingwen Zhang, Zhekai Luo, Sijia Zhang, Rui Ding, Ranran Tang, Yun Li, Zhilin Hu.
      Tumors employ diverse mechanisms to impair conventional dendritic cell (cDC) function within the tumor microenvironment, yet the underlying processes remain unclear. Here, we demonstrate that pentose phosphate pathway (PPP) reduction in late-stage intratumoral cDCs compromises their function. Both pharmacological and genetic inhibition of the PPP attenuate cDC-mediated antitumor responses. Conversely, PPP augmentation restores late-stage intratumoral cDC antitumor capacity. PPP deficiency in cDCs enhances the immune checkpoint PD-L1 expression level, and combining cDC-specific PPP potentiation with immune checkpoint blockade synergistically enhances immunotherapy efficacy. Mechanistically, PPP activation fuels purine metabolism, thereby increasing ATP and GTP levels required for 2'3'-cGAMP synthesis, ultimately promoting cGAS-STING signaling and STING-dependent cDC antitumor responses. The PPP is associated with STING-dependent cDC activities in tumor tissues from female patients with breast cancer. Collectively, our findings establish PPP as an intrinsic metabolic checkpoint in STING-mediated cDC antitumor immunity, and suggest targeting PPP in cDCs as a promising cancer immunotherapy strategy.
    DOI:  https://doi.org/10.1038/s41467-026-70934-x
  33. bioRxiv. 2026 Mar 07. pii: 2026.03.04.709646. [Epub ahead of print]
    Suppression of ITPK1 and IPMK activities impairs mTORC1 signaling in pancreatic β-cells and implicates IP 5 in stabilizing activated mTORC1.
    Clarisse Iradukunda, Edward A Salter, Dilipkumar Uredi, Xiaodong Wang, Andrzej Wierzbicki, Lucia E Rameh.
      mTORC1 integrates growth factor and nutrient signals to regulate cellular metabolism, yet there are no metabolites known to directly regulate mTORC1 activity in cells. Cryo-EM studies revealed that inositol hexakisphosphate (IP 6 ) associates with the FAT domain of mTOR, suggesting that inositol phosphates may directly modulate mTOR activity. We previously showed that higher-order inositol phosphates enhance mTORC1 kinase activity and stability in vitro. Here, we investigated whether inositol phosphate metabolism regulates mTORC1 signaling in pancreatic β-cells. Suppression or acute inhibition of inositol phosphate multikinase (IPMK), as well as knockdown of inositol trisphosphate kinase 1 (ITPK1), selectively reduced cellular IP 5 levels without altering IP 6 and resulted in impaired basal and insulin-stimulated mTORC1 signaling, particularly under physiological glucose and low growth factor conditions. Combined inhibition of IPMK and ITPK1 nearly abolished IP 5 and reduced IP 6 , demonstrating that these enzymes compensate to supply IP 5 for IP 6 synthesis. Importantly, depletion of IP 5 did not impair PI3K/Akt activation but accelerated termination of the mTORC1 signal, indicating a role for IP 5 in stabilizing the active mTORC1 complex. Reduction of inositol phosphate levels did not prevent insulin- or glucose-induced mTORC1 activation, revealing that IP 5 primarily regulates signal persistence rather than initiation. Together, these findings identify IP 5 as a metabolic regulator that prolong mTORC1 activity in β-cells, providing a mechanism by which cellular metabolic state modulates sustained mTORC1 signaling.
    Significance Statement: mTORC1 is a central metabolic regulator whose chronic activation contributes to metabolic disease, yet mechanisms that sustain mTORC1 activity after its activation are poorly understood. We show that enzymes controlling inositol phosphate metabolism regulate the stability of mTORC1 signaling in pancreatic β-cells by maintaining cellular levels of inositol pentakisphosphate (IP 5 ). Reducing IP 5 impairs basal and sustained mTORC1 signaling without affecting upstream growth factor or energy-sensing pathways, revealing a mechanism that controls signal duration rather than activation. These findings identify IP 5 as a metabolic regulator of mTORC1 and suggest that targeting inositol phosphate metabolism may provide a strategy to modulate mTORC1 activity in metabolic disease.
    DOI:  https://doi.org/10.64898/2026.03.04.709646
  34. bioRxiv. 2026 Mar 04. pii: 2026.03.03.709381. [Epub ahead of print]
    Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.
    Sadia Ahmed, Namratha Javvaji, Katherine L Hammond, Kevin M Casin, John W Elrod, Paul M Holloway, Yvonne Couch, Jillian N Simon.
      Mitochondrial Ca 2+ uptake governs metabolism and cell fate, yet how signals from other organelles shape this remains incompletely defined. Although lysosomes are relatively small Ca 2+ stores, their strategic positioning at organelle contact sites suggests they may amplify Ca 2+ transfer within nanodomains. Here, we show that activation of the lysosomal Two-pore channel 2 (TPC2) initiates rapid mitochondrial Ca 2+ uptake through an endoplasmic reticulum-dependent relay requiring IP₃ receptors and the mitochondrial calcium uniporter channel. The extent of mitochondrial Ca 2+ accumulation scales with TPC2 activity without affecting global Ca 2+ responses, identifying TPC2 as a specific amplifier of lysosome-mitochondria Ca 2+ exchange. Moderate TPC2 activation transiently enhances oxidative phosphorylation, whereas sustained enhancement increases susceptibility to Ca 2+ -induced mitochondrial permeability transition. In stroke models, hyperactivation of TPC2 exacerbates injury, while acute pharmacological inhibition at reperfusion confers neuroprotection, including in human iPSC-derived neurons. Thus, lysosomal Ca 2+ release acts as an upstream regulator of mitochondrial energetic resilience under stress.
    DOI:  https://doi.org/10.64898/2026.03.03.709381
  35. Dev Cell. 2026 Mar 23. pii: S1534-5807(26)00082-1. [Epub ahead of print]
    Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states.
    Stefan R Torborg, Jung Yun Kim, Anupriya Singhal, Olivera Grbovic-Huezo, Matilda Holm, Katherine Wu, Xuexiang Han, Yu-Jui Ho, Caj Haglund, Michael J Mitchell, Scott W Lowe, Lukas E Dow, Kenneth L Pitter, Francisco J Sanchez-Rivera, Andre Levchenko, Tuomas Tammela.
