bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–01–18
sixty papers selected by
Christian Frezza, Universität zu Köln
  1. Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
  2. Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
  3. Enhanced crosstalk between α- and δ-cells promotes recurrent hypoglycaemia.
  4. Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
  5. AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.
  6. Spatio-temporal metabolic alterations in cachexia.
  7. Cancer might evade immune defences by stealing mitochondria.
  8. Language model-guided anticipation and discovery of mammalian metabolites.
  9. Mitochondrial transfer from immune to tumor cells enables lymph node metastasis.
  10. Metabolites as signalling molecules in the tumour immune microenvironment.
  11. Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.
  12. Genetic Context Shapes Selection or Decay of Driver Mutations in Colon Cancer.
  13. Nvj3 regulates Dga1-mediated triacylglycerol synthesis and lipid droplet formation at ER contact sites.
  14. Journeys of hope.
  15. Probing intratumoral metabolic compartmentalisation in a patient with fumarate hydratase-deficient renal cancer using clinical hyperpolarised 13C-MRI and mass spectrometry imaging.
  16. Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment.
  17. Potassium ion homeostasis modulates mitochondrial function.
  18. Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway.
  19. Chemical Proteomics Identifies Ketogenesis-Mediated Cysteine Modifications Regulating Redox Function.
  20. Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1.
  21. Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
  22. Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.
  23. tRNA synthetase activity is required for stress granule and P-body assembly.
  24. Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling.
  25. TidyMass2: advancing LC-MS untargeted metabolomics through metabolite origin inference and metabolic feature-based functional module analysis.
  26. Cancer Cells Exploit Neuroimmune Crosstalk to Evade Immunity.
  27. Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer.
  28. Coenzyme A mitigates cystine-deprivation-induced ferroptosis by suppressing the iron-starvation response.
  29. Lifespan-Extending Endogenous Metabolites.
  30. Selection for Postponed Senescence in Drosophila melanogaster Reveals Distinct Metabolic Aging Trajectories Modifiable by the Angiotensin-Converting Enzyme Inhibitor Lisinopril.
  31. 6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
  32. Maternal lipids prime quiescent neural stem cells to reactivate in response to dietary nutrients.
  33. NNMT inhibition counteracts tubular senescence and fibrosis in early stages of chronic kidney disease.
  34. Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network.
  35. Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
  36. Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?
  37. Microbiota-induced T cell plasticity enables immune-mediated tumour control.
  38. Improved flux profiling in genome-scale modeling of human cell metabolism.
  39. Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
  40. Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.
  41. Deficiency of δ-Aminolevulinate Dehydratase Confers a Survival Advantage and Drives Malignancy in Cancer.
  42. Polyamine-dependent metabolic shielding regulates alternative splicing.
  43. Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.
  44. Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.
  45. PIK3CG deficiency promotes metabolic reprogramming in pancreatic Cancer by suppressing GLS2-driven glutamine metabolism.
  46. Chronological lifespan extension and nucleotide salvage inhibition in yeast by isonicotinamide supplementation.
  47. The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans.
  48. Pioneers: Glucose sensing and control of health-span and lifespan.
  49. In situ multi-modal characterization of pancreatic cancer reveals tumor cell identity as a defining factor of the surrounding microenvironment.
  50. Epigenetic and metabolic rewiring in metastatic pheochromocytomas and paragangliomas driven by SDHB mutations.
  51. Targeted Lipid Metabolism Screening Uncovers Regulatory Effects on the STING Immune Response in Mevalonate, Eicosanoid and Fatty Acid Pathways.
  52. Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.
  53. Beyond synthetic lethality in large-scale metabolic and regulatory network models via genetic minimal intervention set.
  54. F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
  55. Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.
  56. A genetically encoded device for transcriptome storage in mammalian cells.
  57. Delineating the copy-number substructure of metastatic tumors with CopyKit.
  58. Clocking intestinal absorption.
  59. Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy.
  60. Separating food intake-dependent and -independent effects in cancer cachexia.
  1. Pharmacol Res. 2026 Jan 10. pii: S1043-6618(26)00011-3. [Epub ahead of print]224 108096
    Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
    Andrea Mancini, Elisabetta Betterini, Matteo Bordi, Francesco Cecconi.
      Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid-liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion-purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.
    Keywords:  Cancer biology; Metabolons; Mitochondria metabolism; Nucleotide metabolism; Organelle contact sites; Purine synthesis
    DOI:  https://doi.org/10.1016/j.phrs.2026.108096
  2. Nat Metab. 2026 Jan 16.
    Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
    Kimberly S Huggler, Kyle M Flickinger, Matthew H Forsberg, Carlos A Mellado Fritz, Gavin R Chang, Meghan F McGuire, Christian M Capitini, Jason R Cantor.
      Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis.
    DOI:  https://doi.org/10.1038/s42255-025-01428-1
  3. Nat Metab. 2026 Jan 13.
    Enhanced crosstalk between α- and δ-cells promotes recurrent hypoglycaemia.
      
    DOI:  https://doi.org/10.1038/s42255-025-01423-6
  4. Nat Aging. 2026 Jan 16.
    Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
    Takuya Kumazawa, Yanxin Xu, Yu Wang, Ji-Won Lee, Tara C O'Brien, Chia-Kang Ho, Murat Cetinbas, Aaron Weiner, Konrad Hochedlinger, Ruslan I Sadreyev, Nabeel Bardeesy, Chia-Wei Cheng, Bin He, Zhixun Dou.
      Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS-STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS-STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.
    DOI:  https://doi.org/10.1038/s43587-025-01048-0
  5. Nat Metab. 2026 Jan 12.
    AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.
    Tyler K T Smith, Logan K Townsend, William J Smiles, Jonathan S Oakhill, Morgan D Fullerton, Gregory R Steinberg.
      The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease.
    DOI:  https://doi.org/10.1038/s42255-025-01442-3
  6. Nat Metab. 2026 Jan 15.
    Spatio-temporal metabolic alterations in cachexia.
    Hui Ming, Miao Yin, Qun-Ying Lei.
      
    DOI:  https://doi.org/10.1038/s42255-025-01440-5
  7. Nature. 2026 Jan 14.
    Cancer might evade immune defences by stealing mitochondria.
    Laura Dattaro.
      
    Keywords:  Cancer; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00123-9
  8. Nature. 2026 Jan 14.
    Language model-guided anticipation and discovery of mammalian metabolites.
    Hantao Qiang, Fei Wang, Wenyun Lu, Xi Xing, Hahn Kim, Sandrine A M Mérette, Lucas B Ayres, Eponine Oler, Jenna E AbuSalim, Asael Roichman, Michael Neinast, Ricardo A Cordova, Won Dong Lee, Ehud Herbst, Vishu Gupta, Samuel L Neff, Mickel Hiebert-Giesbrecht, Adamo Young, Vasuk Gautam, Siyang Tian, Bo Wang, Hannes Röst, Jatinder Baidwan, Russell Greiner, Li Chen, Chad W Johnston, Leonard J Foster, Aaron M Shapiro, David S Wishart, Joshua D Rabinowitz, Michael A Skinnider.
      Despite decades of study, large parts of the mammalian metabolome remain unexplored1. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks in human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains challenging2-4. Biochemical language models have transformed the interpretation of DNA, RNA and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism. Here we present an approach that leverages chemical language models5-7 to anticipate the existence of previously uncharacterized metabolites. We introduce DeepMet, a chemical language model that learns from the structures of known metabolites to anticipate the existence of previously unrecognized metabolites. Integration of DeepMet with mass spectrometry-based metabolomics data facilitates metabolite discovery. We harness DeepMet to reveal several dozen structurally diverse mammalian metabolites. Our work demonstrates the potential for language models to advance the mapping of the mammalian metabolome.
    DOI:  https://doi.org/10.1038/s41586-025-09969-x
  9. Cell Metab. 2026 Jan 12. pii: S1550-4131(25)00545-5. [Epub ahead of print]
    Mitochondrial transfer from immune to tumor cells enables lymph node metastasis.
    Azusa Terasaki, Keshav Bhatnagar, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Han-Li Huang, Lukas Wiggers, Viviana Rodrigues, Cara C Rada, Vishnu Shankar, Suguru Saito, Peter Ofori Ankomah, Theodore Roth, Bill Chiu, Robert West, Lingyin Li, Nathan Reticker-Flynn, Jeffrey D Axelrod, Jonathan R Brestoff, Bo Li, Edgar Engleman, Derick Okwan-Duodu.
      Although the immune system is a significant barrier to tumor growth and spread, established tumors evade immune attack and frequently colonize immune populated areas such as the lymph node. The mechanisms by which cancer cells subvert the tumor-immune microenvironment to favor spread to the lymph node remain incompletely understood. Here, we show that, as a common attribute, tumor cells hijack mitochondria from a wide array of immune cells. Mitochondria loss by immune cells decreases antigen-presentation and co-stimulatory machinery, as well as reducing the activation and cytotoxic capacity of natural killer (NK) and CD8 T cells. In cancer cells, the exogenous mitochondria fuse with endogenous mitochondria networks, leak mtDNA into the cytosol, and stimulate cGAS/STING, activating type I interferon-mediated immune evasion programs. Blocking mitochondrial transfer machinery-including cGAS, STING, or type I interferon-reduced cancer metastasis to the lymph node. These findings suggest that cancer cells leverage mitochondria hijacking to weaken anti-tumor immunosurveillance and use the acquired mitochondria to fuel the immunological requirements of lymph node colonization.
    Keywords:  MERCI; cGAS/STING; immune evasion; lymph node cancer metastasis; mitochondrial transfer
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.014
  10. Nat Rev Immunol. 2026 Jan 12.
    Metabolites as signalling molecules in the tumour immune microenvironment.
    Youxiang Mao, Wenjun Xia, Peng Jiang.
      Alterations in key metabolic pathways are required for tumour development and the adaptation of tumour cells to intrinsic or extrinsic stresses, as well as for the regulation of immune cell fate and immune responses in the tumour microenvironment. In particular, the dysregulation or alteration of certain metabolites produced by tumour cells has been shown to be important in creating the immunosuppressive tumour microenvironment. Recent studies have broadened our understanding of the interactions between metabolites and antitumour immunity. Here we highlight how, beyond their metabolic role, metabolites can function as signalling molecules to modulate the behaviours of immune cells and tumour cells. We also discuss potential therapeutic strategies targeting specific metabolites and future research directions in metabolite sensing.
    DOI:  https://doi.org/10.1038/s41577-025-01258-y
  11. bioRxiv. 2026 Jan 11. pii: 2026.01.09.698662. [Epub ahead of print]
    Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.
