bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–09–07
forty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
  2. Rewiring of cortical glucose metabolism fuels human brain cancer growth.
  3. MitoTraP: mitochondrial protection for cellular proteostasis.
  4. Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
  5. The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.
  6. Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
  7. PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.
  8. PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.
  9. Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
  10. Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.
  11. A History of Cancer Research: Cancer Cell Growth and Metabolism.
  12. Lysosomal reduced thiols are essential for mouse embryonic development.
  13. Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
  14. Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
  15. Knowledge and data-driven two-layer networking for accurate metabolite annotation in untargeted metabolomics.
  16. TRAP1 expression elicits pro-tumoral functions in macrophages associated to malignant peripheral nerve sheath tumor cells.
  17. MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation.
  18. Renalase activates mitochondrial leak metabolism in response to cellular stress and to repair damage after injury.
  19. Homocysitaconate controls inflammation through reshaping methionine metabolism and N-homocysteinylation.
  20. Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
  21. REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3-CD38 axis.
  22. Loss of the Y chromosome drives cancer metabolic reprogramming.
  23. Purine metabolism in tumorigenesis and its clinical implications.
  24. Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue.
  25. Effect of ultra-processed food consumption on male reproductive and metabolic health.
  26. Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
  27. SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer.
  28. ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.
  29. The Central Role of Gut Microbes in Host Purine Homeostasis.
  30. Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma.
  31. 3D chromatin architecture as a predictor of somatic mutations in cancer genomes.
  32. Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
  33. Unsupervised machine learning for mass spectrometry imaging data analysis with in vivo isotope labeling.
  34. Clonal expansion of alveolar fibroblast progeny drives pulmonary fibrosis in mouse models.
  35. Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.
  36. Hepatocyte metabolic adaptations during pregnancy and lactation.
  37. Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
  38. Quiescent OXPHOS-high triple-negative breast cancer cells that persist after chemotherapy depend on BCL-XL for survival.
  39. Single-cell transcriptomic and genomic changes in the ageing human brain.
  40. In situ metabolomics reveals intra-islet metabolite changes upon in vivo stimulation of insulin secretion.
  41. The dual role of taurine in cancer and immune metabolism.
  1. Redox Biol. 2025 Aug 21. pii: S2213-2317(25)00352-0. [Epub ahead of print]86 103839
    Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
    Michel N Kanaan, Charbel Y Karam, Luke S Kennedy, Chantal A Pileggi, Lauren Hamilton, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.
      Muscle satellite cell (MuSC) proliferation is tightly regulated by redox homeostasis and nutrient availability, which are often disrupted in muscular pathologies. Beyond its role in maintaining cellular redox homeostasis, this study identified a key metabolic role for cystine/glutamate antiporter xCT in proliferating MuSCs. We investigated the impact of impaired xCT-mediated cystine import in Slc7a11sut/sut MuSCs isolated from mice that harbor a mutation in the SLC7A11 gene, which encodes xCT. We used complementary approaches to study how disrupted cystine import affects glutathione (GSH) redox, cellular bioenergetics, mitochondrial dynamics, and metabolism. Oxygen consumption rates of Slc7a11sut/sut MuSCs were lower, indicative of compromised mitochondrial oxidative capacity. This was accompanied by a fragmented mitochondrial network associated with OPA1 cleavage and redox-sensitive DRP1 oligomerization. Metabolomic profiling revealed a distinct metabolic signature in Slc7a11sut/sut MuSCs, manifested by major differences in BCAAs, pyrimidines, cysteine, methionine, and GSH. Despite lower overall bioenergetic flux, stable-isotope tracing analyses (SITA) showed that xCT deficiency increased glucose uptake, channeling glucose-derived carbons into de novo serine biosynthesis to fuel cysteine production via the transsulfuration pathway, partially compensating for disrupted GSH redox. Furthermore, xCT deficiency triggered upregulated pyrroline-5-carboxylate synthase (P5CS)-mediated proline reductive biosynthesis. By directing glutamate into proline synthesis, MuSCs apparently downregulate oxidative phosphorylation (OXPHOS) and regulate intracellular glutamate levels in response to impaired cystine/glutamate antiporter function. Our findings highlight the roles of xCT in regulating redox balance and metabolic reprogramming in proliferating MuSCs, providing insights that may inform therapeutic strategies for muscular and redox-related pathologies.