      Control of cell identity and number is central to tissue function, yet principles governing the organization of malignant cells remain poorly understood. Using genetically engineered mouse models and orthotopic allografts with dual WNT reporter systems, we discover that pancreatic ductal adenocarcinoma (PDAC) organizes in a stereotypical pattern, whereby PDAC cells responding to WNT signals (WNT-R) neighbor WNT-secreting cancer cells (WNT-S). Lineage tracing reveals that the WNT-R state is transient and gives rise to a stable WNT-S state. A subset of WNT-S cells expressing DLL1 forms a functional niche for WNT-R cells. The genetic inactivation of WNT secretion or Notch pathway components, or the cytoablation of WNT-S cells, disrupts PDAC tissue organization, suppressing tumor growth and metastasis. Analysis of human PDAC tissues confirms conservation of these populations. PDAC growth depends on an intricately controlled equilibrium of functionally distinct cancer cell states, revealing the fundamental principles governing solid tumor organization and therapeutic opportunities.
    Keywords:  Notch; WNT; gene perturbation; intratumoral heterogeneity; lineage ablation; lineage tracing; pancreas cancer; tissue organization
    DOI:  https://doi.org/10.1016/j.devcel.2026.02.017
  36. Trends Cancer. 2026 Mar 26. pii: S2405-8033(26)00032-4. [Epub ahead of print]
    Dissecting histological transformation.
    Ethan M Earlie, Eric E Gardner, Harold Varmus, Ashley M Laughney.
      The adaptive nature of cancer is a major obstacle limiting durable treatment responses. Histological transformation (HT) is a process whereby one cancer changes into a categorically different tumor type, often following treatment with targeted therapy. Best characterized in lung and prostate adenocarcinomas, HT is particularly disconcerting because the resultant cancer no longer depends on the initial oncogenic driver program, is therapeutically recalcitrant, and is often highly metastatic. Partly because HT is technically difficult to study, this process remains poorly described. As newer therapies broaden the scope of oncogenic drivers that can be targeted, HT may become more prevalent, highlighting the need for further research to dissect these phenomena. We propose that modern experimental and analytical tools present an opportunity to advance our understanding and improve our clinical management of histologically transforming cancers.
    Keywords:  acquired resistance; cellular adaptation; histological transformation
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.001
  37. bioRxiv. 2026 Mar 22. pii: 2026.03.19.713006. [Epub ahead of print]
    Protein domain characterization reveals human MIC60 tolerates loss of helical bundle domain.
    Stephanie M Rockfield, Krishnan Venkataraman, Chih-Hsuan Wu, Randall Wakefield, Alan Wu, Amit Budhraja, Ricardo Rodriguez-Enriquez, Ali Khalighifar, Camenzind G Robinson, Cai Li, Alexandre F Carisey, Joseph Thomas Opferman.
      The mitochondrial contact site and cristae organizing system (MICOS) is essential for cristae junction formation and inner mitochondrial membrane architecture. To define how MICOS integrity is established and maintained, we generated conditional deletion models of Immt (encoding MIC60), a core MICOS subunit, in tissue-specific settings and in cultured cells. Liver-specific deletion of Immt in mice induced profound defects in mitochondrial ultrastructure and function, establishing MIC60 as essential for mitochondrial integrity. Notably, despite the severity of the defects, we did not detect increased apoptosis in liver tissue or in cells. To directly link MIC60 structure to its function, we performed a systemic structure-function analysis of human MIC60 using domain-specific deletion mutants expressed in Immt-deleted cells. We identified that the transmembrane, coiled-coil, and mitofilin domains are required for MICOS assembly, mitochondrial morphology, and respiratory function. Unexpectedly, deletion of the predicted helical bundle (a region spanning 229 amino acids) substantially restored mitochondrial structure and function, nearly matching full-length MIC60. A mutation (K299E) associated with human disease within this domain similarly preserved most MIC60-dependent functions. Together, these results establish MIC60 as a non-redundant regulator of mitochondrial architecture while revealing that a large predicted structural domain is largely dispensable for MIC60s core functions, refining current models of MICOS organization and uncovering unexpected modularity within MIC60.
    DOI:  https://doi.org/10.64898/2026.03.19.713006
  38. bioRxiv. 2026 Feb 07. pii: 2026.02.05.703986. [Epub ahead of print]
    SenCat: Cataloging human cell senescence through multiomic profiling of multiple senescent primary cell types.
    Carlos Anerillas, Gisela Altés, Katarína Grešová, Dimitrios Tsitsipatis, Krystyna Mazan-Mamczarz, Reema Banarjee, Ana S G Cunningham, Martin Salamini-Montemurri, Jen-Hao Yang, Rachel Munk, Martina Rossi, Yulan Piao, Bradley Olinger, Quinn Strassheim, Jennifer L Martindale, Jinshui Fan, Chang-Yi Cui, Supriyo De, Delaney V Rutherford, Ying Hao, Ziyi Li, Jessica Roberts, Yue Andy Qi, Kotb Abdelmohsen, Rafael de Cabo, Allison B Herman, Manolis Maragkakis, Nathan Basisty, Myriam Gorospe.
      There is an urgent need to comprehensively catalog senescence markers across cell types in an organism in order to characterize 'senotypes' and senescent cell heterogeneity. Here, we profiled the transcriptomes and proteomes in 14 different primary human cell types undergoing over 30 senescence paradigms to create a senescence catalog we termed 'SenCat'. We found that, while senescent cells from all primary tissue types did not share a single unique marker, they did activate shared specific metabolic and damage-response pathways implicated in tissue repair. Machine learning analysis of the SenCat transcriptomic and proteomic datasets successfully identified independent sets of senescent human cells, and senescent-like cells in mouse lung and kidney. In sum, SenCat represents a much-needed resource to identify senescent cells across tissues in the body.
    HIGHLIGHTS: Identifying senescent cells in organisms in vivo remains a challengeWe created SenCat: a catalog transcriptomes and proteomes of senescent primary cellsMachine learning (ML) analysis of SenCat identified robust senescence scoresML-derived senescence scores uncovered senescent-like cell dynamics in vivo.
    DOI:  https://doi.org/10.64898/2026.02.05.703986
  39. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00166-1. [Epub ahead of print]36(6): R259-R261
    Cell biology: Killing the prisoner escaping from mitochondria.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria contain their own DNA (mtDNA), which can be released via multiple routes and cause inflammation and disease. A recent study revealed the unexpected role of a mitochondrial nuclease, present in the intermembrane space, in preventing mtDNA escape via mitophagy.
    DOI:  https://doi.org/10.1016/j.cub.2026.02.016
  40. bioRxiv. 2026 Mar 22. pii: 2026.03.19.712965. [Epub ahead of print]
    Cell-specific isotope labeling identifies myo -inositol transfer between neurons and oligodendroglia to support myelin repair.
    Kayla Adkins-Travis, Mun-Gu Song, Michaela Schwaiger-Haber, Kevin Cho, Ronald Fowle-Grider, Stephen L Johnson, Leah P Shriver, Gary J Patti.