    Nneka E Mbah, Damien Sutton, Hanna S Hong, Rashi Singhal, Rosa E Menjivar, Heather Giza, Peter Sajjakulnukit, Matthew Perricone, Zeribe C Nwosu, Jonathan Alektiar, Jason Lin, Daniel Long, Anthony C Andren, Li Zhang, Howard C Crawford, Timothy L Frankel, Marina Pasca di Magliano, Luigi Franchi, Yatrik M Shah, Costas A Lyssiotis.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound metabolic rewiring and a strongly immunosuppressive tumor microenvironment, both of which contribute to poor therapeutic responses. Immunogenic cell death (ICD) represents a potential strategy to overcome immune suppression by coupling tumor cell death to anti-tumor immune activation. Here, we investigated whether targeting amino acid metabolism in PDAC can induce ICD and promote tumor immunity. Through a focused metabolic screen in a panel of syngeneic mouse cancer cell lines, we identified cysteine restriction as a robust inducer of multiple damage-associated molecular patterns (DAMPs) in vitro, hallmark features of ICD. In addition to driving DAMPs, cystine-deprived tumor cells also promoted dendritic cell phagocytosis, maturation, and proinflammatory cytokine production in vitro. Because cysteine deprivation is a known trigger of ferroptosis, we further demonstrated that pharmacologic inhibition of glutathione peroxidase 4 (GPX4) similarly elicited ICD-associated features, which were reversible by the ferroptosis inhibitor Ferrostatin-1. To define additional immune-modulatory signals associated with ferroptosis, we performed metabolomic and lipidomic profiling of cells undergoing, but not yet committed to, ferroptotic death. These analyses revealed selective release of immunosuppressive metabolites and oxidized phospholipids. Consistent with this, conditioned media from ferroptotic cells impaired CD8⁺ T cell proliferation and cytotoxicity in vitro. Thus, together our results indicated that the induction of ferroptotic immunogenic cell death led to the release of both pro- and anti-inflammatory signals. Subsequent analysis in vivo revealed that ferroptotic tumor cells predominantly contributed to a tumor-protective environment. In particular, tumors inoculated with ferroptotic cells were enriched with immunosuppressive myeloid cells and exhibited reduced populations of tumor-infiltrating CD8+ T cells. Further investigation using immune compromised mice suggested that ferroptotic cells may suppress both adaptive and innate immune responses. Collectively, these results underscore the complex and highly context-dependent effects of ferroptosis on tumor immunity, highlighting the critical importance of in vivo models to determine true immunogenic potential within the tumor microenvironment.
    DOI:  https://doi.org/10.64898/2026.01.09.698662
  12. Cancer Discov. 2026 Jan 09. OF1
    Genetic Context Shapes Selection or Decay of Driver Mutations in Colon Cancer.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-003
  13. bioRxiv. 2026 Jan 09. pii: 2026.01.05.695145. [Epub ahead of print]
    Nvj3 regulates Dga1-mediated triacylglycerol synthesis and lipid droplet formation at ER contact sites.
    Daniel Adebayo, Eseiwi Obaseki, Scott Miller, Marwa Aboumourad, Zaid Saadeh, Zachary Pomicter, Lindsey Kreinbring, Mohamad Rahal, Kashvi Vasudeva, Garrett Frost, Reema Smadi, Hanaa Hariri.
      Lipid droplet (LD) biogenesis is essential for lipid homeostasis during nutrient stress, yet how lipid intermediates are spatially organized to support efficient triacylglycerol (TAG) synthesis remains unclear. Here, we identify Nvj3 as a nutrient-responsive regulator that links diacylglycerol (DAG) availability to TAG synthesis and LD formation at the endoplasmic reticulum (ER). Nvj3 is induced by glucose depletion and recruited to LD-associated ER domains. Loss of Nvj3 causes neutral lipid accumulation under steady state conditions but delays TAG synthesis under acute inducible metabolic transitions. Using controlled TAG induction systems, we show that Nvj3 is required to couple Dga1-dependent TAG synthesis to LD formation. In the absence of Nvj3, TAG accumulates but remains inefficiently packaged into LDs. Consistent with this defect, nvj3Δ cells exhibit altered phospholipid remodeling and mislocalization of DAG away from ER domains during starvation. Together, these findings establish Nvj3 as an organizer of lipid availability during metabolic stress and suggest that spatial control of DAG is a key determinant of LD biogenesis.
    Summary: This study identifies Nvj3 as a spatial organizer of Dga1-dependent lipid droplet formation. Nvj3 promotes proper diacylglycerol positioning, and enables efficient triacylglycerol synthesis during metabolic stress. We propose that Nvj3 regulates lipid flux through spatial compartmentalization of diacylglycerol at membrane contact site-associated ER domains.
    DOI:  https://doi.org/10.64898/2026.01.05.695145
  14. Nat Genet. 2026 Jan 12.
    Journeys of hope.
    Yvonne Walburga Joko Fru.
      
    DOI:  https://doi.org/10.1038/s41588-025-02466-x
  15. Commun Med (Lond). 2026 Jan 13.
    Probing intratumoral metabolic compartmentalisation in a patient with fumarate hydratase-deficient renal cancer using clinical hyperpolarised 13C-MRI and mass spectrometry imaging.
    Ines Horvat-Menih, Ruth Casey, James Denholm, Gregory Hamm, Heather Hulme, John Gallon, Alixander S Khan, Joshua Kaggie, Andrew B Gill, Andrew N Priest, Joao A G Duarte, Cissy Yong, Cara Brodie, James Whitworth, Simon T Barry, Richard J A Goodwin, Shubha Anand, Marc Dodd, Katherine Honan, Sarah J Welsh, Anne Y Warren, Tevita Aho, Grant D Stewart, Thomas J Mitchell, Mary A McLean, Ferdia A Gallagher.
       BACKGROUND: Fumarate hydratase-deficient renal cell carcinoma (FHd-RCC) is a rare and aggressive renal cancer subtype characterised by increased fumarate accumulation and upregulated lactate production. Renal tumours demonstrate significant intratumoral metabolic heterogeneity, which may contribute to treatment failure. Emerging non-invasive metabolic imaging techniques have clinical potential to more accurately phenotype tumour metabolism and its heterogeneity.
    METHODS: In this case study we have used hyperpolarised 13C-pyruvate MRI (HP 13C-MRI) to assess 13C-lactate generation in a patient with an organ-confined FHd-RCC. Post-operative tissue samples were co-registered with imaging and underwent sequencing, IHC staining, and mass spectrometry imaging (MSI).
    RESULTS: HP 13C-MRI reveals two metabolically distinct tumour regions. The 13C-lactate-rich region shows a high lactate/pyruvate ratio and slightly lower fumarate on MSI compared to the other tumour region, as well as increased CD8 + T cell infiltration, and genetic dedifferentiation. Compared to the normal kidney, the vascularity in the tumour is decreased, while immune cell fraction is markedly higher.
    CONCLUSIONS: This study shows the potential of metabolic HP 13C-MRI to characterise FHd-RCC and how targeting of biopsies to regions of metabolic dysregulation could be used to obtain the tumour samples of greatest clinical significance, which in turn can inform on early and successful response to treatment.
    DOI:  https://doi.org/10.1038/s43856-025-01371-y
  16. Nat Rev Cancer. 2026 Jan 16.
    Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment.
    Frank Arnold, Annachiara Del Vecchio, Zainab Hussain, Mara H Sherman.
      A fibroinflammatory microenvironment coevolves with many tumour types and profoundly influences disease progression and response to therapy. Pancreatic cancer is the archetype of a fibroinflammatory tumour, with non-malignant stromal elements comprising the volumetric majority of the tumour tissue. A convergence of three factors - technological advances enabling deep understanding of heterocellular crosstalk in these complex tumours; therapeutic advances revealing meaningful vulnerabilities in this notoriously chemoresistant, immunosuppressive disease; and conceptual advances towards distilling the conserved features and key functions of stromal elements amid this complexity - has positioned the field in a promising era for discovery, wherein our ever-improving understanding of the pancreatic tumour microenvironment is poised for translational impact. Emerging pan-cancer analyses highlight features of tumour microenvironments conserved not only among pancreatic cancer specimens but also across anatomic sites, such that lessons learnt about the organization of tumour tissue architecture and the role of oncogenic KRAS signalling in this process in other tumours have shaped our understanding of heterocellular dependencies in pancreatic cancer and vice versa. Here, we review recent developments sculpting our current understanding of the diverse features of the pancreatic tumour microenvironment and emerging means to leverage these developments for the benefit of patients with pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41568-025-00905-9
  17. J Cell Biol. 2026 Apr 06. pii: e202505110. [Epub ahead of print]225(4):
    Potassium ion homeostasis modulates mitochondrial function.
    Adam James Waite, Beiduo Rao, Elizabeth Schinski, Nathaniel H Thayer, Manuel Hotz, Austin E Y T Lefebvre, Celeste Sandoval, Daniel E Gottschling.
      Age-associated decline in mitochondrial membrane potential (MMP) is a ubiquitous aspect of eukaryotic organisms and is associated with many aging-related diseases. However, it is not clear whether this decline is a cause or consequence of aging, and therefore whether interventions to reduce MMP decline are a viable strategy to promote healthier aging and longer lifespans. We developed a screening platform in Saccharomyces cerevisiae to identify mutations that slowed or abrogated the age-associated decline in MMP. Characterization of the longest-lived mutant revealed that reduced internal potassium increased MMP and extended lifespan. Distinct interventions improved cellular MMP and lifespan: deleting a potassium transporter; altering the balance between kinases and phosphatases that control potassium transporter activity; and reducing available potassium in the environment. Similarly, in isolated mitochondria, reducing the concentration of potassium was sufficient to increase MMP. These data indicate that the most abundant monovalent cation in eukaryotic cells plays a critical role in tuning mitochondrial function, consequently impacting lifespan.
    DOI:  https://doi.org/10.1083/jcb.202505110
  18. bioRxiv. 2026 Jan 10. pii: 2026.01.09.698526. [Epub ahead of print]
    Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway.
    Shuke Xiao, Mengjie Wang, Thomas G Martin, Barry Scott, Xing Fang, Xinming Liu, Yongjie Yang, Sipei Fu, Steven D Truong, Jack F Gugel, Gregory L Maas, Marcus P Mullen, Jennifer Hampton Hill, Veronica L Li, Andrew L Markhard, Mingming Zhao, Wei Qi, Saranya C Reghupaty, Meng Zhao, Jan Spaas, Wei Wei, Trine Moholdt, John A Hawley, Christian T Voldstedlund, Erik A Richter, Xiaoke Chen, Katrin J Svensson, Daniel Bernstein, Leslie A Leinwand, Yong Xu, Jonathan Z Long.
      Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response 1-3 . Using untargeted metabolomics, here we show that circulating levels of the metabolite para -tyramine-O-sulfate (pTOS) are increased >1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulfation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance.
