bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–10–25
forty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Cold activates a BH2 metabolic network promoting longevity and proteostasis.
  2. Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer.
  3. BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
  4. NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer.
  5. Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
  6. Mitochondrial transfer between breast cancer cells promotes ROS-dependent proliferation.
  7. Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
  8. Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
  9. Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity.
  10. The rise of reducing reagent-resistant TfR1 dimer marks ferroptosis.
  11. Lung cancer metabolism: a dynamic and adaptive network.
  12. Metabolic hallmarks of regulated cell death.
  13. Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
  14. Metabolite correlation networks reveal complex phenotypes of adaptation-driving mutations.
  15. Phasic metabolic remodeling coordinates cardiac myofibroblast differentiation and function.
  16. Nonadhesive functions of E-cadherin promote cancer cell survival and metastasis.
  17. On the interpretation of diet-specific metabolic effects following weight loss.
  18. Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.
  19. Demand for de novo serine biosynthesis in C. elegans embryos is buffered by the glycine cleavage system and maternal diet.
  20. Context-specific hypermetabolism in humans with mitochondrial defects.
  21. The human microbiome and chronic disease: ten strategic priorities for research and public health.
  22. Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
  23. Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease.
  24. Propionate promotes MHC class I antigen presentation and anti-tumor immunity.
  25. Expanding DepMap: is the juice worth the squeeze?
  26. The Lysosomal Clock: Are We Only as Old as Our Lysosomes?
  27. Proteasome inhibition bidirectionally regulates ferroptosis sensitivity.
  28. MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
  29. In Cellulo Observation of De Novo-Synthesized Nucleotide by Spectral Tracing of Glutamine-Derived Nitrogen Metabolism (QN-STIM) in Cancer Cells.
  30. A cell death ballet in two acts.
  31. HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
  32. A bioavailable GPX4 inhibitor for ferroptosis induction in vivo and tumor suppression.
  33. Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
  34. PHGDH Sustains Oncometabolite Production to Drive Resistance to Mutant IDH Inhibition in Glioma that can be Monitored by Metabolic Imaging.
  35. GRP75-dependent SIMPA mediates inter-organellar quality control.
  36. Cross-Species Profiling of Itaconate-Mediated Modifications by a Universal Probe.
  37. SLC25A20 promotes tumor growth by reprogramming energy metabolism in lung adenocarcinoma.
  38. Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.
  39. Tumor stiffness creates a ferroptotic Achilles' heel through YAP-SKP2 signaling.
  40. A Liquid Chromatography-Mass Spectrometry Method to Quantify Total Coenzyme A Concentration and Isotopic Labeling.
  41. The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.
  42. The tumor macroenvironment as cancer metabolism's next frontier.
  43. Single-oocyte proteome-transcriptome co-profiling reveals a role of dysregulated lactate metabolism in oocyte aging.
  44. Primary tumor-derived lactate primes prostate cancer cells for a dormant fate.
  45. A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes.
  1. Nature. 2026 Oct 21.
    Cold activates a BH2 metabolic network promoting longevity and proteostasis.
    Hyun Ju Lee, Cansu Doğan, Seda Koyuncu, Markus Wehrmann, Murat Artan, Dunja Petrovic, Rute Loureiro, Amit Kumar Sahu, Joana Schnubel, Pavel Grobushkin, Dimitrios Prymidis, Theodoros Georgomanolis, Agnieszka Sokol, Ming Yang, Thorsten Hoppe, Christian Frezza, David Vilchez.
      Moderately cold temperatures extend lifespan and promote health across species1-3, yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4). BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures. In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.
    DOI:  https://doi.org/10.1038/s41586-026-11152-9
  2. Cell. 2026 Oct 23. pii: S0092-8674(26)01186-4. [Epub ahead of print]
    Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer.
    Jun W Kim, Christina M Bebber, Yuqin Dai, Sarah Bopp, Anna Edenhofer, Albert M Li, Thomas Rösner, Lena Berning, Ming Yang, Logan B Leak, Jenny Stroh, Bindesh Shrestha, Ali T Abdallah, Dimitrios Prymidis, Hernando J Olivos, Maya Baron, Thuyen Nguyen, Yan Ting Shue, Yoko Nishiga, Alexandros P Drainas, Andrea C Chaikovsky, Krystina Szylo, Yang Li, Yun P Kang, Parvathy Manoj, Alvaro Quintanal Villalonga, Charles M Rudin, Gina M DeNicola, Scott J Dixon, Christian Frezza, Jiangbin Ye, Silvia von Karstedt, Julien Sage.
      Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here, we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive cancer type with considerable plasticity between neuroendocrine (NE) and non-NE cellular states. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low ASCL1 transcription factor levels underwent ferroptosis upon Cys depletion, whereas ASCL1high cells underwent apoptosis while remaining resistant to ferroptosis. This ferroptosis resistance was driven by the direct transcriptional activation of GCH1 by ASCL1, resulting in increased levels of the antioxidants BH4/BH2. Accordingly, combined Cys depletion and inhibition of BH4/BH2 synthesis reduced tumor growth in patient-derived xenografts. These findings demonstrate that metabolic state influences cell-death susceptibility in SCLC and provide a rationale for therapeutic strategies that exploit these metabolic differences.
    Keywords:  ASCL1; GCH1; SCLC; apoptosis; ferroptosis; heterogeneity; lung cancer; metabolism; neuroendocrine; plasticity
    DOI:  https://doi.org/10.1016/j.cell.2026.09.045
  3. Science. 2026 Oct 22. 394(6822): eaea2181
    BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
    Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.
      The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.
    DOI:  https://doi.org/10.1126/science.aea2181
  4. Sci Adv. 2026 Oct 23. 12(43): eaea1431
    NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer.
    Agustín E Morellato, Natividad Alquezar-Artieda, Alejandro Guerrero-Maldonado, Rajinder Singh, Lilla Beja, Carla Umansky, Laura Perich-Pallaruelo, Mireia Pellicer, Paula Fernandez-Deu, Nicolas Aira, Nour Bourached-Silva, Uciel Chorostecki, Donald J L Jones, Gaël Roué, Richard J Hopkinson, Lucas B Pontel.
      Cancer cells must balance detoxification of reactive metabolic by-products while preserving redox homeostasis, but how this trade-off is managed remains unclear. The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor-erythroid 2-related factor 2 (NRF2) pathway, a key regulator of antioxidant defenses, is frequently hyperactivated in cancer. Formaldehyde, a genotoxic one-carbon by-product, is typically detoxified via glutathione (GSH), which is also essential for suppressing ferroptotic cell death. Here, we show that NRF2 promotes formaldehyde tolerance through up-regulation of the cystine transporter SLC7A11, enabling a protective mechanism that is largely independent of GSH, which remains necessary for ferroptosis resistance. In NRF2-active cells, formaldehyde reacts with cysteine to form a thiazolidine conjugate, and the combination of formaldehyde stress and SLC7A11 inhibition activates the integrated stress response, suppresses global protein synthesis, and markedly compromises cell viability. Together, these findings reveal that NRF2 coordinates ferroptosis resistance and formaldehyde tolerance, exposing a cancer vulnerability through combined inhibition of cystine uptake and GSH synthesis.
    DOI:  https://doi.org/10.1126/sciadv.aea1431
  5. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123
    Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
    Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.
      When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.
    Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2613074123
  6. bioRxiv. 2026 Aug 27. pii: 2026.08.26.747325. [Epub ahead of print]
    Mitochondrial transfer between breast cancer cells promotes ROS-dependent proliferation.
    Noah M Bressler, Taylor Z Stevens, Minna Roh-Johnson.
      Previously, we showed that macrophages transfer mitochondria to breast cancer cells, promoting proliferation in acceptor cancer cells. Transferred mitochondria were depolarized and accumulated reactive oxygen species (ROS), and the mitochondrial transfer-induced proliferation was dependent upon ROS signaling (Kidwell et al. 2023). Our unexpected findings supported a model in which transferred mitochondria act as a signal for proliferation in acceptor cancer cells rather than a direct source of increased bioenergetics. It remains unclear whether this unexpected signaling mechanism is unique to macrophages as the donor cell, or whether this mechanism applies to mitochondrial transfer between other cells within the tumor microenvironment. Here, we show that highly metastatic cancer cells transfer mitochondria to weakly metastatic cancer cells. These transferred mitochondria are depolarized, accumulate ROS, and promote ROS-dependent proliferation in acceptor cancer cells. Furthermore, we specifically attribute this proliferative phenotype to the transfer of mitochondria, as when we isolate mitochondria from highly metastatic cells and apply these purified mitochondria directly to weakly metastatic cells in culture, acceptor cancer cells that internalize the purified mitochondria exhibit increased proliferation in a ROS-dependent manner. These findings support mitochondrial transfer within the breast tumor microenvironment as a signaling axis for proliferation, regardless of donor cell identity.