      Neurons and glial cells are biochemically coupled through the exchange of nutrients, but our knowledge of which metabolites are transferred between them remains limited due to technical challenges. Here, we introduce a strategy to label specific cell types with isotopic tracers so that metabolite transfer can be measured directly in the intact brain. By engineering neurons in mice to metabolize 13 C-labeled cellobiose, a glucose dimer that wild-type cells cannot catabolize, we selectively track neuron-derived metabolites by using mass spectrometry-based metabolomics. Applying this approach enabled us to identify myo -inositol as a critical metabolite synthesized by neurons and transferred to oligodendrocyte progenitor cells (OPCs) via the SLC5A3 transporter. The transfer of myo -inositol from neurons to OPCs promotes OPC proliferation and differentiation by enhancing phosphatidylinositol synthesis and upregulating expression of myelin-associated genes. During demyelination, deficient nutrient transfer can be rescued by dietary supplementation of myo -inositol, which accelerates myelin repair. These findings establish a generalizable technology for tracing intercellular metabolite transfer in vivo and identify a previously unrecognized mechanism of myo -inositol transfer from neurons to glial cells in support of CNS regeneration, revealing a potential metabolic target for therapeutic intervention in neurodegenerative disease.
    DOI:  https://doi.org/10.64898/2026.03.19.712965
  41. Blood. 2026 Mar 24. pii: blood.2025031552. [Epub ahead of print]
    Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
    Silvia Sighinolfi, Laura Cassina, Maria Rosa Lidonnici, Stefano Beretta, Davide Stefanoni, Mariangela Storto, Christina Mayerhofer, Trine A Kristiansen, David T Scadden, Ivan Merelli, Alessandra Boletta, Annamaria Aprile, Giuliana Ferrari.
      Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.
    DOI:  https://doi.org/10.1182/blood.2025031552
  42. bioRxiv. 2026 Mar 18. pii: 2026.03.15.711957. [Epub ahead of print]
    Anticipatory metabolic reprogramming distinguishes caloric restriction from fasting-refeeding cycles.
    Nikkhil Velingkaar, Artem A Astafev, Archana Prabahar, Evelina Trokhimenko, Josefa-Marie B Rom, Gena J Asi, Peng Jiang, Roman V Kondratov.
      Interest in fasting-based dietary interventions to improve metabolic health is growing. Caloric restriction (CR) with one meal per day includes an extended fasting component that contributes to its metabolic and longevity benefits, yet the specific role of fasting within CR remains unclear. Here, we compared mice under CR with those subjected to a fasting-refeeding-fasting (FRF) regimen while controlling pre-fasting food intake and fasting duration. Simultaneous comparison of diet induced changes in plasma insulin and free fatty acids, hepatic mTOR signaling and ketogenesis, total body metabolic rhythms with kinetics of food digestion suggested that gastric emptying served as a primary metabolic trigger in acute fasting. In contrast, in CR, fasting responses were actively regulated and suggested anticipatory mechanisms. At the transcriptomic level, CR enhanced circadian rhythmicity and metabolic gene coordination, whereas FRF disrupted it. In agreement with the expression data, CR improves glucose and fatty acid metabolism while fasting leads to glucose intolerance and fat accumulation in the liver induced glucose intolerance and hepatic steatosis. These findings reveal that CR engages clock-aligned, anticipatory metabolic control, while fasting-refeeding cycles rely on direct nutrient cues. This mechanistic distinction between active and passive metabolic regulation may underlie the superior metabolic and longevity outcomes of caloric restriction.
    DOI:  https://doi.org/10.64898/2026.03.15.711957
  43. Cancer Discov. 2026 Mar 27. OF1
    Stress Responses Tied to Metastasis and Immune Evasion.
      Two studies show that cancer cells co-opt the integrated stress response, via the transcription factor ATF4, to drive both metastasis and immune evasion. Targeting this pathway or its downstream effectors, such as glutamine metabolism and the secreted protein LCN2, may offer a way to limit tumor spread and restore antitumor immunity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NW2026-0029
  44. Cell. 2026 Mar 20. pii: S0092-8674(26)00234-5. [Epub ahead of print]
    Hyperinnervation inhibits organ-level regeneration in mammalian skin.
    Hannah T Tam, Jingyu Peng, Rebecca Freeman, Yulia Shwartz, Shlomi Brielle, Sakshi Garg, Siti Rahmayanti, Stephen J Crocker, Devin Coon, Ya-Chieh Hsu.
      Some mammalian tissues can replace lost cells within one lineage, but organ-level regeneration-restoring diverse cell types across lineages-remains rare. Here, we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular tissues with proper connectivity. However, this ability is lost soon after birth, resulting in failure to restore most cell types and hyperinnervation within the wound bed. Single-cell sequencing identified a postnatal wound-specific fibroblast (PWF) population absent after embryonic wounding. Through an in vivo screen, we discovered that three PWF-enriched genes-Timp1, Cxcl12, and Ccl7-inhibit organ-level regeneration and cause hyperinnervation when overexpressed in embryonic wounds. Reducing hyperinnervation in postnatal wounds through the depletion of Cxcl12 in fibroblasts or nerve ablation enables regeneration of diverse lineages after injury. Our study identifies mechanisms that transition an organ from regenerative to non-regenerative, discovers fibroblast-driven hyperinnervation as a key barrier, and demonstrates that removing this barrier unlocks organ-level regeneration.
    Keywords:  Cxcl12; hyperinnervation; injury repair; nerve-tissue interactions; organ-level regeneration; regeneration; wound healing
    DOI:  https://doi.org/10.1016/j.cell.2026.02.027
  45. Cell Death Dis. 2026 Mar 25.
    Glioblastoma cells that evade chemoradiotherapy-induced cell death exhibit a bifurcated glycolytic program.
    Emma Martell, Helgi Kuzmychova, Ujala Chawla, Akaljot Grewal, Charul Jain, Chitra Venugopal, Christopher M Anderson, Sheila K Singh, Tanveer Sharif.
      Glioblastoma (GBM), the most common malignant brain tumor in adults, remains a highly lethal and incurable cancer, with a 5-year survival rate below 10%. Standard-of-care involves surgical resection followed by concurrent temozolomide chemotherapy and radiation treatment. While these interventions can effectively shrink tumors, they fail to eradicate all malignant cells. Small populations of GBM cells invariably survive and seed recurrent disease, leading to near-universal relapse and the formation of fatal recurrent tumors, typically within 1-2 years of treatment. Here, we investigated the metabolic features that define these surviving cell populations using ten patient-derived GBM models and matched orthotopic xenograft models exposed to a clinically relevant chemoradiotherapy regimen. By sampling living cells at defined treatment intervals and integrating 13C-glucose tracing, quantitative untargeted metabolomics, and nCounter metabolic gene expression profiling, we reconstructed the temporal evolution of glucose metabolism from therapy-naïve to post-treatment states. Across all models, GBM cells that evaded therapy-induced death exhibited a conserved and coordinated reorganization of glycolytic flux. These cells showed enhanced glucose uptake and elevated abundance of upper glycolytic enzymes such as HK1, while lower glycolytic enzymes, including ALDOA, GAPDH, ENO1, and LDHA, were suppressed, resulting in reduced lactate output. This bifurcation of glycolytic metabolism redirected carbon flux toward the pentose phosphate pathway and nucleotide biosynthesis, as well as mitochondrial metabolism, supported by the increased abundance of tricarboxylic acid cycle enzymes. Notably, these adaptations were conserved in recurrent patient-derived orthotopic xenograft tumors in vivo. Together, these findings reveal a fundamental and conserved metabolic state that defines GBM cells surviving chemoradiotherapy. This study deciphers a core metabolic architecture that enables tumor cell survival, persistence, and recurrence following therapy by shifting glycolytic flux away from lactate production to balance biosynthetic demands with mitochondrial metabolism.