    DOI:  https://doi.org/10.64898/2026.01.09.698526
  19. Angew Chem Int Ed Engl. 2026 Jan 16. e19830
    Chemical Proteomics Identifies Ketogenesis-Mediated Cysteine Modifications Regulating Redox Function.
    Yuan-Fei Zhou, Ling Zhang, Zhuoyi L Niu, Xin Wang, Alejandro Storper, Ryan Hunt, Yingming Zhao, Nima Sharifi, Zhipeng A Wang.
      All the studies of ketogenesis-dependent post-translational modifications (PTMs), notably those mediated by ketone bodies, β-hydroxybutyrate (Bhb) and acetoacetate (Acac), have focused on lysine acylations. However, given the chemically diverse and reactive nature of metabolites generated, it remains unclear whether non-lysine modifications can also happen. Here, we develop an acetoacetate-alkyne (Acac-alkyne) chemical probe that enables efficient metabolic labeling, robust fluorescent visualization, and site-specific identification of Acac-modified proteins. By combining chemical proteomics with open-search strategy, we showed that Acac induces previously uncharacterized cysteine modifications in mammalian cells. Notably, cysteine crotonation (Ccr) is validated by employing both probe-based and standard peptide-based co-elution assays. Metabolic pathway tracing further identifies BDH1 and ECHS1 as key enzymes that generate Ccr formation. We further demonstrate that Ccr at PRDX3 C229 site impairs dimerization and redox activity, linking this newly discovered modification to the regulation of cellular reactive oxygen species. Together, these findings establish ketone metabolism as a novel source of cysteine modifications and provide an alternative mechanistic pathway to explain the profound biological effects of ketone bodies.
    Keywords:  Cysteine modifications; Ketone body; Protein modifications; Proteomics; Redox regulation
    DOI:  https://doi.org/10.1002/anie.202519830
  20. Cell Rep. 2026 Jan 14. pii: S2211-1247(25)01620-1. [Epub ahead of print]45(1): 116848
    Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1.
    Weihong Ge, Ryan L Kan, Can Yilgor, Elisa Fazzari, Patricia R Nano, Daria J Azizad, Heer Shinglot, Matthew Li, Joyce Y Ito, Christopher Tse, Hong A Tum, Jessica Scholes, Shivani Baisiwala, Kunal S Patel, David A Nathanson, Aparna Bhaduri.
      Glioblastoma is the most aggressive and deadly form of brain cancer. Here, we leverage our human organoid tumor transplantation (HOTT) co-culture system to explore how extrinsic cues modulate glioblastoma cell types and behavior. HOTT recapitulates core features of major patient tumor cell types and key aspects of neural cell-enriched tumor microenvironment (nTME) gene programs. Our exploration of patient TME interactions preserved in HOTT highlights four receptor-ligand interactions of interest. We knock down all four of these genes in the HOTT microenvironment. We observe that knocking down nTME PTPRZ1, a receptor tyrosine phosphatase implicated in cancer cell migration, results in an increased fraction of mesenchymal cells, enrichment of epithelial-to-mesenchymal gene programs, and an elevated tumor microtube length in co-cultured primary patient tumors. This phenotype is not mediated by PTPRZ1's catalytic activity, suggesting a mechanism of tumor cell fate driven by nTME PTPRZ1, highlighting the strengths of the HOTT system.
    Keywords:  CP: Cancer; CP: Stem cell research; PTPRZ1; glioblastoma; human organoid tumor transplantation; organoid models of brain cancer; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.116848
  21. Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00501-4. [Epub ahead of print]90 103988
    Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
    Viktor Antonsson Garellick, Nadia Gul, Parvin Horrieh, Dyar Mustafa, Angana A H Patel, Martin Dankis, Samantha W Alvarez, Johanna Berndtson, Saeed Mahdavi, Maria Schwarz, Andreas Persson, Fikret Zahirovic, Clotilde Wiel, Volkan I Sayin, Per Lindahl.
      Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino acid sensor protein GCN2 and the integrated stress response lowered the threshold for lipid peroxidation by promoting ATF4-dependent mitochondrial respiration and reactive oxygen species leakage from the electron transport chain under glutathione depletion. The finding provides new insights into lung cancer metabolism and raises the possibility of using amino acid restricted diets in combination with ferroptosis-inducing agents as cancer therapies.
    Keywords:  Amino acids; Ferroptosis; Glutathione; Integrated stress response; Lung cancer; Mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.redox.2025.103988
  22. Nat Chem Biol. 2026 Jan 13.
    Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.
    Lu Hu, Jinyu Lin, Liping Sun, Alison M Berezuk, Katharine S Tuttle, Xing Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Pan Li, Yang Sun, Lisheng Ni, Jianan Zhang, Dazhi Tan, Hiroaki Wakimoto, Daniel P Cahill, Xiaochen Bai, Xuelian Luo, John M Asara, Sriram Subramaniam, Yibing Shan, Xu Wu.
      Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.
    DOI:  https://doi.org/10.1038/s41589-025-02131-8
  23. Genes Dev. 2026 Jan 14.
    tRNA synthetase activity is required for stress granule and P-body assembly.
    Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Translation elongation defects activate the integrated stress response (ISR), but whether and how ribosome stalls are cleared to enable mRNA release for ribonucleoprotein (RNP) granule assembly remain unclear. We show that blocking tRNA aminoacylation generates persistent uncollided ribosome stalls that inhibit stress granule and P-body assembly despite robust ISR activation. Collided ribosomes are rapidly cleared by ZNF598-dependent ribosome-associated quality control within 4 h, while uncollided stalls resist clearance and persist for >16 h. Puromycin releases persistent stalls and restores RNP granule formation. The block in stress granule assembly is generalizable across tRNA synthetase inhibitors and amino acid deprivation. Therefore, stress granules represent signal integrators reporting translation elongation status when initiation is suppressed. Our findings reveal that translation quality control pathways selectively clear collided ribosomes, establish that translation elongation stress uncouples RNP granule assembly from the ISR, and suggest that tolerating uncollided stalls may be adaptive for cotranslational processes essential for cellular function.
    Keywords:  P-bodies; halofuginone; integrated stress response; ribosome collisions; ribosome-associated quality control; stress granules; tRNA synthetase; translation elongation
    DOI:  https://doi.org/10.1101/gad.353535.125
  24. Nat Aging. 2026 Jan 12.
    Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling.
    Javier Moral-Sanz, Isabel Fernández-Carrasco, Valentina Ramponi, Amanda Garrido, Izhar Karbat, Pablo Cabezas-Sainz, Esperanza Rivera-de-Torre, Osama Elsallabi, Roberto Martín-Hernández, José L López-Aceituno, Nathan L Price, Laura Sanchez, Gonzalo Colmenarejo, Álvaro Martínez-Del-Pozo, Irina Vetter, Angel Cogolludo, Francisco Perez-Vizcaino, Jorge Del-Pozo, Eitan Reuveny, Manuel A Fernández-Rojo, Paul D Robbins, Rafael de Cabo, Manuel Serrano, Maria P Ikonomopoulou.
      Senescence is a driver of aging and a barrier to tumor progression, but its persistent accumulation drives inflammation and relapse. Thus, the success of chemotherapy could be jeopardized when senescence emerges in the tumor microenvironment. Here we identified the senolytic properties of a pore-forming toxin, sticholysin I (StnI). StnI and our engineered improved form, StnIG, selectively hampers viability of chemotherapy-induced senescent cancer cells, as well as senescent primary cells. We show that its selectivity is mediated by specific binding and lipid ratios associated with senescence, including compromised membrane bilayer asymmetry. Mechanistically, StnIG triggers sodium and calcium influx and an enduring potassium efflux in senescent cells. Calcium triggers the opening of calcium-activated potassium channels, leading to cell death by apoptosis and pyroptosis. Finally we show that StnIG synergizes with senescence-inducing chemotherapy to drive remission of solid tumors in mice. Our findings define StnI and StnIG as senotoxins with translational potential for cancer therapy.
    DOI:  https://doi.org/10.1038/s43587-025-01030-w
  25. Nat Commun. 2026 Jan 17.
    TidyMass2: advancing LC-MS untargeted metabolomics through metabolite origin inference and metabolic feature-based functional module analysis.
    Xiao Wang, Yijiang Liu, Chao Jiang, Zinuo Huang, Hong Yan, Sunny H Wong, Caroline H Johnson, Jingxiang Zhang, Yifei Ge, Feifan Zhang, Junli Zhang, Renfu Lai, Peng Gao, Xuebin Zhang, Xiaotao Shen.
      Untargeted metabolomics provides a direct window into biochemical activities but faces critical challenges in determining metabolite origins and interpreting unannotated metabolic features. Here, we present TidyMass2, an enhanced computational framework for Liquid Chromatography-Mass Spectrometry (LC-MS) untargeted metabolomics that addresses these limitations. TidyMass2 introduces three major innovations compared to its predecessor, TidyMass: (1) a comprehensive metabolite origin inference capability that traces metabolites to human, microbial, dietary, pharmaceutical, and environmental sources through integration of 11 metabolite databases containing 532,488 metabolites with source information; (2) a metabolic feature-based functional module analysis approach that bypasses the annotation bottleneck by leveraging metabolic network topology to extract biological insights from unannotated metabolic features; and (3) a graphical interface that makes advanced metabolomics analyses accessible to researchers without programming expertise. Applied to longitudinal urine metabolomics data from human pregnancy, TidyMass2 identified diverse metabolites originating from human, microbiome, and environment, and uncovered 27 dysregulated metabolic modules. It increased the proportion of biologically interpretable metabolic features from 5.8% to 58.8%, revealing coordinated changes in steroid hormone biosynthesis, carbohydrate metabolism, and amino acid processing. By expanding biological interpretation beyond MS2 spectra-based annotated metabolites, TidyMass2 enables more comprehensive metabolic phenotyping while upholding open-source principles of reproducibility, traceability, and transparency.
    DOI:  https://doi.org/10.1038/s41467-026-68464-7
  26. Cancer Discov. 2026 Jan 12. OF1
    Cancer Cells Exploit Neuroimmune Crosstalk to Evade Immunity.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-004
  27. Nat Metab. 2026 Jan 15.
    Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer.
    Pauline Morigny, Michaela Vondrackova, Honglei Ji, Kristyna Brejchova, Monika Krakovkova, Konstantinos Makris, Radka Trubacova, Tuna F Samanci, Doris Kaltenecker, Su-Ping Ng, Vignesh Karthikaisamy, Sophia E Chrysostomou, Anna Bidovec, Mariana Ponce-de-Leon, Tanja Krauss, Claudine Seeliger, Olga Prokopchuk, Marc E Martignoni, Melina Claussnitzer, Hans Hauner, Martina Schweiger, Laure B Bindels, Mauricio Berriel Diaz, Stephan Herzig, Dominik Lutter, Ondrej Kuda, Maria Rohm.
      Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour-host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting.
    DOI:  https://doi.org/10.1038/s42255-025-01434-3
  28. FEBS J. 2026 Jan 16.
    Coenzyme A mitigates cystine-deprivation-induced ferroptosis by suppressing the iron-starvation response.
    Mingjun Tan, Yunzhan Li, Lei Sang, Min Wang, Qin Li, Zekun Li, Dongxiao Sun, Xiuchao Wang, Shengyu Yang.
      The labile iron pool in the cell is required for ferroptosis, a form of regulated cell death resulting from excessive lipid peroxidation and membrane damage. Glutathione (GSH) is critical for lipid-peroxide scavenging, and cysteine is the rate-limiting amino acid in GSH synthesis. Cysteine metabolism intricately intertwines with iron metabolism, either directly by participating in assembly of the iron-sulfur cluster or indirectly through the pantothenate pathway and coenzyme A (CoA) synthesis. However, the regulation of iron homeostasis in cystine (Cys2)-deprivation-induced ferroptosis is poorly understood. Here, we show that Cys2 deprivation promotes ferroptosis, at least in part, by activating the iron-starvation response (ISR), and CoA can mitigate ferroptosis by suppressing the ISR. Mechanistically, Cys2 deprivation promotes the oxidation of cytosolic iron-sulfur clusters to activate the ISR; CoA and related small-molecule thiols in the pantothenate pathway suppress the ISR and ferroptosis by preventing the oxidation of iron-sulfur clusters in Cys2-deprived cells. Our findings provide important insight into the regulation of the ISR in Cys2-deprivation-induced ferroptosis, and show that CoA can protect cells from Cys2-deprivation-induced ferroptosis by suppressing the ISR.
    Keywords:  Coenzyme A; cysteine; cystine‐deprivation; ferroptosis; iron‐starvation response; iron–sulfur cluster; pantothenate pathway
    DOI:  https://doi.org/10.1111/febs.70411
  29. Aging Cell. 2026 Feb;25(2): e70371
    Lifespan-Extending Endogenous Metabolites.
    Yizhou Jiang, Jing-Dong J Han.
      Aging is a multifactorial process influenced by genetic, environmental, and metabolic factors. Dysregulated nutrient sensing and metabolic dysfunction are hallmarks of aging, and reduction of insulin/IGF-1 signaling or metabolic interventions such as caloric restriction extend lifespan across species. Endogenous metabolites reflect and mediate these metabolic cues, linking nutrient status to epigenetic and transcriptional programs by serving as cofactors for chromatin-modifying enzymes or as allosteric modulators of transcription factors. Some metabolites have emerged as key regulators of longevity, integrating into networks to concurrently influence multiple aging-related pathways. In this review, we summarize evidence supporting the lifespan-extending effects of key endogenous metabolites across diverse model organisms and discuss their mechanisms of action. These insights underscore the potential of targeting metabolic networks as a multifaceted strategy to delay aging. Finally, we consider the translational promise of metabolite-based interventions to extend healthspan while minimizing adverse effects, and we note remaining challenges such as optimal dosing, context-specific effects, and demonstrating efficacy in humans.
    Keywords:  aging; anti‐aging; lifespan; metabolism; metabolites
    DOI:  https://doi.org/10.1111/acel.70371
  30. Aging Cell. 2026 Feb;25(2): e70375
    Selection for Postponed Senescence in Drosophila melanogaster Reveals Distinct Metabolic Aging Trajectories Modifiable by the Angiotensin-Converting Enzyme Inhibitor Lisinopril.
    Denise Vecchié, Robert R H Anholt, Trudy F C Mackay, Maria De Luca.
      Aging is accompanied by profound changes in energy metabolism, yet the underlying drivers and modulators of these shifts remain incompletely understood. Here, we investigated how life-history evolution shapes metabolic aging and pharmacological responsiveness by leveraging Drosophila melanogaster lines divergently selected for reproductive timing. We measured organismal oxygen consumption rate and performed untargeted metabolomics in young and old flies of both sexes from long-lived "O" lines (selected for female late-life reproduction) and unselected "B" control lines. Males and females from the O lines maintained stable metabolic rates and largely preserved metabolite profiles with age, whereas B line flies showed age-related increases in oxygen consumption, citrate accumulation, and elevated levels of medium- and long-chain fatty acids, hallmarks of mitochondrial inefficiency and impaired lipid oxidation. Aged B flies also displayed elevated S-adenosylmethionine, reduced sarcosine, and diminished heme levels, indicating dysregulation of one-carbon metabolism and impaired heme biosynthesis. Furthermore, Vitamin B6 metabolites, pyridoxamine, pyridoxal, and 4-pyridoxate, increased with aging only in B line females. Motivated by evidence implicating the renin-angiotensin system in metabolic aging, we treated flies with the angiotensin-converting enzyme (ACE) inhibitor lisinopril. Lisinopril prevented the age-related rise in metabolic rate in B line females, aligning their metabolic phenotype with that of O line flies. This suggests that ACE inhibition may buffer against age-associated increases in metabolic rate and contribute to enhanced metabolic stability. Our results show that selection for delayed reproduction and increased lifespan modifies age-related metabolic trajectories and modulates physiological responses to pharmacological intervention.
    Keywords:  energy metabolism; longevity; metabolomics; postponed reproductive senescence; renin‐angiotensin system blockade
    DOI:  https://doi.org/10.1111/acel.70375
  31. Nat Commun. 2026 Jan 14. 17(1): 229
    6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
    Saeed Daneshmandi, Qi Yan, Eduardo Cortes Gomez, Jee Eun Choi, Eriko Katsuta, Ehsan Gharib, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Elizabeth A Repasky, Philip L McCarthy, Hemn Mohammadpour.
      The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-68102-8
  32. bioRxiv. 2026 Jan 06. pii: 2026.01.05.697812. [Epub ahead of print]
    Maternal lipids prime quiescent neural stem cells to reactivate in response to dietary nutrients.
    Md Ausrafuggaman Nahid, Susan E Doyle, Kelly E Dunham, Michelle L Bland, Sarah E Siegrist.
      Stem cell quiescence--a state of mitotic and metabolic dormancy--is essential for tissue homeostasis and for coordinating growth with nutrient availability. Switching between quiescence and proliferation is controlled through stem cell intrinsic and extrinsic cues, with diet being key as diet provides macro-and micro-nutrients needed for synthesizing new membrane, protein, and nucleic acids. Yet, it remains unclear what nutrients control the stem cell switch and whether nutrient sources other than diet are required. Here, we report that lipids deposited maternally in the embryo regulate reactivation of Drosophila neural stem cells (neuroblasts) from quiescence. This maternal nutrient source is in addition to the known dietary amino acids required during larval feeding 1 . Females fed reduced lipid diets or carrying mutations in genes essential for lipid deposition and metabolism produce larvae with fewer stored lipids in neural tissues. Reduced neural lipid stores result in delayed glial growth and neuroblast reactivation due to the inability of neuroblasts to activate PI3-kinase signaling in response to diet-induced expression of insulin-like peptides. Thus, neuroblasts rely on two nutrient sources, maternal and dietary, raising the possibility that quiescent stem cells in general access and utilize stored and acquired nutrients coordinately to switch between stem cell states.
    DOI:  https://doi.org/10.64898/2026.01.05.697812
  33. Cell Rep. 2026 Jan 14. pii: S2211-1247(25)01595-5. [Epub ahead of print]45(1): 116823
    NNMT inhibition counteracts tubular senescence and fibrosis in early stages of chronic kidney disease.
    Lucie Chanvillard, Hildo C Lantermans, Christopher Wall, Jonathan Thevenet, Loes M Butter, Loic Tauzin, Nike Claessen, Stefan Christen, James A Holzwarth, Sonia Karaz, Steve Lassueur, Giulia Lizzo, José Luis Sanchez-Garcia, Sylviane Métairon, Valentina Ferro, Sofia Moco, Erik J M van Bommel, Michael J B van Baar, Anne C Hesp, Daniel H van Raalte, Joris J T H Roelofs, Harshini Neelakantan, Stanley J Watowich, Matthew J Sanders, Jerome N Feige, Vincenzo Sorrentino, Alessandra Tammaro.
      Chronic kidney disease (CKD) is projected to become the fifth leading cause of mortality by 2040. Tubular senescence drives kidney fibrosis, but current treatments do not target senescent cells. Here, we identify nicotinamide-N-methyltransferase (NNMT) as a critical mediator of tubular senescence and kidney fibrosis. Human CKD microarrays link NNMT to senescence and fibrosis transcriptomic signatures, and diabetic kidney disease (DKD) biopsies show NNMT protein associating with p21, fibrosis, and kidney function decline. Spatial transcriptomics in human biopsies demonstrates that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Importantly, this pattern is conserved in aged and DKD mice, mimicking early-stage CKD features. Mechanistically, NNMT overexpression in tubular epithelial cells exacerbates senescence and partial epithelial-to-mesenchymal transition, while selective NNMT inhibition in senescent kidney cells, organoids, and in vivo is protective. Altogether, these findings position NNMT as a promising therapeutic target to reduce tubular senescence and fibrosis in early CKD.
    Keywords:  CP: Metabolism; NNMT inhibitor; S-adenosyl methionine; aging; chronic kidney disease; diabetic kidney disease; epigenetics; kidney fibrosis; kidney organoids; nicotinamide-N-methyltransferase; tubular epithelial cell senescence
    DOI:  https://doi.org/10.1016/j.celrep.2025.116823
  34. Mol Cell. 2026 Jan 14. pii: S1097-2765(25)00987-6. [Epub ahead of print]
    Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network.
    Stephanie Halim, Rebecca M Sebastian, Kristi E Liivak, Jessica E Patrick, Tiffani Hui, David R Amici, Andrew O Giacomelli, Paulina Rios, Vincent L Butty, William C Hahn, Francisco J Sánchez-Rivera, Marc L Mendillo, Yu-Shan Lin, Matthew D Shoulders.
      Protein mutational landscapes are shaped by how amino acid substitutions affect stability and folding or aggregation kinetics. These properties are modulated by cellular proteostasis networks. Heat shock factor 1 (HSF1) is the master regulator of cytosolic and nuclear proteostasis. Chronic HSF1 activity upregulation is a hallmark of cancer cells, potentially because upregulated proteostasis factors facilitate the acquisition and maintenance of oncogenic mutations. Here, we assess how HSF1 activation influences mutational trajectories by which p53 can escape cytotoxic pressure from nutlin-3, an inhibitor of the p53 regulator mouse double minute 2 homolog (MDM2). HSF1 activation broadly increases the fitness of dominant-negative p53 substitutions, particularly non-conservative, biophysically unfavorable amino acid changes within buried regions of the p53 DNA-binding domain. These findings demonstrate that HSF1 activation reshapes the oncogenic mutational landscape by preferentially supporting the emergence and persistence of biophysically disruptive, cancer-associated p53 substitutions, linking proteostasis network activity directly to oncogenic evolution.