    DOI:  https://doi.org/10.64898/2026.08.26.747325
  7. Cell. 2026 Oct 23. pii: S0092-8674(26)01208-0. [Epub ahead of print]
    Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
    Hannah N Bell, Kavya Nair, Kole Tison, Peng Liao, Hongwei Lei, Marwa O El-Derany, Ayijiang Yisimayi, Haiwei Zhang, Ryan Rebernick, Weichao Wang, Yoshitaka Adachi, Cristina Castillo, Nupur K Das, Jinsu An, Vivien R Sutton, Xun Lin, Heng Lin, Xinghao Wang, Yunfei Li, Linda Vatan, Amr Aboud, Shuang Wei, Miguel Gijon, Samantha Goodwin, Yatrik M Shah, Ilona Kryczek, Joseph A Trapani, Margarida Barroso, Judy Lieberman, Weiping Zou.
      Cytotoxic CD8+ T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.
    Keywords:  NK cell; T cell; ferroptosis; granzyme; immune checkpoint blockade; iron; mitochondria; perforin
    DOI:  https://doi.org/10.1016/j.cell.2026.09.062
  8. Cell. 2026 Oct 23. pii: S0092-8674(26)01207-9. [Epub ahead of print]
    Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
    Chenyang Guan, Seungjin Ryu, Mingze Dong, Yitao Zhu, Rae Maeda, Yun-Hee Youm, Subhasis Mohanty, Hee-Hoon Kim, Lucie Orliaguet, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Hal M Hoffman, Stephan Siebel, Andrew Wang, Yaqiu Wang, Yuval Kluger, Albert C Shaw, Thirumala-Devi Kanneganti, Nathan LeBrasseur, Yuki Sugiura, Vishwa Deep Dixit.
      Whether a decline in taurine drives aging is debated, and despite high millimolar intracellular concentrations, its function as a potential guardian of cytosolic homeostasis is unclear. Here, we show that aging increases circulating taurine concentrations in humans and mice. Further elevating taurine in aged mice enhances health span, engaging anti-inflammatory pathways previously linked to youthfulness, and reduces mortality from sepsis and inflammasome-mediated inflammation, suggesting an enantiostatic response. Mechanistically, diverse NLRP3-specific "danger signals" induce taurine efflux from macrophages as a proximal step to activate the inflammasome and the resultant pyroptosis. Taurine restoration in macrophages prevents NLRP3-induced trans-Golgi network disassembly, thereby suppressing NLRP3 inflammasome activation. Conversely, lowering taurine biosynthesis combined with reduced bioavailability in macrophages exacerbated inflammasome activation. In humans, sustained caloric restriction elevates adipose tissue taurine and is accompanied by lower inflammation. Together, we identify taurine as an immunometabolic rheostat that links danger sensing to NLRP3 inflammasome activation, suggesting taurine-based strategies to alleviate inflammaging and inflammasomopathies.
    Keywords:  NLRP3; aging; antiinflammation; caloric restriction; immunometabolism; inflammaging; inflammasome; lifespan; taurine; taurine efflux
    DOI:  https://doi.org/10.1016/j.cell.2026.09.061
  9. iScience. 2026 Nov 20. 29(11): 117722
    Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity.
    Eric R McGregor, Cassandra J McGill, Nicholas L Arp, Josef P Clark, Dominique A Baldwin, Yusi Cui, Alexander Nassar, Di Kuang, Gonzalo Fernandez-Fuente, Yun Hwa Choi, Keenan S Pearson, Jason K Nagorski, Lingjun Li, Judith A Simcox, Jing Fan, Luigi Puglielli, Rozalyn M Anderson.
      Acetyl-CoA is a molecule central to cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 mutations have been linked to peripheral neuropathy, developmental delay with premature death, and intellectual disability with progeria. Here, we show that AT-1 overexpression impacts diverse phenotypes related to neuronal function and plasticity. Differences in ribosomal, synaptic processing, and metabolic pathways were identified at transcriptomic and proteomic levels. Metabolic adaptations included changes in mitochondrial membrane potential, architecture, and respiration, and tracing experiments revealed changes in the fate of glucose favoring glycogen storage over the pentose phosphate pathway. Altered redox was linked to NAD-dependent proteins SIRT1 and CtBP2. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization. Metabolic adaptation was coincident with decreased synaptic activity, indicating that neuronal communication is coordinated, in part, through acetyl-CoA metabolism.
    Keywords:  acetyl-CoA; glucose utilization; lipids; metabolism; mitochondria; neuron
    DOI:  https://doi.org/10.1016/j.isci.2026.117722
  10. Nat Cell Biol. 2026 Oct 21.
    The rise of reducing reagent-resistant TfR1 dimer marks ferroptosis.
    Jianping He, Mackenzie Kelleher, Geraldine Veeckmans, Yuezhong Zhang, Luke Reynolds, Hannah M Tanczos, Zhengrong Huang, Brett P McLaughlin, Mary Ann Martinez Molina, Ava Lightburn, Mira Zamarro, Wesley Huang, Stephenson B Owusu, Magali Walravens, Cyril Willemart, Behrouz Hassannia, Lauren E Pope, Christopher Gager, Alec J Vaughan, Zhe Wang, Simon Weaver, William Boggess, Xin Lu, Thales Papagiannakopoulos, Ana Lidia Flores-Mireles, Parakkal Deepak, Matthew A Ciorba, Bryan G Allen, John M Buatti, Michael S Petronek, Scott J Dixon, Tom Vanden Berghe, Yatrik M Shah, Zachary T Schafer.
      Ferroptosis is an iron-dependent type of cell death caused by excessive membrane lipid peroxidation. It remains a challenge to detect ferroptotic cells, especially in in vivo settings, hindering translational studies. Here we discover that a reducing reagent-resistant (3R) dimer of the transferrin receptor 1 (TfR1) is a highly specific indicator for lipid peroxidation. The 3R dimer is elevated in cells when ferroptosis is induced, either by pharmacological agents or by genetic perturbations. Furthermore, the 3R dimer can be used to detect disease-associated ferroptosis in tissue and in extracellular vesicles isolated from mouse or patient plasma. Given the near-ubiquitous expression of TfR1, we posit that the 3R dimer may function as a ferroptosis marker with widespread potential utility for basic and translational studies.
    DOI:  https://doi.org/10.1038/s41556-026-02107-3
  11. Cell Mol Life Sci. 2026 Oct 19. pii: 389. [Epub ahead of print]83(1):
    Lung cancer metabolism: a dynamic and adaptive network.
    Sara Gholamhosseinian-Najjar, Christian Frezza.
      Lung cancer remains the leading cause of cancer-related mortality worldwide. Although substantial progress has been made in defining the genetic, epigenetic, and molecular drivers of this heterogeneous disease, metabolic reprogramming has only recently emerged as a major determinant of tumour progression and therapeutic response. Cumulative evidence demonstrates that rather than relying on a single nutrient source or pathway, cancer cells integrate glucose and glutamine, fatty acid and one-carbon metabolism, as well as nucleotide biosynthesis, and redox-supporting circuits in a highly context-dependent manner. These programs vary across histological and molecular subtypes, reflecting the influence of lineage identity and oncogenic state on metabolic organisation. In both non-small cell lung cancer and small cell lung cancer, subtype-specific constraints shape distinct metabolic states, yet a common feature is the ability to rapidly shift between alternative nutrients and biosynthetic routes. This adaptability supports continued growth under nutrient limitation, maintains redox homeostasis, and contributes to resistance against conventional and targeted therapies. By summarising current mechanistic evidence, this review presents lung cancer metabolism as an integrated and adaptable system rather than a collection of isolated pathways, and identifies metabolic dependencies that may be leveraged for therapeutic intervention.
    Keywords:  Glucose metabolism; Glutamine metabolism; Lung cancer metabolism; Metabolic plasticity; Nucleotide metabolism; Sulphur metabolism.
    DOI:  https://doi.org/10.1007/s00018-026-06417-5
  12. Cell Res. 2026 Oct 20.
    Metabolic hallmarks of regulated cell death.
    Rui Kang, Xin Chen, Guido Kroemer, Daolin Tang.