    Keywords:  Cysteine; Cystine/glutamate antiporter; Glycolysis; Metabolic reprogramming; Mitochondria; Myopathy; Oxidative phosphorylation; Proline; Skeletal muscle; Slc7a11; System Xc−; Transsulfuration pathway
    DOI:  https://doi.org/10.1016/j.redox.2025.103839
  2. Nature. 2025 Sep 03.
    Rewiring of cortical glucose metabolism fuels human brain cancer growth.
    Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O'Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U Kothari, Navyateja Korimerla, Donna M Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C Andren, Junyoung O Park, Johanna Ten Hoeve, Vijay Tarnal, Kimberly A Redic, Nathan R Qi, Joshua L Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Krithika Suresh, Jann N Sarkaria, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Erina Vlashi, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.
      The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.
    DOI:  https://doi.org/10.1038/s41586-025-09460-7
  3. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]
    MitoTraP: mitochondrial protection for cellular proteostasis.
    Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.
      Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.
    Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
  4. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
    Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
    Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  5. Mol Biol Rep. 2025 Sep 03. 52(1): 861
    The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.
    Yan Zhang, Ying Wu, Aoxing Cheng, Fengjuan Cui, Zhenye Yang, Jing Guo.
       BACKGROUND: Malignant tumors are characterized by their reliance on hyperactive glycolysis (Warburg effect), marked by increased glucose uptake, lactate secretion, and preferential glucose flux into glycolysis and the pentose phosphate pathway (PPP). These metabolic shifts provide energy, biosynthetic precursors, and maintain redox balance, supporting tumor proliferation. However, the regulatory crosstalk between glycolysis and PPP remains poorly understood. This study investigates how tumors coordinate these pathways to drive progression via metabolic reprogramming.
    METHODS AND RESULTS: Exogenous lactate supplementation in A549 cells increased the NADPH/NADP+ ratio, enhanced fatty acid synthesis, and upregulated the PPP. Western blotting revealed lactylation of glucose-6-phosphate dehydrogenase (G6PD), which correlated with intracellular lactate levels, modulated by rotenone treatment or lactate dehydrogenase A (LDHA) overexpression. LDHA knockdown significantly reduced G6PD lactylation. Enzyme assays confirmed that lactylation enhanced G6PD activity. Through truncation and mutagenesis analyses, we identified lysines 45-47 as the key lactylation site, which enhances NADP⁺ binding and promotes G6PD dimerization. Mutation of this site impaired cancer cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, G6PD lactylation serves as a metabolic switch, linking PPP activation to oncogenic progression.
    CONCLUSIONS: Lactate drives tumor progression through G6PD lactylation, activating the PPP and facilitating glycolysis-PPP crosstalk. This study uncovers a novel metabolic rewiring mechanism that promotes oncogenic synergy.
    Keywords:  Cancer; Glucose-6-phosphate dehydrogenase; Lactylation; Pentose phosphate pathway
    DOI:  https://doi.org/10.1007/s11033-025-10960-y
  6. Science. 2025 Sep 04. eadk7978
    Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
    Huihui Huang, Yi Wang, Zsuzsanna K Zsengeller, Joshua M Gorham, Vamsidhara Vemireddy, Amanda J Clark, Hui Pan, Jonathan M Dreyfuss, Vasantha Jotwani, Michael G Shlipak, Mark J Sarnak, Chirag R Parikh, Heather Thiessen-Philbrook, Ronit Katz, Sushrut S Waikar, Nicole J Lake, Monkol Lek, Wen Shi, Daniela Puiu, Yun Soo Hong, Jonathan G Seidman, Dan E Arking, Samir M Parikh.
      Somatically acquired mitochondrial DNA mutations accumulate with age, but the mechanisms and consequences are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored ATP generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (p < 10-7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
    DOI:  https://doi.org/10.1126/science.adk7978
  7. Cell Rep. 2025 Aug 29. pii: S2211-1247(25)00970-2. [Epub ahead of print]44(9): 116199
    PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.