    DOI:  https://doi.org/10.1038/s41419-026-08646-9
  46. bioRxiv. 2026 Mar 04. pii: 2026.03.04.709625. [Epub ahead of print]
    Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
    Amber Crabtree, Suraj Thapliyal, Mohd Mabood Khan, Edgar Garza Lopez, Andrea Marshall, Calixto Pablo Hernandez Perez, Oleg Kovtun, Jenny C Schafer, Dea Pulatani, Yuho Kim, Sepiso K Masenga, Annet Kirabo, Jeremiah Afolabi, Melanie McReynolds, Renata O Pereira, Prasanna Venkhatesh, Prasanna Katti, Brian Glancy, Antentor Hinton.
      Mitochondrial structural plasticity is a critical adaptive response to cellular stress, yet the transcriptional networks governing the formation of specialized mitochondrial architectures remain poorly defined. Here, we identified and demonstrated that activating transcription factor 4 (ATF4), the master regulator of the integrated stress response, directly regulates mitochondrial morphological remodeling through a novel ATF4-NRF1/Nrf2-MFN2 signaling axis. Using serial block-face scanning electron microscopy and three-dimensional reconstruction in Drosophila flight muscle, primary myotubes, and human skeletal muscle, we show that overexpression of ATF4 promotes significant mitochondrial elongation, increased cristae concentration, enhanced mitochondrial-endoplasmic reticulum contact site (MERC) formation, and the initiation of Mitochondrial Nanotunnels. In contrast, loss of ATF4 results in mitochondrial fragmentation and impaired aerobic capacity. Chromatin immunoprecipitation sequencing reveals direct ATF4 binding at the promoters of the genes encoding NRF1 and Nrf2, which in turn regulate MFN2 expression. Small-molecule inhibition studies further establish that activation of this hierarchical pathway is both necessary and sufficient for stress-induced mitochondrial structural adaptation. Together, these findings position ATF4 as a master regulator of mitochondrial architectural plasticity, providing a direct mechanistic link between cellular stress signaling and organelle remodeling.
    DOI:  https://doi.org/10.64898/2026.03.04.709625
  47. Nat Immunol. 2026 Mar 24.
    MHC class I on target cells regulates CD4+ T cell-mediated immunity.
    Emma Lauder, Mahnoor Gondal, Meng-Chih Wu, Akira Yamamoto, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Arul M Chinnaiyan, Pavan Reddy.
      Major histocompatibility complex (MHC) class I and class II molecules present antigens to CD8+ and CD4+ T cells respectively. Here we uncover a previously unrecognized role for MHC class I in modulating CD4+ T cell-mediated immunity. In allogeneic graft-versus-host disease and tumor models, we demonstrate that the absence of MHC class I on target cells significantly increases their susceptibility to CD4+ T cell cytotoxicity. Transcriptomic and functional studies suggest that this was because of heightened sensitivity to enhanced ferroptosis of the target cells. In large human transcriptomic and sequencing datasets, a role for CD4+ T cells in enhancing immune checkpoint blocker-mediated responses in persons with melanoma and mismatch-repair-deficient colon cancers that have downregulated MHC class I was suggested. These findings revise and expand the known role of MHC class I in CD8+ T cell and natural killer cell immunity and demonstrate a previously unrecognized role in CD4+ T cell-mediated cancer and alloimmunity.
    DOI:  https://doi.org/10.1038/s41590-026-02480-z
  48. Mol Cell. 2026 Mar 23. pii: S1097-2765(26)00138-3. [Epub ahead of print]
    RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
    Shubo Zhao, Chloe S Palma-Chaundler, Carla M Engel, Jacqueline Cordes, Daniel Nixdorf, Michael Y Luo, Selay Kaya, Aldwin Suryo Rahmanto, Diana van den Heuvel, Timur Mackens-Kiani, Pedro Weickert, Simon Lam, Vipul Gupta, Julia Philippou-Massier, Ivan Bagarić, Jonathan Bohlen, Graeme Hewitt, Martijn S Luijsterburg, Roland Beckmann, Petra Beli, Danny D Nedialkova, Christopher J Carnie, Marion Subklewe, Stephen P Jackson, Julian Stingele.
      Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.
    Keywords:  GCN1; GCN2; RNA damage; RNF25; acute myeloid leukemia; azacytidine; chemotherapy; integrated stress response; ribosome collisions; ubiquitylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.024
  49. Nat Rev Genet. 2026 Mar 23.
    Genetic influences on haematopoiesis.
    Michael Poeschla, Vijay G Sankaran.
      Haematopoiesis has long been a paradigm for understanding how human genetic variation can influence physiology in health and disease, ranging from the genetic characterization of Mendelian blood diseases to population-scale genomic studies of blood cell phenotypes and diseases. More recently, advances in single-cell genomics and variant-to-function mapping are enabling mechanistic insights into how genetic variation shapes blood cell development. Alongside inherited variation, the characterization of somatic mutations accumulating in haematopoietic stem cells during the lifespan has revealed clonal haematopoiesis as a ubiquitous evolutionary process, with heterogeneous clonal expansions impacting haematopoietic function and disease risk. Insights from genetic studies of haematopoiesis are translating into therapeutic applications, transforming treatment for monogenic blood disorders and promising broader applications. As methods continue to advance, haematopoiesis will remain central to understanding how genetic variation influences human biology, disease susceptibility and therapeutic response.
    DOI:  https://doi.org/10.1038/s41576-026-00947-1
  50. bioRxiv. 2026 Mar 17. pii: 2026.03.13.711672. [Epub ahead of print]
    ATM functions as a rheostat of metabolic stress in small-cell lung cancer.
    Debdatta Halder, Utsav Sen, Vrinda Jethalia, Subhamoy Chakraborty, Andrew Elliott, Kedwin Ventura, Ari Vanderwalde, Balazs Halmos, Hossein Borghaei, Tin Htwe Thin, Alan Soto, Mirela Berisa, Rachel Brody, Deniz Demircioglu, Dan Hasson, Triparna Sen.