      Regulated cell death (RCD) is characterized by distinct molecular execution mechanisms, but its initiation, progression, and biological consequences are increasingly recognized as being shaped by cellular metabolism. Bioenergetic state, redox homeostasis, nutrient availability, metal ion metabolism, inflammatory metabolism, and organelle function collectively determine cellular susceptibility to death and influence the activation and execution of diverse RCD programs. In this review, we synthesize the metabolic hallmarks of established, independently validated, and recently proposed forms of RCD, highlighting both their mechanistic diversity and their extensive metabolic convergence. We then examine the endogenous mechanisms that maintain metabolic homeostasis and discuss how their disruption reshapes cell death responses in human disease and therapeutic contexts. Together, these insights provide a guide to  the metabolic landscape of RCD and reveal metabolism not only as a modifier of cell death, but as a fundamental determinant of when, how, and with what consequences cells die. We conclude by discussing key conceptual and mechanistic challenges and emerging opportunities for therapeutically exploiting the metabolic control of RCD.
    DOI:  https://doi.org/10.1038/s41422-026-01306-9
  13. Leukemia. 2026 Oct 23.
    Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
    Ilias Sinanidis, Panagiotis Tsakiroglou, Benjamin Dubner, Rebecca Foertsch, Julia Gondek, InYoung Choi, Bogdan Paun, Teodora Supeanu, Liang Zhao, Gabriel Ghiaur, W Brian Dalton.
      Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation of the serine synthesis pathway (SSP) can fuel tumor growth, and cancers with this phenotype are often sensitive to. SSP inhibitors. In parallel, dietary restriction of serine and glycine (SG) can suppress some cancers, but the determinants of sensitivity to. this approach are poorly understood. This is especially true in acute myeloid leukemia (AML), where serine metabolism has been less explored. We report that a subset of human AML cell lines and primary samples are completely dependent on external serine, known as serine auxotrophy. These leukemias consistently suppressed the SSP enzyme PSAT1, failed to. synthesize serine, responded to. SG restriction in vivo, and were rescued by restoring PSAT1. We also found that SG restriction synergized with venetoclax in serine auxotrophic AML, and that MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy. These findings define a metabolically distinct AML subtype and nominate it for targeting by SG restriction.
    DOI:  https://doi.org/10.1038/s41375-026-03176-x
  14. Nat Commun. 2026 09 16. pii: 10900. [Epub ahead of print]17(1):
    Metabolite correlation networks reveal complex phenotypes of adaptation-driving mutations.
    Sharon Samuel, Weronika Jasinska, Ezra Sternlicht, Matvey Nikelshparg, Daniel Kleiner, Shai Pilosof, Shimon Bershtein.
      Metabolic adaptation is often driven by mutations in pleiotropic genes that affect metabolism globally. However, identifying which phenotypes produced by such mutations drive selection remains difficult. Here, we consider metabolite correlation networks as a systems-level phenotype whose emergent properties reflect the combined effects of biochemical reactions and regulation. We hypothesize that mutation-induced changes in the covariance structure of these networks constitute complex phenotypes linking genetic change to bacterial fitness, and that node-level shifts can identify metabolites and pathways mechanistically associated with adaptation. We test this hypothesis by applying adaptive laboratory evolution to a metabolically suboptimal Escherichia coli strain in which metK, encoding methionine adenosyltransferase (MAT), is replaced by an ortholog from Ureaplasma urealyticum. Untargeted metabolite correlation networks reveal that evolution shifts S-adenosylmethionine (SAM), the MAT product, from a peripheral node to a key connector between network clusters. None of the accumulated pleiotropic mutations causing the shift directly affect MAT activity or SAM metabolism, indicating that this transition emerges from system-level metabolic reorganization. Targeted metabolomics of nodes showing similar shifts identifies additional metabolites involved in SAM-related pathways. These findings establish metabolite correlation networks as a framework for mapping genotype-phenotype-fitness relationships and prioritizing metabolic nodes linked to adaptive mechanisms.
    DOI:  https://doi.org/10.1038/s41467-026-77850-0
  15. Redox Biol. 2026 Oct 16. pii: S2213-2317(26)00440-4. [Epub ahead of print]98 104441
    Phasic metabolic remodeling coordinates cardiac myofibroblast differentiation and function.
    Collin K Wells, Lianay Gutierrez Luque, Daniel C Nguyen, Madison S Teer, Ning Chen, Yania Martinez-Ondaro, Pawel K Lorkiewicz, Richa Singhal, Maleesha De Silva, Bradford G Hill.
      Fibroblast differentiation into matrix-producing, contractile myofibroblasts is accompanied by metabolic reprogramming, but whether these changes precede differentiation or arise from the activated phenotype remains unclear. We integrated time-resolved extracellular flux analysis, transcriptomics, stable isotope-resolved metabolomics, and metabolic interventions to define the relationship between metabolism and myofibroblast differentiation in adult mouse cardiac fibroblasts stimulated with transforming growth factor-β (TGFβ). TGFβ increased glycolysis within 1.5 h, before broad transcriptional remodeling and induction of periostin and α-smooth muscle actin. Mitochondrial respiration initially declined but increased at 48 h as the phenotype emerged, accompanied by smaller, less elongated mitochondria and greater respiratory capacity. [U-13C6]-glucose tracing revealed progressive incorporation of glucose-derived carbon into glycolytic intermediates, nucleotide sugars, and glycerol 3-phosphate, followed later by increased labeling of tricarboxylic acid cycle intermediates. TGFβ-treated fibroblasts also demonstrated enhanced insulin-stimulated glycolysis. Replacing glucose with galactose attenuated collagen and periostin induction, whereas glyceraldehyde 3-phosphate dehydrogenase inhibition prevented induction of collagen, periostin, and α-smooth muscle actin. Conversely, glucose transporter 1 or mutant PFK2 (GlycoHi) overexpression increased glycolysis without inducing myofibroblast markers. Together, these loss- and gain-of-function studies indicate that glycolytic activity is required for complete differentiation but is not sufficient to initiate the phenotype. Inhibition of mitochondrial Complex I or ATP synthase preferentially reduced collagen abundance, while glycolytic and Complex I inhibition diminished TGFβ-induced collagen gel contraction. These findings define a phasic metabolic program in which early glycolytic activation precedes transcriptional and phenotypic remodeling, whereas mitochondrial respiratory capacity increases later and distinct metabolic nodes selectively regulate collagen abundance and contractile behavior.
    Keywords:  Biosynthesis; Fibroblast; Fibrosis; Glycolysis; Mitochondria; Stable isotope
    DOI:  https://doi.org/10.1016/j.redox.2026.104441
  16. J Cell Biol. 2026 Nov 02. pii: e202507222. [Epub ahead of print]225(11):
    Nonadhesive functions of E-cadherin promote cancer cell survival and metastasis.
    Ryan L Huizar, James V McCann, Malak Amer, Beza Woldemeskel, Daisuke Murata, Nanami Senoo, Abhijit Deb Roy, Benjamin C Orsburn, Steven M Claypool, Hiromi Sesaki, Miho Iijima, Namandjé N Bumpus, Takanari Inoue, Andrew J Ewald.
      E-cadherin suppresses invasion and promotes metastasis in invasive ductal breast cancer, through suppression of reactive oxygen species (ROS). We sought to determine the cellular source of apoptosis-inducing ROS and to identify the domains of E-cadherin that are essential for cancer cell survival. Inhibition of mitochondria-derived ROS was sufficient to rescue cell death following E-cadherin deletion, in both 3D colony formation and in vivo metastasis assays. We next generated Cdh1 constructs by mutating amino acids or deleting domains, then tested their ability to rescue colony formation in E-cadherin-deleted cells. Surprisingly, E-cadherin constructs in which the extracellular domains were deleted, adhesion was compromised, or catenin interactions were blocked could rescue elevated mitochondrial ROS and 3D colony formation. Conversely, a construct lacking the cytoplasmic domain was unable to rescue ROS or cell death. Our findings reveal that E-cadherin's ability to regulate mitochondrial ROS, cancer cell survival, and metastatic outgrowth is separable from its role in intercellular adhesion.
    DOI:  https://doi.org/10.1083/jcb.202507222
  17. Cell Metab. 2026 Oct 22. pii: S1550-4131(26)00385-2. [Epub ahead of print]
    On the interpretation of diet-specific metabolic effects following weight loss.
    Faidon Magkos.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.010
  18. Nat Commun. 2026 09 18. pii: 10949. [Epub ahead of print]17(1):
    Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.
    Blanca Majem, Min-Sik Lee, Kyung Cheul Shin, Insia Naqvi, Courtney Dennis, Lucas Dailey, Sarah Jeanfavre, Mari Mino-Kenudson, Joao B Xavier, Clary B Clish, Deepti Mathur, Nada Y Kalaany.