    Keywords:  HSP70; HSP90; cancer evolution; chaperones; deep mutational scanning; heat shock factor I; mutational buffering; p53; protein folding; proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.013
  35. Nat Commun. 2026 Jan 10.
    Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
    Minh Duc Nguyen, Ana Sierra-Magro, Vivek Singh, Anas Khawaja, Alba Timón-Gómez, Antoni Barrientos, Joanna Rorbach.
      The mitochondrial respiratory chain comprises four multimeric complexes (CI-CIV) that drive oxidative phosphorylation by transferring electrons to oxygen and generating the proton gradient required for ATP synthesis. These complexes can associate into supercomplexes (SCs), such as the CI + CIII₂ + CIV respirasome, but how SCs form, by joining preassembled complexes or by engaging partially assembled intermediates, remains unresolved. Here, we use cryo-electron microscopy to determine high-resolution structures of native human CI + CIII₂ + CIV late-assembly intermediates. Together with biochemical analyses, these structures show that respirasome biogenesis concludes with the final maturation of CIV while it is associated with fully assembled CI and CIII₂. We identify HIGD2A as a placeholder factor within isolated and supercomplexed CIV that is replaced by subunit NDUFA4 during the last step of CIV and respirasome assembly. This mechanism suggests that placeholders such as HIGD2A act as molecular timers, preventing premature incorporation of NDUFA4 or its isoforms and ensuring the orderly progression of pre-SC particles into functional respirasomes. Since defects in CIV assembly, including NDUFA4 deficiencies, cause severe encephalomyopathies and neurodegenerative disorders, understanding the molecular architecture and assembly pathways of isolated and supercomplexed CIV offers insight into the pathogenic mechanisms underlying these conditions.
    DOI:  https://doi.org/10.1038/s41467-025-68274-3
  36. Biochem Pharmacol. 2026 Jan 08. pii: S0006-2952(26)00025-0. [Epub ahead of print]245 117694
    Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?
    Brian J Day.
      Immunometabolism is an emerging field that explores how metabolic pathways shape immune cell function, fate, and response. Immune cells undergo dynamic metabolic reprogramming to meet the energetic and biosynthetic demands of activation, differentiation, and effector activity. While glycolysis and oxidative phosphorylation (OxPhos) are well-established regulators of immune responses, recent discoveries suggest that endogenously produced cyanide may serve as a novel modulator of mitochondrial metabolism. Traditionally viewed as a toxic compound, cyanide is now being recognized for its potential role in regulating OxPhos through inhibition of complex IV in the electron transport chain, thereby influencing the balance between glycolysis and mitochondrial respiration. This review synthesizes current knowledge on the metabolic regulation of immune cells-including T cells, macrophages, dendritic cells, B cells, and natural killer (NK) cells-and highlights the role of core pathways such as glycolysis, fatty acid oxidation (FAO), and amino acid metabolism. It also explores how cyanide formation and metabolism intersect with innate immunity, particularly through the generation of thiocyanate and its role in antimicrobial defense. Furthermore, the review discusses how nutritional status integrate with metabolic cues to fine-tune immune responses. Finally, the clinical implications of immunometabolic regulation are examined in the context of autoimmune diseases, cancer, infections, and metabolic disorders. The potential of cyanide as a therapeutic modulator of immune metabolism is considered, offering new perspectives on immune regulation and disease intervention.
    Keywords:  Cancer; Immunity; Infection; Inflammation; Metabolic disorders; Metabolic switch; Therapeutics
    DOI:  https://doi.org/10.1016/j.bcp.2026.117694
  37. Nature. 2026 Jan 14.
    Microbiota-induced T cell plasticity enables immune-mediated tumour control.
    Tariq A Najar, Yuan Hao, Yuhan Hao, Gabriela Romero-Meza, Alexandra Dolynuk, Emma Almo, Dan R Littman.
      Therapies that harness the immune system to target and eliminate tumour cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumour immune response by inhibiting negative regulators of T cell activation1-3, is remarkably successful in a subset of cancer patients. Yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB4-9. The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with several studies demonstrating association of microbiota composition with clinical response10-16. However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we use a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific T helper 17 (TH17) cell effector program in the small intestine lamina propria (SILP)17, to investigate how colonization with this microbe affects the efficacy of ICB in restraining distal growth of tumours sharing antigen with SFB. We find that anti-programmed cell death protein 1 (PD-1) treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor (TCR) clonal lineage tracing, fate mapping and peptide-major histocompatability complex (MHC) tetramer staining, we identify tumour-associated SFB-specific T helper 1 (TH1)-like cells derived from the homeostatic TH17 cells induced by SFB colonization in the SILP. These gut-educated ex-TH17 cells produce high levels of the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF) within the tumour microenvironment (TME), enhancing antigen presentation and promoting recruitment, expansion and effector functions of CD8+ tumour-infiltrating cytotoxic lymphocytes and thereby enabling anti-PD-1-mediated tumour control. Conditional ablation of SFB-induced IL-17A+CD4+ T cells, precursors of tumour-associated TH1-like cells, abolishes anti-PD-1-mediated tumour control and markedly impairs tumour-specific CD8+ T cell recruitment and effector function within the TME. Our data, as a proof of principle, define a cellular pathway by which a single, defined intestinal commensal imprints T cell plasticity that potentiates PD-1 blockade, and indicate targeted modulation of the microbiota as a strategy to broaden ICB efficacy.
    DOI:  https://doi.org/10.1038/s41586-025-09913-z
  38. Cell Rep Methods. 2026 Jan 12. pii: S2667-2375(25)00311-X. [Epub ahead of print] 101275
    Improved flux profiling in genome-scale modeling of human cell metabolism.
    Cyriel A M Huijer, Xiang Jiao, Yun Chen, Rosemary Yu.
      Understanding human cell metabolism through genome-scale flux profiling is of interest to diverse research areas of human health and disease. Metabolic modeling using genome-scale metabolic models (GEMs) has the potential to achieve this, but has been limited by a lack of appropriate input data as model constraints. Here, we compare the commonly used consumption and release (CORE) method to a regression-based method (regression during exponential growth phase; REGP). We found that the CORE method is not reliable despite being prevalent in human studies, whereas the exchange fluxes determined by REGP provide constraints that substantially improve GEM simulations for human cell lines. Our results show that the GEM-simulated feasible flux space is constrained to a biologically plausible region, allowing an exploration of the basic organizing principles of the feasible flux space. These improvements help to fulfill the promise of GEMs as a valuable tool in the study of human metabolism and future development of translational applications.
    Keywords:  CP: metabolism; CP: systems biology; cell metabolism; feasible flux space; flux profiling; genome-scale metabolic modeling
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101275
  39. Science. 2026 Jan 15. 391(6782): eadq9006
    Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
    Danhui Liu, Chuanli Zhou, Xiaochen Wang, Zhou Luo, Ruiyao Xu, Shanshan Huo, Lina Guo, Xuemei Luo, Shuhan Yang, Arielle Click, Janiece Vancil, Paola Barajas, Victor Mijares, Hamid Baniasadi, Nan Yan, Jan Rehwinkel, Dustin C Hancks, Elizabeth H Chen, Shuang Liang, Zhenyu Zhong.
      Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome hyperactivation and excessive interleukin (IL)-1β production in macrophages by disrupting SAM and HD domain-containing protein 1 (SAMHD1), a deoxynucleoside triphosphate (dNTP) hydrolase crucial for nucleotide balance. This caused aberrant accumulation of dNTPs, which can be transported into mitochondria, and initiated mitochondrial DNA (mtDNA) neosynthesis, which increased the presence of oxidized mtDNA and triggered NLRP3 hyperactivation. Deletion of SAMHD1 promoted NLRP3 hyperactivation in cells isolated from zebrafish, mice, and humans. SAMHD1-deficient mice showed elevated circulating IL-1β, insulin resistance, and metabolic dysfunction-associated steatohepatitis. Blocking dNTP mitochondrial transport prevented NLRP3 hyperactivation in macrophages from obese patients and SAMHD1-deficient mice. Our study revealed that obesity by inhibiting SAMHD1 rewired macrophage nucleotide metabolism, thereby triggering NLRP3 inflammasome hyperactivation to drive disease progression.
    DOI:  https://doi.org/10.1126/science.adq9006
  40. Nat Immunol. 2026 Jan 15.
    Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.
    Matthew T Stier, Allison E Sewell, Erin L Mwizerwa, Chooi Ying Sim, Samantha M Tanner, Casey M Nichols, Heather H Durai, Erin Q Jennings, Paul Lindau, Erin M Wilfong, Sarah N Obeidalla, V Eric Kerchberger, Dawn C Newcomb, Julie A Bastarache, Lorraine B Ware, Jeffrey C Rathmell.
      Metabolic and immunologic dysfunction, including pathological CD4+ T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the metabolic properties of human CD4+ T cells from critically ill patients with and without sepsis and healthy adults. CD4+ T cells in critical illness showed subset-specific metabolic plasticity, with regulatory T (Treg) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted Treg cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of Treg cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in Treg cells. These findings indicate that metabolic dysfunction was a contributor to CD4+ T cell remodeling in critical illness and suggest avenues to restore effective immunity.
    DOI:  https://doi.org/10.1038/s41590-025-02390-6
  41. Genes Cells. 2026 Jan;31(1): e70082
    Deficiency of δ-Aminolevulinate Dehydratase Confers a Survival Advantage and Drives Malignancy in Cancer.
    Seiya Watanabe, Taku Chibazakura.
      Heme synthesis has been considered essential, yet cancer cells paradoxically maintain high proliferation despite suppressing the pathway, with low expression of δ-aminolevulinate dehydratase (ALAD), the second enzyme of the pathway, which correlates with a poor prognosis. We propose that this suppression is a novel survival strategy to avoid toxic intermediates. Supporting this, we observed that cancer cells vigorously grow after the complete knockout of the essential ALAD gene, demonstrating the pathway's non-essentiality in malignancy. This ALAD suppression offers a dual advantage: evading growth suppression and promoting malignant phenotypes (epithelial-mesenchymal transition). Crucially, the toxicity induced by reactivating the pathway is not dependent on conventional porphyrin (PpIX) or reactive oxygen species, but rather on an unknown intermediate metabolite upstream of PpIX. Activating the heme pathway, for example, by administration of its starting substrate 5-aminolevulinic acid, provides the impetus for a new therapeutic approach to break this defense.