      ATM is best known as a guardian of genomic stability, yet its contributions to oncogenic signaling in aggressive malignancies like small-cell lung cancer (SCLC) remain poorly understood. Despite ATM being an established clinical vulnerability in SCLC, its influence on dysregulated tumorigenic circuits remains unclear. We demonstrate that inhibition of ATM disrupts the AKT-mTORC1-4EBP1 signaling axis, leading to attenuation of the master regulator of stress, ATF4. ATF4 and MYC appear to co-regulate one another in a feedback loop critical for redox homeostasis. ATM inhibition perturbs both the expression and function of MYC and ATF4, leading to increased intracellular reactive oxygen species, impaired glutathione recycling, and ferroptotic cell death, thereby exposing a crucial dependency of SCLC on stress-adaptive signaling. We uncover previously unrecognized metabolic vulnerability in SCLC, nominating ATM as a regulator of adaptive stress, expanding its role beyond canonical DNA damage repair (DDR) and highlighting therapeutically exploitable opportunities in aggressive tumors.
    Statement of Significance: The metabolic landscape of SCLC remains poorly characterized, particularly its interaction with dysregulated signaling networks, limiting the development of effective strategies to overcome therapeutic resistance. Our work reveals an expanded role for ATM beyond DNA repair, positioning it as a key regulator of metabolic rewiring and highlighting new therapeutic opportunities for SCLC.
    DOI:  https://doi.org/10.64898/2026.03.13.711672
  51. J Cell Biol. 2026 Apr 06. pii: e202603036. [Epub ahead of print]225(4):
    How strong is a mitochondrial targeting signal?
    Carlotta Peselj, F-Nora Vögtle.
      In this issue, Yan et al. show that mitochondrial targeting signals (presequences) vary widely in import strength. Using the quantitative MitoLuc and PotLuc assays, they dissect multiple parameters of protein import and reveal how presequence features influence mitochondrial targeting efficiency and stress sensitivity.
    DOI:  https://doi.org/10.1083/jcb.202603036
  52. Redox Biol. 2026 Mar 19. pii: S2213-2317(26)00128-X. [Epub ahead of print]92 104130
    Copper deprivation reprograms antioxidant defense to suppress ferroptosis via SLC7A11.
    Qian Xue, Ziyuan Chen, Jiao Yang, Kaixuan Ren, Xiaofen Li, Xi Chen, Ding Yan, Yuan Wang, Daolin Tang, Jinbao Liu, Xin Chen.
      Copper is an essential trace element that governs diverse cellular functions and influences cell fate. However, how cells adapt to copper deprivation remains poorly understood. Here, we identify a copper-ferroptosis regulatory axis mediated by the cystine transporter SLC7A11. We show that copper loss, induced either by silencing of the copper importer SLC31A1 or by pharmacological chelation, leads to a marked upregulation of SLC7A11. This adaptive response enhances glutathione synthesis, bolsters antioxidant defenses, and protects cells from ferroptosis. Mechanistically, copper deprivation activates AMPK, which stabilizes the transcription factor NRF2 to drive SLC7A11 expression. Functionally, SLC31A1 depletion diminishes ferroptosis-dependent tumor suppression in xenograft models, while dietary copper restriction alleviates ferroptosis-mediated pancreatic injury in experimental acute pancreatitis. Together, these findings reveal copper deprivation as a robust condition driving ferroptosis resistance and suggest that dietary or pharmacological copper modulation could provide new strategies to fine-tune ferroptosis in cancer and tissue injury.
    Keywords:  AMPK; Copper; Ferroptosis; NRF2; SLC31A1; SLC7A11
    DOI:  https://doi.org/10.1016/j.redox.2026.104130
  53. Int Immunopharmacol. 2026 Mar 23. pii: S1567-5769(26)00392-9. [Epub ahead of print]177 116547
    The pivotal role of metabolism in shaping tumor-associated macrophages phenotype and function.
    Mei Jun, Tiantian Li, Yilin Shi, Hang Yin, Wenjie Wu, Xinmin Dong, Xigetu He, Xiong Lai.
      Tumor progression is critically shaped by the dynamic interplay between tumor cells and the tumor microenvironment (TME). The TME harbors a diverse array of immune cells, encompassing T cell, B cell, NK cell and macrophages. Among these, TAMs profoundly shape tumor growth and metastasis by interacting with tumor cells and other immune cells. To adapt to the varied immune and metabolic cues in the TME, they undergo dynamic metabolic reprogramming, which recent advances have shown to involve extensive remodeling of glucose, lipid, and amino acid metabolism, along with the tricarboxylic acid cycle. However, critical knowledge gaps remain regarding the cellular heterogeneity of TAM metabolic reprogramming, divergent metabolic signatures across TAM subsets, and context-dependent variations in metabolic rewiring among different cancer types. However, the mechanisms by which these metabolic alterations translate into distinct functional phenotypes and shape the immune landscape of the TME remain poorly defined. This review systematically synthesizes the current knowledge on how metabolic remodeling in TAMs regulates their polarization and pro-tumor functions. We specifically focus on delineating the heterogeneity of TAM metabolic features across tumor types and subsets and discuss the implications of these metabolic variations for TAM-mediated immunosuppression. Furthermore, we summarize the representative therapeutic agents targeting key metabolic nodes in TAMs. By integrating emerging insights into TAM metabolism and associated pharmacologic interventions, this review aims to identify key unanswered questions and provide a theoretical framework for developing precision immunotherapies that target TAM metabolic nodes without compromising anti-tumor immunity.
    Keywords:  Amino acid metabolism; Glucose metabolism; Lipid metabolism; Metabolic reprogramming; Tricarboxylic acid cycle; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.intimp.2026.116547
  54. bioRxiv. 2026 Mar 18. pii: 2026.03.16.711688. [Epub ahead of print]
    Systemic Cysteine Elevation Sustains T-Cell Activation to Potentiate PD-1 Blockade.
    Xiaoshuang Wang, Zi Wang, Yuqi Guo, Fangxi Xu, Jinhui Zhu, Scott C Thomas, Deepak Saxena, Jinghang Xie, Xin Li.
      Resistance to immune checkpoint inhibition remains a major barrier in pancreatic cancer treatment. Here, we show that concurrent administration of probiotics restores sensitivity to anti-PD-1 therapy in pancreatic cancer mouse models. Mice treated with the combination of anti-PD-1 and probiotics demonstrate robust tumor control, accompanied by enrichment of microbial pathways governing cysteine biosynthesis, elevated serum cysteine levels, and increased T cell function. Serum cysteine levels, rather than intratumoral cysteine concentrations, inversely correlate with tumor burden. Functionally, cysteine directly promotes T cell survival, activation, and cytotoxicity while its restriction induces uncoupled transcriptional-translational stress and impairs T cell function. Oral cysteine supplementation synergizes with anti-PD-1 therapy in pancreatic cancer mice, reducing tumor burden and enhancing intratumoral T cell activation, phenocopying probiotics-mediated immune restoration. These findings suggest systemic cysteine availability as a tractable metabolic target to enhance cancer immunotherapy.