      Cachexia or body wasting is a significant contributing factor to the morbidity and mortality of pancreatic cancer. Despite an unmet need, its metabolic underpinnings remain poorly understood. Here, we characterize a mouse model that recaptures the longitudinal progression of human cachexia during pancreatic cancer development. We profile the metabolomes of pre-, early- and late-stage cancer-associated cachexia in male and female pancreas, its interstitial fluid (IF), plasma, liver, adipose tissue and skeletal muscle. We find that each tissue has a unique metabolome and trajectory across stages and reveal a marked lipid enrichment in the tumor IF. Using mathematical modeling, we identify metabolites participating in cross-tissue networks and in vivo validate a lactate-glucose conversion. We find systemic metabolic changes prior to weight loss and use feature selection algorithms to identify early detection markers. Our study provides a resource for system-wide metabolic evolution of pancreatic cancer and associated cachexia, highlighting the potential for timely diagnostics and interventions.
    DOI:  https://doi.org/10.1038/s41467-026-77745-0
  19. J Biol Chem. 2026 Oct 21. pii: S0021-9258(26)02539-1. [Epub ahead of print] 113667
    Demand for de novo serine biosynthesis in C. elegans embryos is buffered by the glycine cleavage system and maternal diet.
    Joanna Zaino, Amanda Anderson, Omar Rachidi Alaoui, Olga Ponomarova.
      Metabolic network plasticity helps organisms survive change, including dietary fluctuations, transitions between developmental stages and genetic perturbations. To maintain a robust supply of resources under these conditions, metabolic networks must rebalance flux across individual pathways. However, how pathways coordinate their activity to support homeostasis remains poorly understood. Here, we use metabolomics, dietary supplementation, and genetic screening to investigate how the network compensates for the loss of phosphoglycerate dehydrogenase PHDH-1, the rate-limiting enzyme in serine biosynthesis. We find that PHDH-1 dysfunction causes developmental delay and substantially alters the metabolome of C. elegans embryos, but not that of adult animals. Despite these perturbations, Δphdh-1 mutant embryos remain viable through the compensatory activity of enzymes that we identified through a genetic interaction screen. The identified PHDH-1 interactions span the metabolic network and are alleviated by maternal serine supplementation, revealing wide-ranging functional links between serine metabolism and distant pathways. We further demonstrate how the joint action of PHDH-1, the glycine cleavage system and the maternal diet sustains embryonic one-carbon metabolism. Overall, our results reveal how metabolic networks buffer the supply of one-carbon units to compensate for enzyme dysfunction and support robust development.
    Keywords:  C. elegans; Metabolism; embryo; glycine cleavage system; one-carbon metabolism; phosphoglycerate dehydrogenase; serine
    DOI:  https://doi.org/10.1016/j.jbc.2026.113667
  20. Cell Press Blue. 2026 Oct 07. pii: 100129. [Epub ahead of print]
    Context-specific hypermetabolism in humans with mitochondrial defects.
    Evan D Shaulson, Alexander J Sercel, Shannon Rausser, Samantha Leonard, Kathryn Whyte, Faris Zuraikat, Heather Seid, Qiuhan Huang, Alex Junker, Darshana Kapri, Mangesh Kurade, David Shire, Joanna Chen, Caroline Trumpff, Catherine Kelly, Natalia Bobba-Alves, Kris Englestad, Herman Pontzer, Wei Shen, Seth A Creasy, Edward L Melanson, Michael Rosenbaum, Marie-Pierre St-Onge, Dympna Gallagher, Michio Hirano, Martin Picard.
      Pathogenic mitochondrial DNA (mtDNA) defects test how impaired oxidative phosphorylation reshapes human energy expenditure. We studied adults with confirmed mtDNA defects (MitoD) and healthy controls using whole-room indirect calorimetry, doubly labeled water, quantitative magnetic resonance, actigraphy, autonomic monitoring, mood assessments, plasma inflammatory markers, and growth differentiation factor 15 (GDF15). Under behaviorally clamped conditions, fat-free mass-adjusted 24-h energy expenditure (24-h EE) was consistently higher in MitoD, with higher non-resting expenditure per unit wrist acceleration by day, and blunted sleep-related metabolic suppression at night. In contrast, free-living total daily energy expenditure (TDEE) was similar between groups despite lower physical activity in MitoD, consistent with behavioral compensation within a constrained energy budget. Plasma GDF15 was ~5-fold higher in MitoD and tracked with disease severity, systemic inflammation, fatigue, energetic burden, and lower habitual activity. These findings identify a persistent energetic burden in MitoD that is buffered in daily life and associated with elevated GDF15.
    Keywords:  GDF15; doubly labeled water; energy expenditure; fatigue; hypermetabolism; metabolic phenotyping; mitochondrial disease; resting energy expenditure; sickness behavior; whole-room indirect calorimetry
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100129
  21. Nat Med. 2026 Oct 23.
    The human microbiome and chronic disease: ten strategic priorities for research and public health.
    Martin J Blaser, Frederic D Bushman, Maria Gloria Dominguez-Bello, Eran Elinav, Sangeeta Khare, Rob Knight, Jennie H Kwon, Sarkis K Mazmanian, Majdi Osman, Nicola Segata, Tim Spector, Jennifer A Wargo, Suchitra K Hourigan.
      
    DOI:  https://doi.org/10.1038/s41591-026-04730-x
  22. Gastroenterology. 2026 Oct 21. pii: S0016-5085(26)07348-8. [Epub ahead of print]
    Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
    Alica K Michels, Sabrina Calderon, Ethan Nghiem, Eleni Zimmer, Leonor Schubert Santana, Rima Singh, Tim Eiseler, Chantal Allgöwer, Gregory Tong, Sharon Wu, Kevin Gulay, Mumina Sadullozoda, Austin Silva, Cecily Anaraki, Natalie Yousefian, Devon F Pendlebury, Cameron Geller, Alina Chao, Dennis Juarez, Thomas Seufferlein, Cholsoon Jang, Aimee L Edinger, Marcus Seldin, Alexander Muir, Thomas F Martinez, Alexander Kleger, David K Chang, Herve Tiriac, Jennifer B Valerin, David A Fruman, Christopher J Halbrook.
       BACKGROUND & AIMS: Gemcitabine remains a cornerstone of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) but acquired resistance limits its efficacy. While both microenvironment-derived metabolites and intrinsic metabolic reprogramming have been implicated in gemcitabine resistance, the relationship between these mechanisms remains poorly understood. We investigated the metabolic adaptations accompanying acquired gemcitabine resistance and identified therapeutically actionable vulnerabilities.
    METHODS: Acquired gemcitabine-resistant PDAC models were generated and characterized. The effects of physiological pyrimidines on gemcitabine response were evaluated alongside changes in pyrimidine metabolism. Sensitivity to inhibition of the mevalonate pathway was assessed in vitro and in immunocompetent mouse models. Metabolite rescue experiments were performed to identify critical downstream mediators of statin activity and HMGCR expression was analyzed for its association with clinical response to gemcitabine.
    RESULTS: PDAC cells with acquired gemcitabine resistance exhibited diminished sensitivity to physiological extracellular pyrimidines due to suppression of the pyrimidine salvage pathway. This metabolic rewiring created a selective dependency on the mevalonate biosynthesis pathway, rendering gemcitabine resistant cells highly sensitive to statins. Statin treatment selectively inhibited the growth of gemcitabine-resistant tumors in mice. Metabolite rescue studies identified geranylgeranyl pyrophosphate depletion, not cholesterol limitation, as a principal mediator of statin sensitivity. HMGCR expression declined progressively during the acquisition of gemcitabine resistance and low HMGCR expression levels predicted poor response to gemcitabine-based therapy in PDAC patients.
    CONCLUSIONS: Acquired gemcitabine resistance drives metabolic reprogramming that suppresses pyrimidine salvage while creating a therapeutically exploitable dependence on the mevalonate pathway. These findings identify pharmacological inhibition of HMGCR as a metabolic vulnerability in gemcitabine resistance and support HMGCR expression as a candidate biomarker for treatment stratification in PDAC patients.
    Keywords:  3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR); Chemotherapy resistance; Pancreatic ductal adenocarcinoma; Statin
    DOI:  https://doi.org/10.1053/j.gastro.2026.09.027
  23. Nat Commun. 2026 09 22. pii: 11013. [Epub ahead of print]17(1):
    Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease.
    Gaurav Kumar Lohia, Ying-Tsun Chen, Samantha Chen, Ayesha Beg, Erin Theiller, Aomeng Cui, Ahmed M Moustafa, Sebastián A Riquelme.