    Keywords:  5‐aminolevulinic acid; cancer metabolism; heme biosynthesis pathways; δ‐aminolevulinate dehydratase
    DOI:  https://doi.org/10.1111/gtc.70082
  42. Nature. 2026 Jan 14.
    Polyamine-dependent metabolic shielding regulates alternative splicing.
    Amaia Zabala-Letona, Mikel Pujana-Vaquerizo, Belen Martinez-Laosa, Maria Ponce-Rodriguez, Saioa Garcia-Longarte, Isabel Mendizabal, Ana Gimeno, Malgorzata Rogalska, Joycelyn Tan, Diana Cabrera, Sebastiaan van Liempd, Pilar Ximenez-Embun, Sergio Espinosa, Maider Fagoaga-Eugui, Francesca Peccati, Maciej Zakrzewski, Ianire Astobiza, Mikel Arana-Castañares, Sarah Cherkaoui, Maria Sendino, Inés Martín-Barros, Amaia Ercilla, Laura Bozal-Basterra, Onintza Carlevaris, Amaia Arruabarrena-Aristorena, Encarnación Pérez-Andrés, Telmo Santamaría-Zamorano, Juan A Ferrer-Bonsoms, Fernando Carazo, Maciej Cieśla, Cesar Lobato, Joan Seoane, Natalia Martín-Martín, Rosa Barrio, James D Sutherland, Ana M Aransay, Juan Manuel Falcón-Pérez, Barbara Martínez-Pastor, Angel Rubio, Francisco J Blanco, Michael D Hogarty, Raphael J Morscher, Edurne Berra, Remigiusz A Serwa, Jesús Jiménez-Barbero, Gonzalo Jiménez-Osés, Alejo Efeyan, Lydia Finley, Jose M Lizcano, Javier Muñoz, Juan Valcarcel, Arkaitz Carracedo.
      Metabolites are central to cellular homeostasis. Although much emphasis has been placed on their relevance to meet energetic and biosynthetic demands, metabolic intermediates also function as signalling molecules. Here we show that polyamines, small polycations that are critical to cellular homeostasis1-3, regulate the process of alternative pre-mRNA splicing. We find that inhibition of polyamine synthesis increases phosphorylation of spliceosomal proteins, concomitant with perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modelling combined with biochemical assays revealed that polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 small nuclear ribonucleoprotein SF3 subcomplex, thus preventing the action of upstream kinases. We refer to this molecular process by which polyamines regulate protein phosphorylation as metabolic shielding.
    DOI:  https://doi.org/10.1038/s41586-025-09965-1
  43. bioRxiv. 2026 Jan 06. pii: 2026.01.05.697775. [Epub ahead of print]
    Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.
    Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend.
      Therapy resistance is the leading cause of cancer-related deaths. Drug-tolerant persister cells (DTPs) represent a major barrier to cancer cure, mediating resistance through adaptive cell state transitions and driving tumor progression. Here, we investigate metabolic differences between DTPs and drug-sensitive cancer cells using integrated fluxomics. Proteomic profiling and extracellular flux analyses revealed that DTPs upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that DTPs utilize glucose to fuel the pentose phosphate pathway (PPP) to generate NADPH and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that DTPs sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. These findings reveal a systems-level shift in DTP metabolism that maintains antioxidant activity for cell survival, highlighting potential new targets and treatment paradigms to overcome therapy resistance.
    DOI:  https://doi.org/10.64898/2026.01.05.697775
  44. J Inherit Metab Dis. 2026 Jan;49(1): e70142
    Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.
    Karin Terburgh, Nastassja Sweeney, Roan Louw.
      The deficiency of mitochondrial complex I (CI), a key regulator of cellular energy homeostasis and metabolic flexibility, is a prevalent driver of cardiovascular pathology in mitochondrial disorders. The Ndufs4 knockout (KO) mouse model of Leigh syndrome (LS), which lacks a critical CI subunit, exhibits severe cardiac abnormalities secondary to encephalomyopathy. However, the metabolic basis of LS-associated cardiac dysfunction remains poorly understood. This study aims to evaluate how whole-body CI deficiency affects cardiac bioenergetics and metabolism in late-stage Ndufs4 KO mice. We assessed respiratory chain enzyme activities and oxygen consumption rates using kinetic spectrophotometric assays and high-resolution respirometry, respectively, in mitochondria isolated from Ndufs4 KO and wild-type mouse hearts. Cardiometabolic profiling was performed on a well-powered cohort, employing untargeted GC-TOFMS, 1H-NMR and semi-targeted LC-MS/MS. Ndufs4 KO hearts showed a 98.9% reduction in CI activity and a 63.9% decline in CI-driven respiration, halving CI's contribution to combined CI + II respiration and prompting a shift toward CII-driven respiration. Cardiometabolic profiles revealed significant reductions in energy-generating substrates, including long-chain fatty acids, glucose, lactic acid and 3-hydroxybutyric acid, along with lower levels of anaplerotic amino acids and TCA cycle intermediates, particularly succinic acid. Additionally, profound disruptions were observed in dimethylglycine, glutamic acid and lysine metabolism. We conclude that whole-body CI deficiency results in severe cardiac bioenergetic and metabolic dysregulation, characterised by reduced CI-dependent respiration and extensive substrate reduction across multiple metabolic pathways. These findings underscore the metabolic vulnerability of the CI-deficient heart and suggest potential therapeutic targets for managing cardiomyopathy in mitochondrial disease.
    Keywords:  Leigh syndrome; Ndufs4 knockout mice; complex I deficiency; heart metabolism
    DOI:  https://doi.org/10.1002/jimd.70142
  45. Int Immunopharmacol. 2026 Jan 14. pii: S1567-5769(25)02095-8. [Epub ahead of print]172 116106
    PIK3CG deficiency promotes metabolic reprogramming in pancreatic Cancer by suppressing GLS2-driven glutamine metabolism.
    Lu Han, Die Zhang, Weidong Xiao, Chunyan Zeng, Youxiang Chen.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) undergoes profound metabolic reprogramming. This study aims to elucidate how PIK3CG deficiency drives glutamine (Gln) metabolic reprogramming in PDAC.
    METHODS: We first identified PIK3CG as a key differentially expressed gene in PDAC and confirmed that its expression level correlates with patient survival. We established both in vitro and in vivo PIK3CG-knockdown (PIK3CG-KD) models. Using these models, we assessed its regulatory effects on the Gln metabolic pathway, mitochondrial reactive oxygen species (mtROS) accumulation, mitochondrial membrane potential, and tumor cell pyroptosis. Moreover, we delineated the specific molecular mechanism linking PIK3CG to downstream signaling. This mechanism crucially involves GLS2, a key enzyme in glutamine metabolism.
    RESULTS: PIK3CG deficiency suppresses the mechanistic target of rapamycin complex 1 (mTORC1) pathway, leading to enhanced phosphorylation of S6K2. This disrupts the interaction between nuclear S6K2 (Glu163) and P53 (Arg273), ultimately inhibiting GLS2 transcription. Consequently, a series of metabolic disturbances ensue: glutamate (Glu) accumulates substantially, Gln catabolism is blocked, and its influx into the TCA cycle is restricted, resulting in reduced α-ketoglutarate (α-KG) levels. The deficiency in α-KG triggers a significant accumulation of mtROS. Notably, despite elevated ROS levels, pyroptosis is suppressed and accompanied by exacerbated inflammation. Conversely, GLS2 overexpression rescues all the aforementioned phenotypes induced by PIK3CG-KD-including tumor growth, elevated mtROS, suppression of pyroptosis, and inflammatory response-while restoring Gln metabolic homeostasis.
    CONCLUSION: Our study reveals a novel mechanism by which PIK3CG-KD regulates Gln metabolism and mitochondrial function via the S6K2/P53/GLS2 axis, providing a rationale for metabolic intervention and precision therapy in PIK3CG-deficient PDAC.
    Keywords:  GLS2; Glutamine metabolism; PIK3CG; Pancreatic ductal adenocarcinoma; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.116106
  46. J Biol Chem. 2026 Jan 13. pii: S0021-9258(26)00028-1. [Epub ahead of print] 111158
    Chronological lifespan extension and nucleotide salvage inhibition in yeast by isonicotinamide supplementation.
    Agata I Kalita, Christopher T Letai, Elisa Enriquez-Hesles, Lindsey N Power, Swarup Mishra, Shekhar Saha, Manikarna Dinda, Dezhen Wang, Pankaj K Singh, Jeffrey S Smith.
      Isonicotinamide (INAM) is an isomer of the NAD+ precursor nicotinamide (NAM) that stimulates the enzymatic activity of Sir2, an NAD+-dependent histone deacetylase from the budding yeast, Saccharomyces cerevisiae. Supplementing INAM into growth media promotes the replicative lifespan (RLS) of this single cell organism by maintaining intracellular NAD+ homeostasis. INAM also extends yeast chronological lifespan (CLS), but the underlying mechanisms remain largely uncharacterized. To identify cellular pathways potentially impacted by INAM, in this study we perform a chemical genomics screen of the yeast knockout (YKO) collection for mutants sensitized to growth inhibition by INAM. Significant Gene Ontology (GO) terms for candidate genes include transcription elongation factors, metabolic pathways converging on one-carbon metabolism, and de novo purine biosynthesis, collectively suggesting that INAM perturbs nucleotide metabolism. Indeed, INAM causes dose-dependent depletion of intracellular cytidine, uridine, and guanosine, ribonucleosides derived from the breakdown of nucleotide monophosphates (NMPs) via nucleotidases (Phm8, Sdt1, Isn1) or the alkaline phosphatase Pho8. We also find that INAM directly inhibits recombinant nucleotidase activity using cytidine or nicotinamide mononucleotide (NMN) as substrates and inhibits alkaline phosphatase activity quantitated from whole cell extracts. Lastly, we find that Phm8 and Pho8 are specifically required for INAM-induced CLS extension, implicating them as likely functional targets in vivo. Taken together, the findings suggest a model whereby partial impairment of nucleotide and/or NAD+ salvage pathways by INAM can trigger a hormetic stress response that supports enhanced quiescence during chronological aging.
    Keywords:  NAD(+); chronological aging; isonicotinamide; nucleotidase; nucleotides; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2026.111158
  47. Nat Metab. 2026 Jan 15.
    The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans.
    Stefan Christen, Karine Redeuil, Laurence Goulet, Maria-Pilar Giner, Isabelle Breton, Riccardo Rota, Adrien Frézal, Atiye Nazari, Pieter Van den Abbeele, Jean-Philippe Godin, Sophie Nutten, Bernard Cuenoud.