    DOI:  https://doi.org/10.64898/2026.03.16.711688
  55. Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261428840
    mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
    Richard Boulton-McDonald, Eva Sidlauskaite, Jiri Neuzil, Michelangelo Campanella.
      Mitochondrial sites of contact with the nucleus, hereafter referred to as Nucleus-Associated Mitochondria (NAM), are specialised domains that enable communication, influencing cellular function. Previous studies have shown that these contacts can be stabilised by protein scaffolds acting as tethers to promote retrograde signalling, particularly during apoptotic stress. This is facilitated via the mitochondrial protein TSPO. In this study, we have investigated a mitochondrial DNA (mtDNA)-depleted (ρ0) 4T1 cell model to further inform the role of NAM in retrograde communication between corrupted mitochondria and the nucleus. Our data report an increase in NAM frequency in mtDNA-depleted cells compared to the mtDNA-retaining parental 4T1 line. Using a combination of cellular assays, transmission electron microscopy, and epigenetic profiling, we have found that under conditions of mtDNA loss, mitochondria become enriched in TSPO, evading mitophagic clearance and are prone to forming stable contacts with the nucleus. This coincides with an extreme reduction in DNA methylation, as well as histone modifications associated with chromatin decondensation.
    Keywords:  NAM; TSPO; VDAC; contact sites; mitochondria
    DOI:  https://doi.org/10.1177/25152564261428840
  56. bioRxiv. 2026 Mar 16. pii: 2026.03.13.710876. [Epub ahead of print]
    An enzymatic-metabolic sensing axis in taste cells detects glucose-yielding carbohydrates.
    Aracely Simental-Ramos, Sandrine Chometton, A-Hyun Jung, Amelia Cave, Thisun Udagedara, Caroline Metyas, Lilly Mai, Grace Tang, Jonathan Fan, Madeline Obrzut, Lindsey A Schier.
      Glucose is a potent reinforcer of intake, yet most foods contain complex saccharides that do not yield free glucose until after digestion. How the oral sensory system rapidly evaluates the potential metabolic value of food remains unclear. Here, we identify an oral enzymatic-metabolic sensing mechanism that enables detection of glucose-yielding carbohydrates independent of canonical sweet taste receptors. Using genetic, virogenetic, molecular, and behavioral approaches in mice, we show that glucokinase (GCK) in taste cells is necessary for the attraction to glucose-containing sugars. We further demonstrate that maltase glucoamylase (MGAM), a glycosidic enzyme expressed on and near taste cells, facilitates rapid oral sugar sensing. Disruption of either GCK or MGAM in the major taste fields selectively attenuates the attraction to maltose and a carbohydrate-rich mixed diet, establishing both as intermediaries in the initial transduction pathway for complex saccharides that ultimately give rise to nutrient reward. Molecular profiling of taste papillae further revealed that deficient sweet sensing was accompanied by a compensatory increase in lingual MGAM, highlighting an adaptive mechanism for maintaining oral carbohydrate sensitivity. Together, these findings reveal that the oral epithelium actively preprocesses and metabolically evaluates dietary carbohydrates, providing a mechanism for rapid estimation of energetic value prior to ingestion.
    Significance Statement: Carbohydrates strongly motivate eating, yet most are consumed in complex forms that do not immediately release glucose. We show that the oral epithelium contains an adaptive enzymatic-metabolic sensing system that enables rapid evaluation of glucose-yielding carbohydrates before digestion. Two enzymes, maltase glucoamylase and glucokinase, act locally in taste fields to preprocess and metabolically assess complex sugars, biasing ingestive behavior toward energetically favorable foods. This mechanism operates independently of canonical sweet taste receptors and is dynamically regulated by dietary experience and receptor sensitivity. These findings reveal that the mouth actively estimates the energetic value of food prior to ingestion, reshaping our understanding of how nutrient sensing guides dietary choice.
    DOI:  https://doi.org/10.64898/2026.03.13.710876
  57. Cancer Cell. 2026 Mar 26. pii: S1535-6108(26)00155-8. [Epub ahead of print]
    Cancer type-specific variation in patterns of driver alterations across 50,000 tumors.
    Chaitanya Bandlamudi, Daniel Muldoon, Ino de Bruijn, Mingxuan Zhang, Michael V Gormally, Emily C Harrold, Subhiksha Nandakumar, Shaleigh A Smith, Mark Y Jeng, Sydney Woods, Kanika Arora, Walid K Chatila, Bastien Nguyen, Henry Walch, Jun Woo, Craig M Bielski, Christopher Fong, Thinh N Tran, Gaofei Zhao, Miika Mehine, Maria A Perry, Sam E Tischfield, Allison L Richards, Suraj Rajendran, Hongxin Zhang, Christoph K Kreitzer, Ronak Shah, Risha Huq, Jesse Galle, Tina Alano, Ramyasree Madupuri, Ritika Kundra, Justin Jee, Karl Pichotta, Michele Waters, Richard A Hickman, Josephine K Dermawan, Jie-Fu Chen, Anton Safonov, Konrad H Stopsack, Ritesh R Kotecha, Hira A Rizvi, Claire F Friedman, Pedram Razavi, Ezra Rosen, Yonina R Murciano-Goroff, Luc G T Morris, James A Fagin, Ingo K Mellinghoff, Ping Chi, Neerav N Shukla, Adam J Schoenfeld, Gregory J Riely, Charles M Rudin, Alexander Drilon, Jake June-Koo Lee, Hikmat A Al-Ahmadie, Gopa Iyer, Anna M Varghese, Eileen M O'Reilly, Zsofia K Stadler, Mark E Robson, Ed Reznik, JianJiong Gao, Diana Mandelker, Irina Ostrovnaya, Satshil Rana, Gowtham Jayakumaran, Anita Bowman, Abhinita Mohanty, Anoop Rema Balakrishnan, Aijazuddin Syed, Ryan N Ptashkin, Jacklyn Casanova-Murphy, Debyani Chakravarty, Ryma Benayed, Maria E Arcila, Sarat Chandarlapaty, Helena A Yu, Neal Rosen, Mark T A Donoghue, Christopher A Klebanoff, Rona Yaeger, A Rose Brannon, Ahmet Zehir, Marc Ladanyi, Nikolaus Schultz, David B Solit, Michael F Berger.