      Cystic fibrosis (CF), caused by CFTR mutations, is characterized by progressive pulmonary remodeling, particularly during bacterial infection. This pathological environment, exacerbated by altered epithelial growth, leads to thickened airway walls, inducing permanent narrowing and long-term breathing difficulties. However, what drives this adverse milieu remains unclear. Here, we identify activation of the de novo pathway of pyrimidine synthesis (DNPPS) as a central contributor of CF lung remodeling. In response to impaired mitochondrial bioenergetics, CFTR-mutant epithelial cells engage compensatory DNPPS activity, functionally coupling mitochondrial oxidative metabolism to pyrimidine production and, inadvertently, promoting proliferation. This phenotype is reversible with CFTR modulators and pharmacologic DNPPS inhibitors using clinically established agents. Strikingly, Pseudomonas aeruginosa, the predominant CF pathogen, undergoes convergent pyrimidine adaptation, activating its own DNPPS machinery to amplify biomass and sustain a remodeled niche. Together, these findings define pyrimidine metabolism as a shared host-pathogen axis driving epithelial restructuring and bacterial persistence in the CF lung.
    DOI:  https://doi.org/10.1038/s41467-026-77940-z
  24. Cell Metab. 2026 Oct 21. pii: S1550-4131(26)00393-1. [Epub ahead of print]
    Propionate promotes MHC class I antigen presentation and anti-tumor immunity.
    Suyao Li, Dong Guo, Qingqing Yang, Yizhi Cao, Yu Dong, Xiaoming Jiang, Xinyao Tian, Dou Nie, Lihui Wu, Qingang Wu, Xuxiao He, Yanyan Hu, Rongxuan Zhu, Ning Zhu, Shudi Luo, Yinan Shen, Yuhao Wang, Zhexu Chi, Ying Yuan, Daqian Xu, Weilin Wang, Yuan Ding, Zhimin Lu.
      Defective tumor antigen presentation promotes immune evasion and resistance to immune checkpoint blockade. Here, we identified the short-chain fatty acid propionate as a potent enhancer of major histocompatibility complex class I (MHC class I) antigen presentation. Propionate stabilizes MHC class I on tumor cells, promotes CD8+ T cell infiltration and activation, and suppresses tumor growth. Mechanistically, the E3 ubiquitin (Ub) ligase STUB1 directly interacts with human leukocyte antigen (HLA)-A to mediate K168/K170 polyubiquitination and subsequent degradation. Propionate directly binds STUB1 through hydrogen bonds involving K30 and N34, residues that overlap with the MHC class I-binding interface. This interaction blocks STUB1-mediated MHC class I polyubiquitination, thereby stabilizing MHC class I, enhancing T cell receptor (TCR) engagement and T cell activation, and restraining tumor growth. Importantly, propionate or the propionate-producing probiotic Akkermansia muciniphila markedly enhanced anti-PD-1 efficacy. These findings uncover a non-metabolic moonlighting function of short-chain fatty acids in regulating tumor immunity and provide a rationale for leveraging dietary propionate or propionate-producing probiotics to enhance immune checkpoint therapy.
    Keywords:  MHC class I; SCFA; STUB1; immune response; immune therapy; propionate; tumor; ubiquitination
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.018
  25. Cell Res. 2026 Oct 21.
    Expanding DepMap: is the juice worth the squeeze?
    Samir Zaidi, Charles L Sawyers.
      
    DOI:  https://doi.org/10.1038/s41422-026-01311-y
  26. Traffic. 2026 Dec;27(4): e70056
    The Lysosomal Clock: Are We Only as Old as Our Lysosomes?
    Alexis Diaz Vegas, Thierry Galli.
      Lysosomes are a major organelle involved in intracellular degradation, membrane traffic and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Puszynska and colleagues now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis. The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders and vulnerability to late-onset neurodegeneration.
    DOI:  https://doi.org/10.1111/tra.70056
  27. Cell Chem Biol. 2026 Oct 21. pii: S2451-9456(26)00369-7. [Epub ahead of print]
    Proteasome inhibition bidirectionally regulates ferroptosis sensitivity.
    Magdalena B Murray, Rishi Upadhyay, Krystina J Szylo, Aastha Gautam, Judith Goncalves, Giovanni Forcina, Ananya Vinayak, Onn Brandman, Scott J Dixon.
      Ferroptosis is a non-apoptotic cell death mechanism whose fundamental regulation continues to be elucidated. The proteasome is an essential multiprotein complex important for protein turnover. How proteasome function regulates ferroptosis is difficult to study given that proteasome inhibition causes apoptosis. Here, we isolated the effects of proteasome inhibition on ferroptosis by combining small molecule cell death inducers, pathway-specific cell death inhibitors, and direct cell death imaging. We find that proteasome inhibition enhances sensitivity to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition while simultaneously promoting resistance to ferroptosis induced by system xc- inhibition. Sensitization to GPX4 inhibition requires protein synthesis but not the apoptosis execution machinery and is opposed by the activating transcription factor 4 (ATF4) stress response pathway. These findings establish proteasome-mediated protein turnover as a context-dependent regulator of ferroptosis and identify protein synthesis and ATF4 as key determinants of GPX4 inhibitor sensitivity.
    Keywords:  ATF4; Necrosis; cancer; iron metabolism; lipid peroxidation; oxidative stress; protein synthesis; ubiquitination
    DOI:  https://doi.org/10.1016/j.chembiol.2026.09.020
  28. Cell. 2026 Oct 22. pii: S0092-8674(26)01205-5. [Epub ahead of print]
    MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
    Shuke Xiao, Alan Sheng-Hwa Tung, Jan Spaas, Sipei Fu, Xudong Chen, Tuan Kiet Trinh, Maria Dolores Moya-Garzon, Veronica L Li, Hannah T Cessna, Kentaro Ito, Saranya C Reghupaty, Chao Lin, Xuchao Lyu, Steffen H Raun, Miles D W Tyner, Arthur Germakovski, Jacob Tondreau, Megan Yeckley, Wei Wei, Michael R Howitt, Mark D Parker, Jason A Sprowl, Stephen M Hinshaw, Jonathan Z Long.
      Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple local intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) as a model system, we identify the orphan transporter MCT6/SLC16A5 as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe in vitro, mediates Lac-Phe efflux in cells, and is required for maintaining normal circulating Lac-Phe levels in vivo, particularly following metformin treatment or high-intensity exercise. High-fat-diet-fed mice with global or intestinal epithelial-specific deletion of MCT6 exhibit resistance to metformin-associated weight loss. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-knockout (KO) mice. These data connect MCT6 to Lac-Phe and gut glycolytic flux and underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.
    Keywords:  Lac-Phe; MCT6; SLC16A5; circulating; lactate; metabolites; metformin; obesity; transporter; weight loss
    DOI:  https://doi.org/10.1016/j.cell.2026.09.058
  29. Anal Chem. 2026 Sep 29. 98(38): 28330-28336
    In Cellulo Observation of De Novo-Synthesized Nucleotide by Spectral Tracing of Glutamine-Derived Nitrogen Metabolism (QN-STIM) in Cancer Cells.
    Jiro Karlo, Surya Pratap Singh.
      De novo nucleotide biosynthesis is directly linked to glutamine-derived nitrogen metabolism in mammalian cells. It is a fundamental process tightly tied to cellular growth, proliferation, and metabolic reprogramming, particularly in cancer cells. Direct detection and imaging of glutamine-derived nitrogen metabolism at single-cell resolution remains a challenge. The conventional liquid chromatography-mass spectrometry-based approach for detecting de novo-synthesized nucleotide studies is mostly performed on metabolites extracted from a group of cells, which makes it inherently destructive. Herein, we introduce a vibrational spectroscopy-based single-cell metabolic detection and imaging framework, "glutamine (Q)-derived nitrogen spectral tracing and imaging (QN-STIM)". Using this strategy, we detected and mapped nitrogen flow from glutamine to de novo-synthesized nascent nucleotides at the single-cell level. First, a proof-of-concept analysis was conducted in human embryonic kidney HEK293T cells and demonstrated the feasibility of this approach in cancer cells, namely human lung carcinoma A549, human glioblastoma U87 MG, and mouse hepatoma Hepa1-6. QN-STIM technique holds immense potential to be an adjunct tool to advance our understanding of nucleotide dynamics during differentiation, stress adaptation, and immune activation, and to evaluate responses to metabolic drugs in cellulo.
    DOI:  https://doi.org/10.1021/acs.analchem.6c03877
  30. Science. 2026 Oct 22. 394(6822): 383-384
    A cell death ballet in two acts.
    Cristina Muñoz-Pinedo, Seamus J Martin.
      Two proteins that permeabilize mitochondria promote cell death through distinct mechanisms.
    DOI:  https://doi.org/10.1126/science.aem1247
  31. FASEB J. 2026 Oct 31. pii: e72407. [Epub ahead of print]40(20):
    HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
    Ko Suzuki, Jun-Ichiro Takahashi, Kiriko Kaneko, Kazumichi Furuyama.