      Nicotinamide adenine dinucleotide (NAD(H)) and its phosphorylated form NADP(H) are vitamin B3-derived redox cofactors essential for numerous metabolic reactions and protein modifications. Various health conditions are associated with disturbances in NAD+ homeostasis. To restore NAD+ levels, the main biosynthetic pathways have been targeted, with nicotinamide (Nam), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) being the most prominent boosters. However, while many preclinical studies have examined the effects of these precursors, a direct comparison in humans is lacking, and recent rodent research suggests that the NAD+-boosting effects of NR and NMN may depend on their microbial conversion to nicotinic acid (NA), a mechanism not yet confirmed in humans. Here we show in a randomized, open-label, placebo-controlled study in 65 healthy participants that 14 days of supplementation with NR and NMN, but not Nam, comparably increases circulatory NAD+ concentrations in healthy adults. Unlike the chronic effect, only Nam acutely and transiently affects the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, we identify that NR and NMN give rise to NA and specifically enhance microbial growth and metabolism. We further demonstrate ex vivo in whole blood that NA is a potent NAD+ booster, while NMN, NR and Nam are not. Ultimately, we propose a gut-dependent model for the modes of action of the three NAD+ precursors with NR and NMN elevating circulatory NAD+ via the Preiss-Handler pathway, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway. Overall, these results indicate a dual effect of NR and NMN and their microbially produced metabolite NA: a sustained increase in systemic NAD+ levels and a potent modulator of gut health. ClinicalTrials.gov identifier: NCT05517122 .
    DOI:  https://doi.org/10.1038/s42255-025-01421-8
  48. J Mol Biol. 2026 Jan 09. pii: S0022-2836(26)00007-0. [Epub ahead of print] 169634
    Pioneers: Glucose sensing and control of health-span and lifespan.
    Sheng-Cai Lin.
      My independent career started based on a simple doctrine of protein multifunctionality, by intuitively choosing the protein called AXIN, which has turned out to be the protagonist of my scientific life. This led us to discover the sensing pathway for glucose which links to AMPK and mTORC1, two master metabolic controllers. We found that AXIN binds LKB1, an upstream kinase of AMPK, and that the AXIN:LKB1 complex translocates to the lysosomal surface after the lysosomal aldolase senses low glucose (fructose-1,6-bisphosphate as the direct signal) to activate AMPK and concomitantly inhibit mTORC1. Remarkably, we found that the lysosomal glucose-sensing AMPK pathway is shared by metformin, a glucose-lowering drug known to also extend lifespan and reduce cancer risk. In search of metabolites enriched in calorie-restricted mice and able to activate AMPK via the lysosomal pathway, we identified that lithocholic acid (LCA) as such a factor. We also identified TULP3 as the LCA receptor, which signals to activate sirtuins, increase NAD+, activate AMPK and inhibit mTORC1. In translation, we have identified an aldolase inhibitor termed aldometanib, which mimics glucose starvation to activate AMPK. Aldometanib can alleviate fatty liver, lower blood glucose, and extend lifespan in animals. Surprisingly, aldometanib can also mobilize tumoricidal CD8+ T cells to infiltrate and contain hepatocellular carcinomas (HCC), enabling HCC-bearing mice to live to ripe ages, the endpoint of cancer therapy. Our work has thus revealed that glucose acts as a messenger that signals through a specialized route to control health-span and lifespan. We will continue to explore the teleological meaning of glucose as a "chosen" molecule.
    Keywords:  AMPK; AXIN; and lifespan; glucose sensing; health-span; lysosome
    DOI:  https://doi.org/10.1016/j.jmb.2026.169634
  49. Cell Rep. 2026 Jan 13. pii: S2211-1247(25)01599-2. [Epub ahead of print]45(1): 116827
    In situ multi-modal characterization of pancreatic cancer reveals tumor cell identity as a defining factor of the surrounding microenvironment.
    Anna Lyubetskaya, Brian Rabe, Andrew Kavran, Yulong Bai, Andrew Fisher, Alba Font-Tello, Anne Lewin, Hannah Pliner, Yunfan Fan, Lauren Giampapa, Yelena Cheng, Chao Dai, Ruifeng Hu, Tom Lila, Alexandre P Alloy, Mike Mason, Constance Brett, Todd Brett, Fayaz Seifuddin, Steven Vasquez Grinnell, Soren R Stahlschmidt, Yilin Zhao, Ryan Golhar, Isaac Neuhaus, Daniel Carrera, Carlos Rios, Pradeep Kar, Abhishek Shukla, Rachael Bashford-Rogers, Matthew J Meyer, Enas Abu Shah, Lara Heij, Shivan Sivakumar, Jimena Trillo-Tinoco, Benjamin J Chen, Konstantinos J Mavrakis, Eugene Drokhlyansky.
      Pancreatic ductal adenocarcinoma is heterogeneous, with low tumor purity, a prominent microenvironment, and complex architecture, which preclude the identification of shared tumor-intrinsic and stromal biology within and across patients. We overcame these challenges by achieving necessary resolution and context through the application of complementary genomics, pathology, and machine-learning approaches to characterize primary untreated tumors from 39 patients. We captured 340,000 spatial low-bulk and 530,000 spatial single-cell transcriptomes and observed a spectrum of classical-to-basal tumor subtypes present within all patients. We found that each subtype has distinct regulators, stromal neighborhoods, microenvironment, extracellular matrix, and histology corresponding to multiple immunosuppressive and therapy resistance mechanisms. We defined key tumor heterogeneity features, including the presence of mixed KRAS mutations and tertiary lymphoid structures, identifying biomarkers that distinguish the latter from lymph nodes. Lastly, by leveraging patient, cell, and mouse data, we determined which aspects of tumor biology are recapitulated in bulk datasets and reductionist models.
    Keywords:  CP: Cancer; PDAC; hypoxia; oncology; pancreatic adenocarcinoma; pancreatic cancer; single cell; spatial genomics; spatial transcriptomics; tumor microenvironment; tumor subtype
    DOI:  https://doi.org/10.1016/j.celrep.2025.116827
  50. Commun Biol. 2026 Jan 15.
    Epigenetic and metabolic rewiring in metastatic pheochromocytomas and paragangliomas driven by SDHB mutations.
    Tamara Cubiella, Juan José Alba-Linares, Jaime San-Juan-Guardado, Alvaro Suarez-Priede, Nerea Gómez-Suárez, Maria Tous, Irina Bancos, Carles Villabona, Teresa Serrano, Isabel Tena, Maribel Del Olmo, Lluis Forga, Nuria Valdés, Mario F Fraga, María-Dolores Chiara.
      Pheochromocytomas and paragangliomas (PPGLs) with SDHB mutations frequently develop metastases, but the molecular mechanisms driving this progression remain unclear. Here we show that SDHB-mutant metastatic PPGLs display an amplified hypermethylation signature, particularly in genes involved in neuronal differentiation, building on previous findings in SDHx-mutated tumors. This epigenetic shift is already detectable in benign SDHB-mutant tumors, suggesting early priming toward a less differentiated state. In parallel, we identify hypomethylation of genes linked to carbohydrate metabolism, notably the fructose transporter SLC2A5. Functional assays reveal that SDHB loss, hypoxia, exogenous succinate, and fructose availability promote tumor cell growth and induce cell-type-restricted, SDHB-dependent, induction of SLC2A5 expression. These findings highlight the dual role of SDHB mutations in driving epigenetic reprogramming and metabolic adaptation, promoting tumor cell plasticity and survival under metabolic stress. By uncovering a fructose-driven metabolic vulnerability, our study provides insights into the molecular mechanisms underlying metastatic PPGLs and identifies potential therapeutic targets at the intersection of epigenetic and metabolic regulation.
    DOI:  https://doi.org/10.1038/s42003-026-09543-9
  51. bioRxiv. 2026 Jan 05. pii: 2026.01.05.697750. [Epub ahead of print]
    Targeted Lipid Metabolism Screening Uncovers Regulatory Effects on the STING Immune Response in Mevalonate, Eicosanoid and Fatty Acid Pathways.
    Sofia Skobelkina, Ella L Brunsting, Darren J Perkins.
      The cGAS/STING pathway is a critical signaling hub that orchestrates type I interferon (IFN) responses, autophagy, and programmed cell death in response to double-stranded DNA (dsDNA) or cyclic dinucleotides. While traditionally characterized as a sensor of foreign or mis-localized self dsDNA, recent evidence demonstrates that STING also integrates information about the homeostasis of cellular lipid biosynthesis into the innate inflammatory response. This integration occurs most notably through STING's sensitivity to de novo cholesterol synthesis. However, given that mammalian cells undergo widespread lipid metabolic reprogramming, characterized by alterations in the synthesis of many lipid species in addition to cholesterol, during processes such as malignant transformation to cancer or during infection by intracellular pathogens, we hypothesized that STING function may be regulated by perturbations in other undescribed lipid pathways. To investigate potential other facets of the STING-lipid interface, we have performed a targeted small molecule screen across multiple lipid metabolic pathways, including the mevalonate, PPAR (fatty acid), and arachidonic acid pathways. Our findings reveal that positively and negatively perturbing enzymes within these diverse lipid paths including lipoxygenases and cyclooxygenases can significantly modulate STING-dependent signal transduction and transcriptional programs, identifying metabolic nodes that link lipid homeostasis with innate immune signaling. These results suggest that existing lipid-lowering and metabolic therapies may have unappreciated immunomodulatory effects on STING applicable in cancer and infectious disease, offering new opportunities for therapeutic intervention.
    DOI:  https://doi.org/10.64898/2026.01.05.697750
  52. Nat Commun. 2026 Jan 15.
    Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.
    Tim Vervliet, Jens Loncke, Marko Sever, Karan Ahuja, Chris Van den Haute, Tomas Luyten, Grace E Stutzmann, Catherine Verfaillie, Tihomir Tomašič, Geert Bultynck.
      Lysosomal and endoplasmic reticulum (ER) Ca2+ release mutually influence each other's functions. Recent work revealed that ER-located ryanodine receptor(s) (RyR(s)) Ca2+ release channels suppress autophagosome turnover by the lysosomes. In familial Alzheimer's disease, inhibiting RyR hyperactivity restored autophagic flux by normalizing lysosomal vacuolar H+-ATPase (vATPase) levels. However, the mechanisms by which RyRs control lysosomal function and how this involves the vATPase remain unknown. Here, we show that RyRs interact with the ATP6v0a1 subunit of the vATPase, contributing to ER-lysosomal contact site formation. This interaction suppresses RyR-mediated Ca²⁺ release, leading to reduced lysosomal exocytosis. Pharmacological inhibition of RyR activity mimics these effects on lysosomal exocytosis. Retaining lysosomes inside cells via RyR inhibition increases ER-lysosomal contact site formation, rendering lysosomes more available for autophagic flux. In summary, these findings establish RyR/ATP6v0a1 complexes as ER-lysosomal tethers that dynamically and Ca2+ dependently regulate the intracellular availability of lysosomes to participate in autophagic flux.