      The oncogenic impact of somatic driver alterations is shaped by tissue context. Classifying alterations by cancer type and evaluating their context-specific properties requires large cohorts of genomically profiled and clinically annotated tumors. Here, we define cancer type-specific patterns of driver alterations, including 164 newly identified hotspots, in 54,331 tumors from 48,179 patients spanning 448 histological cancer subtypes. One-third of all drivers arose in non-canonical contexts and exhibited distinct features, including increased subclonality, later emergence, and divergent biological properties. Within cancer types, gene fusions and other distinct patterns of co-occurring drivers are indicative of earlier age of disease onset. We also identify ancestry-specific differences in human leukocyte antigen (HLA)-restricted driver neoantigens affecting T cell receptor therapy eligibility, and demonstrate cancer-type-specific patterns of intrinsic resistance via somatic HLA loss. Our findings highlight that functional roles of driver alterations depend on the cancer types and clinical contexts in which they arise.
    Keywords:  HLA genotype; HLA loss of heterozygosity; age of cancer diagnosis; cancer type-specific; clinical sequencing; driver alterations; hotspots; neoantigen-directed TCR therapies; precision oncology; tissue-specific
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.003
  58. Exp Physiol. 2026 Mar 25.
    Dietary interventions in acute kidney injury: From molecular mechanism to clinical trials.
    Felix C Koehler, Pedro Rojas-Morales, Roman-Ulrich Müller.
      Ageing impairs renal resilience with an elevated risk of frequent and harmful acute kidney injury (AKI) that causes substantial morbidity and mortality among hospitalized patients. Since different damaging stimuli at the molecular, cellular and functional level contribute to this loss in kidney function, AKI's pathophysiology is heterogeneous and complex, and consequently, the development of pharmacological approaches is lagging behind. On the other hand, dietary interventions, such as caloric restriction, periodic fasting, ketogenic diets and restriction of sulfur-containing amino acids have shown immense potential in preserving kidney function in various rodent models of AKI. Deciphering the underlying, but conserved, molecular mechanisms or renal resilience in mice and humans will help to pave the way to successful transfer to the patient setting and may allow the identification of druggable targets. As these diet-induced protective effects of preconditioning are not limited to the kidney, dietary interventions may even be extended to other tissues like the brain or the heart in the context of AKI and beyond.
    Keywords:  acute kidney injury; dietary interventions; resilience
    DOI:  https://doi.org/10.1113/EP092817
  59. Cell Signal. 2026 Mar 20. pii: S0898-6568(26)00147-6. [Epub ahead of print] 112495
    TRIM69 potentiates the cGAS-STING signalling pathway by promoting STING ubiquitination.
    Shixin Chen, Li Yi, Mengzhou Xue, Chunfu Zheng.
      The cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is in charge of cytosolic DNA sensing and, as a result, the production of 2'3' cyclic GMP-AMP (cGAMP), which acts as a second messange molecule to activate the stimulator of interferon genes (STING) and the type I interferon (IFN-I) signalling pathway. We demonstrated that the E3 ubiquitin ligase enzyme TRIM69-induced ubiquitination of STING is necessary for cGAS-STING-mediated IFN-I production during antiviral innate immunity. A direct connection between TRIM69 and STING is essential for the ability of TRIM69 to activate the K63-linked ubiquitination of STING, which results in a significant increase in dimerization and downstream activation of TBK1. These findings suggest that TRIM69 is a novel, positive regulatory protein of the cytosolic DNA-sensing pathway, promoting the cGAS-STING signalling pathway.
    Keywords:  DNA-sensing; STING; TRIM69; Ubiquitination; cGAS
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112495
  60. Cell Death Dis. 2026 Mar 26.
    PCDHGC3 silencing promotes clear cell renal cell carcinoma metastasis via mTOR/HIF2α activation, lipid metabolism rewiring, and ferroptosis evasion.
    Lucía Celada, Tamara Cubiella, Jaime San-Juan-Guardado, Álvaro Suárez-Priede, Nerea Gómez-Suárez, Laura Salerno, Eduardo Murias, Marina Da Silva Torres, Joshua A Weiner, Helena Herrada-Manchón, M Alejandro Fernández, María-Dolores Chiara.
      Clear cell renal cell carcinoma (ccRCC) remains a major clinical challenge due to its high metastatic potential and limited treatment options. Here, we identified PCDHGC3 as a critical tumor suppressor, whose downregulation drives ccRCC aggressiveness. Through integrated molecular analyses, we demonstrated that PCDHGC3 deficiency promoted proliferation, epithelial-to-mesenchymal transition, and metastatic dissemination in both in vitro and in vivo models. Mechanistically, PCDHGC3 knockdown activated mTOR signaling, leading to aberrant HIF2α stabilization, a well-established oncogenic driver in ccRCC. Upstream of this cascade, PCDHGC3 loss was associated with increased focal adhesion kinase (FAK) activation, providing a context-specific link between membrane signaling and mTOR-HIF2α pathway activation. Pharmacological inhibition of mTOR suppresses HIF2α activity and targeting either pathway partially rescues the hyperproliferative and pro-metastatic phenotype of PCDHGC3-deficient cells. Proteomic analysis further revealed that PCDHGC3 loss reprograms lipid metabolism, particularly by increasing fatty acid synthesis and lipid droplet (LD) formation. We identify PLIN2, a HIF2α-regulated gene, as a key mediator of LD stability in PCDHGC3-knockdown cells. By sequestering lipids into LDs, PLIN2 protects against ferroptosis, an iron-dependent form of cell death triggered by lipid peroxidation. Notably, PLIN2 knockdown increases ferroptotic sensitivity, revealing LD biogenesis as a major survival mechanism in PCDHGC3-deficient ccRCC. Together, these findings establish a PCDHGC3-mTOR-HIF2α-PLIN2 axis that underlines both metastatic behavior and ferroptosis evasion. Clinically, this suggests that combining ferroptosis inducers with mTOR or HIF2α inhibitors-and potentially targeting PLIN2-could provide a multifaceted therapeutic strategy against advanced ccRCC. By elucidating the tumor-suppressive role of PCDHGC3, this study expands our understanding of clustered PCDH biology and offers novel insights for ccRCC management.
    DOI:  https://doi.org/10.1038/s41419-026-08643-y
  61. Cell Signal. 2026 Mar 23. pii: S0898-6568(26)00148-8. [Epub ahead of print]143 112496
    Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.
    Lujing Mao, Juan Zou, Huimin Jin, Wenyan Liao, Yukun Li, Daichao Wu.