      Intracellular energy metabolism is strictly regulated by hormones and intracellular metabolites for the appropriate use of energy resources such as carbohydrates and fatty acids. Mitochondria are essential organelles in eukaryotic cells since they contain several metabolic machineries required for oxidative phosphorylation, such as the tricarboxylic cycle, electron transport chain, and fatty acid β-oxidation (FAO). Previously, we reported that FAO activity is increased in CLPX-knockout HepG2 cells (CLPX-KO cells). CLPX is the substrate recognition subunit of the mitochondrial protease ClpXP that regulates intracellular heme levels through the degradation of ALAS1 in the mitochondrial matrix. ALAS1 is the rate-limiting enzyme for heme biosynthesis; thus, we examined whether heme regulates FAO activity. We found that the inhibition of heme synthesis in CLPX-KO cells decreased FAO activity; in contrast, hemin treatment increased FAO activity in wild-type HepG2 cells (CLPX-WT cells). Furthermore, pretreatment of CLPX-WT cells with a chemical inhibitor or specific siRNA targeting the heme degradation enzyme HMOX1 blocked FAO activation induced by hemin, indicating that heme catabolites rather than heme itself are responsible for FAO activation by heme. Among the heme catabolites, we identified carbon monoxide (CO) as an essential metabolite for FAO activation through the activation of the LKB1/AMPK signaling pathway. In this manuscript, we revealed the previously unknown role of CO as an intrinsic inducer of mitochondrial FAO activity and revealed that an excess amount of heme increases FAO activity via CO production by HMOX1.
    Keywords:  AMP‐activated kinase; carbon monoxide; fatty acid oxidation; heme; heme oxygenase; mitochondria
    DOI:  https://doi.org/10.1096/fj.202603280R
  32. Cell. 2026 Oct 21. pii: S0092-8674(26)01200-6. [Epub ahead of print]
    A bioavailable GPX4 inhibitor for ferroptosis induction in vivo and tumor suppression.
    Nathchar Naowarojna, Xin Gu, Zijian Pan, Jun Yu, Kaiyin Huang, Yuyang Zeng, Yuheng Xie, Yuan Zhang, Fengxiang Wang, Jingxuan Mao, Yanxiong Yu, Tianshu William Wu, Jinshi Yu, Shi'en Liu, Senhao Xiao, Lijie Bai, Dongqi Li, Zhenkun Wu, Caiyi Wei, Qiu Li, Hongqing Yao, Xiaoxiao Zhang, Yupan Li, Guanglei Xie, Lei Gao, Jinheng Pan, Lijun Wang, Jin Hu, Xuefei Feng, Qin Peng, Shan Feng, Xi Wang, Yuqi Wang, Tao Peng, Yikai Wang, Yilong Zou.
      Ferroptosis is implicated in multiple human diseases, but the lack of bioavailable inducers has limited its physiological study and therapeutic translation. Here, we report KY0418, a selective covalent inhibitor of glutathione peroxidase 4 (GPX4) featuring an isourea warhead, with high plasma stability and broad tissue distribution after oral dosing in mice. KY0418 specifically targets GPX4SeCys46 to induce ferroptosis hallmarks in human and mouse cancer cell lines, with greater selectivity than existing inhibitors. In a standardizable acute-liver-injury mouse model, KY0418 triggers ferroptotic ultrastructural changes matching those of established inducers, and systemic administration remodels tissue metabolism and generates hydroxyl radicals detectable by a chemiluminescent probe. Subcutaneous tumors from different cancers exhibited variable responses to KY0418 treatment, from no effect to about 70% growth inhibition, but KY0418 consistently eradicated circulating tumor cells and suppressed metastasis across multiple cancer models. These findings position KY0418 as a tool for advancing in vivo ferroptosis research and its clinical translation.
    Keywords:  cancer metastasis; chemical probe; circulating tumor cells; computational drug design and discovery; covalent inhibitors; drug bioavailability; ferroptosis inducer; glutathione peroxidase 4; hydroxyl radical probe; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.cell.2026.09.053
  33. Nat Chem Biol. 2026 Oct 22.
    Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
    Dina Y Bass, Ekaterina S Potekhina, Alexander V Ivanenko, Aleksandr A Moshchenko, Dmitry A Korzhenevskiy, Alexey M Nesterenko, Evgeny K Shevchenko, Anastasia E Karnaeva, Natalia F Zakirova, Alexander V Ivanov, Liubov E Shimolina, Marina V Shirmanova, Olga V Lyang, Olga I Patsap, Olga M Kudryashova, Guzel R Gazizova, Elena I Shagimardanova, Sofia S Mariasina, Vasiliy A Ivlev, Ivan Bogeski, Oleg A Gusev, Vsevolod V Belousov.
      Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, is characteristic of tumor cells. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon. Warburg metabolism is beneficial for rapidly proliferating cells; however, the metabolic consequences of activation of mitochondrial respiration in such cells remain unclear. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate from ᴅ-alanine directly in the mitochondrial matrix, bypassing restricted pyruvate influx. In cancer cells, Grubraw-produced mitochondrial pyruvate increased oxidative metabolism. Chemogenetic activation of mitochondria slowed the growth rate of human melanoma xenografts. Moreover, activation of cancer cell mitochondria suppressed the transcription of genes that control cell-cycle progression, cell proliferation and DNA replication. Surprisingly, we found that cancer cells with Warburg metabolism control carbon flux by disposing of excess mitochondrial pyruvate produced by Grubraw and exporting it out of the cell.
    DOI:  https://doi.org/10.1038/s41589-026-02350-7
  34. Cancer Res. 2026 Oct 22.
    PHGDH Sustains Oncometabolite Production to Drive Resistance to Mutant IDH Inhibition in Glioma that can be Monitored by Metabolic Imaging.
    Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Joanna J Phillips, Jennie W Taylor, Pavithra Viswanath.
      Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. The IDHm inhibitor vorasidenib suppresses D-2HG production and prolongs progression-free survival in some, but not all, patients. Here, using patient-derived models, genetically engineered glioma cells, orthotopic xenografts, and patient tissue, we showed that phosphoglycerate dehydrogenase (PHGDH) mediates intrinsic resistance to vorasidenib by sustaining D-2HG production despite IDHm inhibition. Silencing PHGDH suppressed residual D-2HG synthesis and restored vorasidenib sensitivity in resistant models, whereas PHGDH overexpression restored D-2HG production and induced resistance in sensitive models. Importantly, restoration of intracellular D-2HG rescued growth despite continued vorasidenib treatment, demonstrating a causal role for residual D-2HG production in the resistant phenotype. Mechanistically, a permissive chromatin state characterized by increased H3K4me3, reduced H3K27me3, and enhanced ATF4 occupancy at the PHGDH promoter facilitated PHGDH upregulation in resistant models. Pharmacologic induction of this chromatin state induced PHGDH expression, restored D-2HG production, and conferred resistance to vorasidenib in sensitive models. Consistently, tumor tissue from patients with poor response to IDHm inhibitor treatment exhibited higher PHGDH expression, coupled with the ATF4-enriched permissive chromatin state observed in resistant models. Finally, deuterium metabolic imaging of D-2HG production from diethyl-[3,3'-2H]-α-KG provided an early, non-invasive readout of response and resistance to vorasidenib in vivo. Collectively, this study identifies a chromatin-regulated ATF4-PHGDH-D-2HG axis as a mechanism of intrinsic resistance to IDHm inhibition and establishes diethyl-[3,3'-2H]-α-KG as a metabolic imaging probe for interrogating treatment response in IDHm gliomas.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4071
  35. Nature. 2026 Oct 21.
    GRP75-dependent SIMPA mediates inter-organellar quality control.
    Fan Yu, Lingyu Jiang, Hanyu Liu, Song Yang, Yuan Yuan, Hongzhen Jin, Jinming Liu, Xi Liu, Yu Dong, Dongfeng Ren, Jie Kang, Yan Huang, Qi Meng, Feng Bai, Yanjun Li, Shuoguo Li, Huadong Liu, Wei Zhao, Jia Xiao, Quan Chen.
      Mitochondria are bound by a double membrane and are semiautonomous organelles, rendering them highly vulnerable to global and internal proteostatic stress1. Multiple surveillance mechanisms at proteostatic and inter-organellar levels have evolved to maintain mitochondrial integrity and cellular health2-7. However, the precise mechanisms by which proteostatic damage relays stress signals across organelles and how the quality surveillance machinery coordinates these functions remain unknown. Here we report that under proteostatic stress, damaged mitochondrial proteins are sequestered to form stress-induced mitochondrial protein aggregates (SIMPAs) that activate specific quality control mechanisms in a spatially confined manner without perturbing the mitochondrial network. Quantitative proteomic and correlative light-electron microscopy analysis revealed that SIMPA mediates inter-organellar communication via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes. Mechanistically, GRP75 coordinates SIMPA biogenesis and focally activates endoplasmic reticulum unfolded protein response pathways via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes for the targeted clearance of SIMPAs. Functionally, in both cellular and liver disease models, we found that a GRP75-dependent SIMPA signalling cascade attenuates mitochondrial stress and preserves mitochondrial integrity under proteotoxic stress. Overall, we show that SIMPAs, functioning as protein condensates, serve as a central cross-compartment communication hub for mitochondrial quality control, supporting cellular and organismal fitness.