    DOI:  https://doi.org/10.1038/s41467-025-68054-z
  53. Bioinform Adv. 2026 ;6(1): vbaf319
    Beyond synthetic lethality in large-scale metabolic and regulatory network models via genetic minimal intervention set.
    Naroa Barrena, Carlos Rodriguez-Flores, Luis V Valcárcel, Danel Olaverri-Mendizabal, Xabier Agirre, Felipe Prósper, Francisco J Planes.
       Motivation: The integration of genome-scale metabolic and regulatory networks has received significant interest in cancer systems biology. However, the identification of lethal genetic interventions in these integrated models remains challenging due to the combinatorial explosion of potential solutions. To address this, we developed the genetic Minimal Cut Set (gMCS) framework, which computes synthetic lethal interactions-minimal sets of gene knockouts that are lethal for cellular proliferation- in genome-scale metabolic networks with signed directed acyclic regulatory pathways. Here, we present a novel formulation to calculate genetic Minimal Intervention Sets, gMISs, which incorporate both gene knockouts and knock-ins.
    Results: With our gMIS approach, we assessed the landscape of lethal genetic interactions in human cells, capturing interventions beyond synthetic lethality, including synthetic dosage lethality and tumor suppressor gene complexes. We applied the concept of synthetic dosage lethality to predict essential genes in cancer and demonstrated a significant increase in sensitivity when compared to large-scale gene knockout screen data. We also analyzed tumor suppressors in cancer cell lines and identified lethal gene knock-in strategies. Finally, we demonstrate how gMISs can help uncover potential therapeutic targets, providing examples in hematological malignancies.
    Availability and implementation: The gMCSpy Python package now includes gMIS functionalities. Access: https://github.com/PlanesLab/gMCSpy.
    DOI:  https://doi.org/10.1093/bioadv/vbaf319
  54. J Biol Chem. 2026 Jan 12. pii: S0021-9258(26)00026-8. [Epub ahead of print] 111156
    F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
    Anirban Chakraborty, Santi M Mandal, Mikita Mankevich, Rajam S Mani, Shandy Shahabi, Manohar Kodavati, Sravan Gopalkrishnashetty Sreenivasmurthy, Nisha Tapryal, Dale J Hamilton, Balaji Krishnan, Muralidhar L Hegde, Michael Weinfeld, Gourisankar Ghosh, Tapas Hazra.
      Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks, is a potential cause for its compromised functionality. Here we show that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly decreased in the mitochondrial extract of HD patients' brains due to a lower level of fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Such decrease in PNKP activity leads to persistent DNA strand breaks that are refractory to subsequent steps for repair completion. Both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria and PFKFB3 is part of a mitochondrial DNA repair complex containing HTT, PNKP, DNA Pol γ (POLG) and Lig IIIα. Notably, PNKP binds F2,6BP (Kd= 525±25 nM) and utilizes it as a cofactor. The levels of both F2,6BP and PFKFB3 are significantly decreased in the mitochondrial extract of HD mouse striatal neuronal cells and patients' brain. Activity of PNKP is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored its activity. Moreover, supplementation of F2,6BP in HD cells restored PFKFB3 level, mitochondrial genome integrity and partially restored mitochondrial membrane potential, mitochondrial respiration and prevented pathogenic aggregate formation. Importantly, F2,6BP supplementation significantly restored mitochondrial genome integrity in an HD Drosophila model. Our findings, therefore, suggest that F2,6BP-mediated restoration of PNKP activity could have a profound impact in ameliorating neurodegenerative symptoms in HD.
    Keywords:  DNA strand break repair; Huntington’s disease; PNKP; fructose-2,6-bisphosphate; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2026.111156
  55. Redox Biol. 2026 Jan 09. pii: S2213-2317(26)00017-0. [Epub ahead of print]90 104019
    Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.
    Jiahui Wang, Rongqing Li, Li Qian.
      Intercellular mitochondrial transfer is recognized as a central mechanism that shapes redox homeostasis, metabolic plasticity, and cellular resilience across multiple tissues. Through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction channels (GJCs), and cell fusion, mitochondria move between donor and recipient cells to restore bioenergetic capacity, buffer oxidative stress, and tune redox-sensitive signaling networks. Recent work has begun to clarify the regulatory framework governing donor-recipient specificity, cargo selection, and the stress-activated cues that trigger organelle exchange. Mitochondrial transfer also exerts distinct, context-dependent influences on disease trajectories. It mitigates injury in neurological damage, ischemia-reperfusion conditions, immune dysfunction, aging, and inflammatory pain, largely by reprogramming mitochondrial function and reactive oxygen species (ROS) dynamics. Conversely, in cancer, mitochondrial acquisition enhances metabolic flexibility, invasiveness, and resistance to therapy. Current therapeutic approaches, including mitochondrial transplantation, EV-based delivery systems, and mitochondria-enhanced immune cells, highlight the translational potential of manipulating mitochondrial exchange, yet face challenges such as mitochondrial fragility, inefficient targeting, and immunogenicity. Deeper mechanistic insight into how mitochondrial transfer remodels redox signaling and metabolic adaptation will be essential for converting this biological process into next-generation organelle-level interventions for redox-driven disorders.
    Keywords:  Extracellular vesicles (EVs); Immunometabolism; Mitochondrial therapeutics; Mitochondrial transfer; Tunneling nanotubes (TNTs)
    DOI:  https://doi.org/10.1016/j.redox.2026.104019
  56. Science. 2026 Jan 15. eadz9353
    A genetically encoded device for transcriptome storage in mammalian cells.
    Yu-Kai Chao, Michelle Wu, Qiyu Gong, Fei Chen.
      Understanding how cells make decisions over time requires the ability to link past molecular states to future phenotypic outcomes. We present TimeVault, a genetically encoded system that records and stores transcriptomes within living mammalian cells for future readout. TimeVault leverages engineered vault particles that capture mRNA through poly(A) binding protein. We demonstrate that the transcriptome stored by TimeVaults is stable in living cells for over 7 days. TimeVault enables high-fidelity transcriptome-wide recording with minimal cellular perturbation, capturing transient stress responses and revealing gene expression changes underlying drug-naive persister states in lung cancer cells that evade EGFR inhibition. By linking past and present cellular states, TimeVault provides a powerful tool for decoding how cells respond to stress, make fate decisions, and resist therapy.
    DOI:  https://doi.org/10.1126/science.adz9353
  57. Mol Cell. 2026 Jan 13. pii: S1097-2765(25)01024-X. [Epub ahead of print]
    Delineating the copy-number substructure of metastatic tumors with CopyKit.
    Junke Wang, Darlan Conterno Minussi, Alexander Davis, Runmin Wei, Hanghui Ye, Emi Sei, Aislyn Schalck, Yun Yan, Hua-Jun Wu, Shanshan Bai, Cheng Peng, Min Hu, Anna Casasent, Alejandro Contreras, Hui Chen, David Hui, Senthil Damodaran, Mary E Edgerton, Scott Kopetz, Bora Lim, Nicholas Navin.
      Tumors are composed of a myriad of subclones that bulk DNA sequencing (DNA-seq) methods cannot accurately resolve. Single-cell DNA-seq methods were developed to address this issue, yet their data analysis remains challenging. Here, we present CopyKit, a comprehensive tool for single-cell DNA copy-number analysis to resolve clonal substructure and reconstruct genetic lineages. Additionally, we introduce "scquantum" to estimate the integer copy-number states of single cells. We performed single-cell DNA-seq of 11,845 cells from one primary breast tumor, two liver metastases, and three primary tumors with matched metastatic tissues. These data identified the subclones from the primary tumors that seeded the metastatic lesions and their associated copy-number events. The data also provided evidence of both subclonal intermixing and spatial segregation in different regions of the liver metastasis. These applications show that CopyKit is a powerful approach for the analysis of high-throughput single-cell copy-number data.
    Keywords:  cancer genomics; computational ploidy estimation; copy-number analysis; intratumor heterogeneity; metastasis; scDNA-seq; single-cell genomics; tumor evolution
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.026
  58. Nat Cell Biol. 2026 Jan;28(1): 1
    Clocking intestinal absorption.
    Angela R Parrish.
      
    DOI:  https://doi.org/10.1038/s41556-025-01865-w
  59. Nat Immunol. 2026 Jan 16.
    Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy.
    Alberto G Conti, Alexander C Evans, Teresa von Linde, Christian Deo T Deguit, Sarah K Whiteside, Alexander J Wesolowski, Charlotte J Imianowski, Yumi Yamashita-Kanemaru, Layla Dahmani, Jack Chapman, Ardon M Pillay, Aws Al-Deka, Randy Greaves, Oliver Burton, Panagiota Vardaka, Shienny Sampurno, Iván Pérez-Núñez, Nicole Y L Saw, Jie Yang, Andrew J M Howden, Klaus Okkenhaug, Suman Mitra, Bartlomiej Swiatczak, Ian A Parish, Rahul Roychoudhuri.
      Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states. Physiological T cell responses are maintained by quiescent stem-like/memory cells dependent upon the transcription factor BACH2. Here we show that quantitative control of BACH2 dosage regulates differentiation along the continuum of stem and effector CD8⁺ T cell states, enabling engineering of synthetic states with persistent antitumor activity. While conventional high-level overexpression of BACH2 enforces quiescence and hinders tumor control, low-dose BACH2 expression promotes persistence without compromising effector function, enhancing anticancer efficacy. Mechanistically, low-dose BACH2 partially attenuates Jun occupancy at highly AP-1-dependent genes, restraining terminal differentiation while preserving effector programs. Similarly, dose optimization enables effective deployment of quiescence factor FOXO1. Thus, quantitative control of gene payloads yields qualitative effects on outcome with implications for quiescence factor deployment in cell therapy.
    DOI:  https://doi.org/10.1038/s41590-025-02389-z
  60. bioRxiv. 2026 Jan 06. pii: 2025.04.24.650538. [Epub ahead of print]
    Separating food intake-dependent and -independent effects in cancer cachexia.
    Yanshan Liang, Young-Yon Kwon, Sheng Hui.
      Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle tissues, with diminished food intake due to anorexia commonly cited as a cause. However, to what extent reduced food intake drives these symptoms and other cachexia phenotypes, such as fatigue, remains generally unclear in preclinical models and patient populations. Here we demonstrate the critical need to address this question in cancer cachexia research. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and wasting of fat and muscle, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing fatigue. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.
    DOI:  https://doi.org/10.1101/2025.04.24.650538
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