      Metabolic reprogramming within the tumor microenvironment is a critical driver of CD8+ T cell dysfunction that limits the efficacy of cancer immunotherapy. While glucose and amino acid deprivation are well-characterized, lipid metabolic rewiring has emerged as a fundamental determinant of T cell fate. This review systematically examines the mechanisms by which the tumor microenvironment disrupts CD8+ T cell lipid metabolism to promote functional exhaustion and ferroptosis. We first discuss how local stressors such as hypoxia and acidosis alongside systemic host factors including obesity and hyperlipidemia synergistically impose a metabolic siege on infiltrating T cells. We then detail the molecular pathways of dysregulation revealed by recent lipidomic profiling, including CD36-mediated uptake of oxidized lipids that drives ferroptosis, as well as the dysregulation of cholesterol homeostasis that impairs TCR signaling and induces endoplasmic reticulum stress via the IRE1α-XBP1 axis, which directly drives the transcriptional expression of immune checkpoints. Finally, we evaluate therapeutic strategies such as pharmacological modulation of lipid transporters and metabolic engineering of CAR-T cells which hold promise for restoring metabolic fitness and reinvigorating antitumor immunity.
    Keywords:  CD8(+) T cells; Ferroptosis; Immunotherapy; Lipid metabolism; T cell exhaustion; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112496
  62. Dev Cell. 2026 Mar 23. pii: S1534-5807(26)00118-8. [Epub ahead of print]
    When stress signals to skin: Sympathetic nerves tune immune surveillance.
    Grecia Ortiz Flores, Sakeen Wali Kashem.
      Neural signals are increasingly recognized as modulators of cancer immunity, yet how they influence immune memory within tissues remains unclear. Zhang et al. reveal that sympathetic signaling acts indirectly through epidermal keratinocytes to restrain tissue-resident memory T cell positioning in the skin, uncovering a neuro-epithelial mechanism that shapes tumor immunosurveillance.
    DOI:  https://doi.org/10.1016/j.devcel.2026.03.006
  63. Nat Chem Biol. 2026 Mar 25.
    Biomolecular condensates mediate C-N bond formation.
    Xiaowei Song, Yuefeng Ma, Michael W Chen, Wen Yu, Xiao Yan, Jinheng Xu, Lecheng Lyu, Anthony A Hyman, Yifan Dai, Richard N Zare.
      We discover that biomolecular condensates, formed by intrinsically disordered proteins without inherent chemical activity, can spontaneously drive nonenzymatic reductive amination. These condensates facilitate reactions between amines and aldehydes or ketones, yielding imines, which are subsequently hydrogenated to form alkylated amines leading to C-N bond formation. Our experiments show that condensates modulate the reductive amination of diverse types of metabolite containing carbonyl groups. Using combinatorial metabolomics, we found that condensates generate previously unknown metabolites through the dimerization of natural amines with ketones and aldehydes. Metabolomics in living cells confirms that the ability of condensates in mediating C-N bond formation enables the synthesis of new metabolites and regulates cellular pathways. These findings uncover a previously unrecognized inherent function of biomolecular condensates, redefining their roles in metabolism. This further highlights the broader influence of condensates on chemical homeostasis and biochemical regulation in biological and prebiotic chemistry.
    DOI:  https://doi.org/10.1038/s41589-026-02169-2
  64. bioRxiv. 2026 Mar 05. pii: 2026.03.03.709404. [Epub ahead of print]
    Simulated Microgravity Recapitulates Aspects of Biological Aging in Humans.
    Fei Wu, Alexander Chebykin, Anna Rychkova, Kevin Schneider, Matias Fuentealba, Abhayjit Saini, Heather Halaweh, Nathan Bracey, Mark Davis, Daniel A Winer, David Furman.
      Spaceflight and microgravity profoundly affect human physiology and have been proposed to recapitulate key features of biological aging, yet the underlying mechanisms remain incompletely understood. Here, we performed whole-genome transcriptomic profiling to define immune cell alterations associated with both natural aging and simulated microgravity. Leveraging the longitudinal nature of the Stanford 1,000 immunomes Project, we compared peripheral blood mononuclear cells (PBMCs) exposed to rotating wall vessel bioreactor with matched samples collected up to 9 years later from the same individuals. We quantified changes across aging hallmarks, molecular pathways, gene modules, cellular energetics, disease risk and vaccine-response signatures. Microgravity-induced transcriptional closely tracked subject-level aging trajectories spanning across disease risk domains including those affecting the metabolic, musculoskeletal and circulatory systems, and multiple aging hallmarks involving nutrient sensing, intrinsic capacity, chronic inflammation, proteostasis, cellular senescence and metabolic regulation. Independent validation using Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH) profiling confirmed these observed metabolic adaptations and revealed reduced mitochondrial dependence with minimal compensatory glucose dependence across immune cell subsets, features that strongly parallel aging biology. Consistent with previous findings, longitudinal changes indicated that close of 1/3 of participants do not follow population trajectories but these can be partly predicted with simulated microgravity exposure. Together, this within-donor framework establishes simulated microgravity as a scalable and experimentally tractable platform to model aspects of biological aging in humans and accelerating the prioritization of candidate countermeasures for spaceflight and aging on Earth.
    DOI:  https://doi.org/10.64898/2026.03.03.709404
  65. bioRxiv. 2026 Mar 09. pii: 2026.03.08.710403. [Epub ahead of print]
    Ribosome Molecular Aging Shapes Translation Dynamics.
    Jordy F Botello, Lifei Jiang, Peter J Metzger, Troy J Comi, Aya A Abu-Alfa, Qiwei Yu, Margaret S Ebert, Minkyu Lee, Lennard W Wiesner, Maya Butani, Claire J Weaver, Andrej Košmrlj, Ileana M Cristea, Clifford P Brangwynne.
      Cellular homeostasis relies on continual renewal of cellular components, yet some complexes like ribosomes persist for long periods, raising the question of whether extended molecular age impacts functional fidelity. Here, we introduce a spatiotemporal mapping strategy to resolve biomolecular life stages, and show that intracellular ribosome aging alters translational dynamics at specific transcripts. Molecularly aged ribosomes exhibit impaired elongation at basic amino acid-rich sequences, leading to increased pausing, premature termination, and ribosome collisions. By profiling ribosomal RNA modifications, we find that molecular aging increases the collision propensity of specific ribosome subpopulations. Consistent with our findings, enrichment of aged ribosomes in cells amplifies molecular age-dependent translation defects. In vivo labeling of ribosomes in aged C. elegans demonstrates that molecularly aged ribosomes shape translational dynamics during organismal aging. These findings identify ribosome molecular age as a determinant of translational dynamics, and link molecular aging of a core gene-expression complex to organismal aging.
    HIGHLIGHTS: A pulse-chase labeling strategy enables mapping subcellular demographics of macromolecular complexes in space and time.Molecular aging of ribosomes drives differential mRNA translation and shapes elongation dynamics.The collision propensity of specific ribosome subpopulations increases with molecular age.Older ribosomes shape translation dynamics during organismal aging.
    DOI:  https://doi.org/10.64898/2026.03.08.710403
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