    DOI:  https://doi.org/10.1038/s41586-026-10733-y
  36. J Am Chem Soc. 2026 Oct 14. 148(40): 43200-43208
    Cross-Species Profiling of Itaconate-Mediated Modifications by a Universal Probe.
    Bin Ma, Dongyang Liu, Weidi Xiao, Chu Wang.
      The immunometabolite itaconate can covalently modify proteins through cysteine itaconation and lysine itaconylation. Current bioorthogonal itaconate probes show biased specificity for profiling cysteine itaconation in macrophages versus bacteria and are not compatible with profiling lysine itaconylation at all. Here, we report isoC3A, a universal probe designed for the comprehensive chemoproteomic profiling of these two types of itaconate-mediated modifications in both eukaryotic and prokaryotic cells. In situ profiling of Salmonella-infected macrophages by isoC3A captures the dynamic changes of itaconate-mediated modifications in the proteomes of host cells and bacteria simultaneously. It also revealed that itaconate targets critical cysteine residues on the aconitate hydratase, enhances its dehydration activity to boost the cis-aconitate level, and drives a positive feedback loop to sustain itaconate biosynthesis. Together, these findings establish isoC3A as a universal probe for exploring the covalent targets of itaconate and suggest a metabolic amplification mechanism in innate immunity.
    DOI:  https://doi.org/10.1021/jacs.6c10764
  37. Cell Death Dis. 2026 Jul 23. pii: 893. [Epub ahead of print]17(1):
    SLC25A20 promotes tumor growth by reprogramming energy metabolism in lung adenocarcinoma.
    Xing Liu, Xiaoyu Song, Cong Gan, Ye Wang, Mingxin Ni, Min Zhang, Shaodi Wen, Yahui Cao, Changhua Yi, Man Tian, Apeng Chen.
      Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. The molecular alterations in tumors that promote metabolic diversity and distinct targetable dependencies remain poorly defined. The mitochondrial transporter SLC25A20, also known as carnitine-acylcarnitine translocase (CACT), is crucial for fatty acid β-oxidation (FAO) by importing acylcarnitines into the mitochondrial matrix. Here, we demonstrate that SLC25A20 is significantly upregulated in lung adenocarcinoma (LUAD) tissues and cells, and its expression correlates with poor patient survival. Gain- and loss-of-function experiments reveal that SLC25A20 promotes tumor cell proliferation, survival, migration, and invasion by enhancing FAO-associated mitochondrial bioenergetics and suppressing apoptosis. Mechanistically, SLC25A20-mediated FAO maintains mitochondrial function and supports oxidative phosphorylation (OXPHOS), thereby sustaining tumor bioenergetics and redox homeostasis. Pharmacological inhibition or genetic silencing of SLC25A20 impairs tumor growth in vivo. These findings establish SLC25A20 as a key metabolic driver in LUAD and suggest it may be a therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-09119-9
  38. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2610766123
    Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.
    Sara Bermudez, Jung-Hyun Choi, Niaz Mahmood, Jacob W Vogel, Hashem Almousa, Ziying Huang, Sung-Hoon Kim, Vivian Yuchan Zhu, Linqiao Zhou, Diana Casas-Antillon, Moein Yaqubi, Danielle Cozachenco, Jo Anne Stratton, Oskar Hansson, Luke Healy, Argel Aguilar-Valles, Nahum Sonenberg.
      In Alzheimer's disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway promotes microglial neuroprotective functions by engaging multiple cell receptors. However, the relevant downstream effectors are not fully understood. mTOR complex 1 (mTORC1) promotes mRNA translation by phosphorylating and inactivating eukaryotic translation initiation factor 4E-binding protein 1 and 2 (4E-BP1/2), which are expressed in microglia. 4E-BP1 levels in cerebrospinal fluid (CSF) are elevated in AD and correlate with markers of microglial reactivity and disease progression. Using linear regression analysis, we found that elevated CSF 4E-BP1 levels strengthen the association between soluble TREM2 levels and neurodegeneration in amyloid-positive individuals. To investigate the underlying mechanism, we performed in vitro experiments demonstrating that amyloid-β inactivated 4E-BP1 in murine microglia. The mTOR-mediated inactivation is highly dependent on Spleen Tyrosine Kinase (SYK) signaling and repeated exposure to amyloid-β impaired this process, whereas prolonged exposure increased 4E-BP1 levels in microglia. Deletion of 4E-BP1/2 resulted in increased mitochondrial mass and oxidative phosphorylation, reduced pro-inflammatory signaling, and protected microglia from amyloid-induced apoptosis. Thus, impaired 4E-BP1 inactivation-due to reduced mTOR signaling or excess 4E-BP1-disrupts immune resolution, leading to metabolic exhaustion and microglial cell death. We identify the SYK-mTORC1-4E-BP1 signaling axis as a key regulator of microglial mitochondrial biogenesis and immune resolution in AD.
    Keywords:  Alzheimer’s disease; inflammation; mTOR; microglia
    DOI:  https://doi.org/10.1073/pnas.2610766123
  39. JCI Insight. 2026 Oct 22. pii: e204554. [Epub ahead of print]
    Tumor stiffness creates a ferroptotic Achilles' heel through YAP-SKP2 signaling.
    Emma Villares, Nico Taber, Shao-Chin Wu, Connor Amelung, Jianli Wu, Chao-Chieh Lin, Jen-Tsan Chi, Sharon Gerecht.
      Matrix stiffness is a hallmark of aggressive solid tumors and strongly associated with therapeutic resistance and poor prognosis. This mechanical barrier represents a major unmet challenge in oncology, as current strategies rarely address how matrix mechanics themselves drive treatment resistance. Here, we identified ferroptosis, an iron-dependent form of cell death, as a potential long-sought vulnerability that can be exploited to eliminate mechanically resistant tumors. Using genetic and chemical approaches, we investigated how matrix stiffness sensitizes cancer cells to ferroptosis and whether this vulnerability can be therapeutically targeted. We found that cancer cells cultured on stiff matrices were more sensitive to ferroptosis than those on soft matrices, as evidenced by reduced cell viability and elevated lipid peroxidation. Furthermore, we found that matrix stiffness induced YAP activation, which upregulated its target gene SKP2, a key mediator required for the heightened ferroptosis sensitivity observed under stiff conditions. Finally, using an injectable hydrogel system, we demonstrated that stiffened tumors were resistant to chemotherapy but remained highly susceptible to ferroptosis induction, resulting in markedly reduced tumor volume and weight. Our findings established ferroptosis as a stiffness-dependent vulnerability mediated by a YAP-SKP2 signaling axis, revealing a mechanotransductive pathway that may be leveraged to target treatment-refractory tumors.
    Keywords:  Cancer; Cell biology; Cell stress; Extracellular matrix; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.204554
  40. J Am Soc Mass Spectrom. 2026 Oct 07. 37(10): 2453-2462
    A Liquid Chromatography-Mass Spectrometry Method to Quantify Total Coenzyme A Concentration and Isotopic Labeling.
    Amelia L Taylor, Nathaniel W Snyder, Caroline R Bartman.
      Coenzyme A is an essential cofactor synthesized from pantothenate, which carries activated acyl groups in cellular metabolic reactions. Coenzyme A participates in catabolism of carbohydrates, fats, and amino acids; biosynthesis of fatty acids, cholesterol, and heme; and protein modification, including acetylation and 4-phosphopantetheinylation. Despite CoA's critical functions, the regulation of CoA levels and the rate of CoA synthesis in different cell types and disease states are not well understood. Acyl-CoA species are challenging to measure due to instability, poor ionization, and the wide range of biochemical properties conferred by different acyl chain lengths; moreover, most current methods cannot measure CoA isotopic labeling, required to quantify the CoA synthesis rate or to measure concentration using isotope-labeled internal standards. Here, we describe a method to quantify the concentration and isotopic labeling of total CoA, defined as the sum of CoASH plus all acyl-CoA species. Acyl-CoA species are hydrolyzed using sodium hydroxide to remove acyl chains; then, CoA is derivatized with N-ethylmaleimide (NEM). Following protein precipitation and solid-phase extraction, samples are analyzed by liquid chromatography-mass spectrometry. This method is linear in a wide range that captures mouse tissue CoA levels, with accuracy within 15% error and precision below 15% relative standard deviation for standards and tissue samples. We applied this method to measure total CoA concentration in five mouse tissues and the total CoA synthesis rate in mouse liver via infusion of 13C-15N-pantothenate. Overall, this method offers a tractable approach to measure total CoA concentration and synthesis rate in health and disease.
    DOI:  https://doi.org/10.1021/jasms.6c00206
  41. Cell. 2026 Oct 19. pii: S0092-8674(26)01117-7. [Epub ahead of print]
    The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.
    Eric I Elliott, Tomomi M Yoshida, Susana C B R Nakandakari, Scott Pope, Cuiling Zhang, Timothy Nottoli, Jae Jin Chae, Daniel L Kastner, Richard A Flavell, Vishwa Deep Dixit, Vijay A Rathinam, Fayyaz S Sutterwala, Andrew Wang.
      Red-meat-containing diets are epidemiologically associated with diseases of chronic inflammation, while diets that restrict red meat improve health. Yet, it is uncertain how red meat incites inflammation. Here, we discover that ʟ-carnitine, an amino acid highly concentrated in skeletal muscle myocytes, drives inflammasome activation in lipopolysaccharide (LPS)-challenged mice and LPS-primed murine and human macrophages. We find that extracellular ʟ-carnitine represses mevalonate synthesis, thereby triggering activation of the pyrin inflammasome, downstream of cellular import by the high-affinity ʟ-carnitine transporter OCTN2. We find that the inflammatory response to skeletal muscle injury also requires pyrin and OCTN2. Thus, in summary, we identify macrophages as sentinels of exogenous and endogenous extracellular ʟ-carnitine that serve as a proxy for skeletal myocyte damage, and we open the field to examine the mechanistic basis for how excess dietary intake of carnitine-rich food drives inflammatory disease.
    Keywords:  ASC; MEFV; OCTN2; SLC22A5; caspase-1; inflammasome; interleukin-17a; interleukin-1β; pyrin; rhabdomyolysis; sepsis; ʟ-carnitine
    DOI:  https://doi.org/10.1016/j.cell.2026.09.015
  42. Trends Cancer. 2026 Oct 20. pii: S2405-8033(26)00218-9. [Epub ahead of print]
    The tumor macroenvironment as cancer metabolism's next frontier.
    Allison B Grenell, Joe L Rowles, Ronnie Fowle-Grider, Yin Cao, Leah P Shriver, Gary J Patti.
      The deregulated utilization of nutrients by tumors, first observed over a century ago, is recognized as a hallmark of cancer and continues to be exploited clinically to image neoplastic disease. Despite this historic focus on cancer cells and, more recently, their neighbors, metabolic reprogramming is not limited to the tumor microenvironment. Tumors also have the capacity to rewire the metabolism of cells throughout the body, including those at distant sites, often referred to as the tumor macroenvironment. Alterations in the metabolism of noncancerous tissues outside the local tumor ecosystem are gaining attention, but their origins and consequences remain incompletely defined. A deeper understanding of these changes may reveal previously unrecognized signatures of disease and unexplored opportunities for therapeutic intervention.
    Keywords:  cachexia; glucose; glutamine; lipids; tumor macroenvironment; whole-body metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2026.09.007
  43. Nat Commun. 2026 09 21. pii: 10994. [Epub ahead of print]17(1):
    Single-oocyte proteome-transcriptome co-profiling reveals a role of dysregulated lactate metabolism in oocyte aging.
    Lanrui Cao, Hao Wu, Yirong Jiang, Yaxue Hou, Zhuo Yang, Yuan Wang, Peipei Ren, Panpan Zhao, Xiaofeng Ni, Shuai Liu, Na Kong, Xin Sheng, Yinli Zhang, Songying Zhang, Jianfeng Xiao, Cunqi Ye, Heng-Yu Fan, Yongcheng Wang, Xiaomei Tong, Qun Fang, Xudong Fu.
      The age-related decline in oocyte quality is a major risk factor for female infertility. Although transcriptome has been examined in aged oocytes, proteomic landscape, which reflects primary gene functional executors, remains largely unexplored. This gap limits our understanding of oocyte aging. To address this, we perform single-cell proteome/transcriptome co-profiling of GV/MII-aged oocytes from mice and humans, revealing species- and stage-specific proteomic/transcriptomic changes during oocyte aging. Strikingly, we observe uncoupled proteomic and transcriptomic alterations, indicating that proteomic changes in aged oocytes are not primarily driven by RNA levels. Furthermore, we capture molecular heterogeneity in aged oocytes and identify MCT4 as a candidate marker of oocyte aging. Functional studies suggest MCT4 contributes to aging-associated oocyte defects via lactate export, and its inhibition improves aged-oocyte quality. These findings indicate altered lactate metabolism as a candidate marker and intervention target for oocyte aging and underscore the value of our profiling in dissecting oocyte aging.
    DOI:  https://doi.org/10.1038/s41467-026-77910-5
  44. Sci Adv. 2026 Oct 23. 12(43): eaeb8595
    Primary tumor-derived lactate primes prostate cancer cells for a dormant fate.
    Luigi Ippolito, Erica Pranzini, Giulia Gangarossa, Marta Iozzo, Giuseppina Comito, Giacomo Venditti, Sara Roccabianca, Elisa Pardella, Matteo Lulli, Alice Santi, Gabriella Nesi, Elisa Giannoni, Paola Chiarugi.
      The metastatic outcome depends on the state of disseminated cancer cells (DCCs) leading to overt metastasis or undergoing dormancy. Before distant organ colonization, primary tumor microenvironment may shape the decision between proliferation and dormancy. Here, we identify lactic acid (LA), a highly abundant environmental metabolite at the primary site in prostate cancer (PCa), as a key inducer of dormant state. LA-uploading PCa cells undergo a proliferation delay, associated with stemness, therapy tolerance, and invasiveness through the nuclear receptor subfamily 2 group F member 1 (COUP-TF1/NR2F1) activation. These traits rely on LA-driven accumulation of lipid droplets (LDs), which serve as reservoirs of lipid-derived acetyl moieties essential for histone acetylation. Notably, the epigenetic reader BRD4 is essential for COUP-TF1 expression and for establishing and maintaining dormancy. In metastatic sites, where LA levels are low, dormant features are lost, allowing DCCs to support metastatic growth. Last, targeting LA-mediated LD formation or BRD4 activation prevents dormancy entry, reducing PCa cell adaptability and increasing vulnerability to antiproliferative therapies.
    DOI:  https://doi.org/10.1126/sciadv.aeb8595
  45. Nat Metab. 2026 Oct 21.
    A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes.
    Qing Liu, Ying Cheng, Dandan Yan, Wenjie Wu, Zhenchuan Lei, Qiaoyun Long, Ziyu Zhao, Yuan Gao, Baile Wang, Tianshi Feng, Jihoon Shin, Jiayu Zhao, Shiting Zhao, Kang Chen, Kingyip Cheng, Xiaoqiang Yao, Ping Gu, Xuefei Gao, Ching-Lung Cheung, Shingo Kajimura, Pengtao Liu, Donghai Wu, Wei Sun, Jinfeng Xiao, Zexin Lin, Yi Wang, Maxwell Kwok, Ngar Yun Ellen Poon, Cheng Hu, Aimin Xu, Hannah Xiaoyan Hui.
      Uncoupling protein 1 (UCP1)-independent energy dissipation has been proven to serve physiological functions in beige adipocytes. Here we show that a futile sodium/potassium (Na+/K+) transport cycle is preferentially amplified in mouse and human beige adipocytes and contributes to UCP1-independent energy expenditure. In mice, cold exposure activates a sympathetic-thyroid hormone signaling axis that coordinatedly induces the Na+/K+-ATPase subunit ATP1A2 together with Na+ and K+ channels, increasing bidirectional ion flux across the plasma membrane while maintaining ionic balance. Atp1a2+Kcnk3+ adipocytes are detected in mouse inguinal white adipose tissue after cold exposure. Acute inhibition of Na+/K+-ATPase reduces energy expenditure in mouse and human beige adipocytes, whereas overexpressing Atp1a2 in murine adipocytes potentiates energy expenditure, independent of UCP1. Adipocyte-specific Atp1a2 deletion impairs thermogenic capacity and exacerbates diet-induced obesity in mice. Expression of a human ATP1A2 missense variant reduces ATP1A2-dependent respiration in mouse adipocytes. Together, these identify ion transport as a tunable ATP-consuming mechanism that expands the thermogenic repertoire of beige adipocytes.
    DOI:  https://doi.org/10.1038/s42255-026-01630-9
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