    Gurpreet K Arora, Ryan M Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R Anderson, Cynthia Y Zhang, Shea F Grenier, Li Ling, Sophia Crabtree, Guillem Lambies, Chantal Pauli, David A Scott, Yoav Altman, Benji Portillo, Rabi Murad, Cosimo Commisso, Brooke M Emerling.
      Phosphoinositide kinases generate distinct phosphoinositides that regulate pathways to support tumorigenesis. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) have garnered interest for their role in cancer metabolism; however, their function in pancreatic ductal adenocarcinoma (PDAC) remains unexplored. We identify PI5P4Kα as a critical dependency to support the unique metabolic demands of PDAC cells through its key role in the acquisition of essential metabolic substrates, including glucose and iron. Our data show that inhibition of PI5P4Kα creates a metabolic bottleneck that PDAC cells cannot overcome through adaptive shifts, leading to cancer-specific apoptotic cell death that is reversible by iron supplementation. Notably, we find that PI5P4Kα knockdown suppresses tumor growth in a xenograft mouse model of PDAC. These results not only illuminate the mechanistic underpinnings of PI5P4Kα function in PDAC but also position it as a promising therapeutic target for this disease.
    Keywords:  CP: Cancer; CP: Metabolism; PI5P4K; PIP4K; apoptosis; autophagy; glucose; iron; metabolism; nutrient stress; pancreatic cancer; phosphoinositide kinase
    DOI:  https://doi.org/10.1016/j.celrep.2025.116199
  8. Cancer Res. 2025 Sep 05.
    PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.
    Katrina I Paras, Julia S Brunner, Angela M Montero, Jacob A Boyer, Benjamin T Jackson, Sangita Chakraborty, Abigail Xie, Kristina Guillan, Armaan Siddiquee, Lourdes Pajuelo Torres, Joshua D Rabinowitz, Andrew L Kung, Daoqi You, Filemon S Dela Cruz, Lydia W S Finley.
      PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here, we showed that PAX3-FOXO1+ RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1+ cells displayed increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence was rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimicked the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slowed the growth of multiple PAX3-FOXO1+ tumor xenograft models but not the fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominate methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0315
  9. EMBO Rep. 2025 Aug 29.
    Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
    Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.
      Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
    Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing
    DOI:  https://doi.org/10.1038/s44319-025-00536-z
  10. Nat Genet. 2025 Aug 28.
    Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.
    Matthew A McLoughlin, Sruthi Cheloor Kovilakam, William G Dunn, Muxin Gu, Jake Tobin, Yash Pershad, Nicholas Williams, Daniel Leongamornlert, Kevin Dawson, Laura Bond, Ludovica Marando, Sean Wen, Rachael Wilson, Giampiero Valenzano, Vasiliki Symeonidou, Justyna Rak, Aristi Damaskou, Malgorzata Gozdecka, Xiaoxuan Liu, Clea Barcena, Josep Nomdedeu, Paul Costeas, Ioannis D Dimitriou, Edoardo Fiorillo, Valeria Orrù, Jose Guilherme de Almeida, Thomas McKerrell, Matthew Cullen, Irina Mohorianu, Theodora Foukaneli, Alan J Warren, Chi Wong, George Follows, Anna L Godfrey, Emma Gudgin, Francesco Cucca, Eoin McKinney, E Joanna Baxter, Moritz Gerstung, Jonathan Mitchell, Daniel Wiseman, Alexander G Bick, Margarete Fabre, Pedro M Quiros, Jyoti Nangalia, Siddhartha Kar, George S Vassiliou.
      The mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. First, by studying 454,098 UK Biobank participants, we find that, unlike most CH subtypes, splicing-factor-mutant CH is more common in those with shorter genetically predicted telomeres, as is CH with mutations in PPM1D and the TERT gene promoter. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor mutations 'rescuing' HSCs from critical telomere shortening. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and identify a potential shared mechanism through which different splicing factor mutations drive leukemogenesis. Understanding the mechanistic basis of these observations can open new therapeutic avenues against splicing-factor-mutant CH and hematological or other cancers.
    DOI:  https://doi.org/10.1038/s41588-025-02296-x
  11. Cold Spring Harb Perspect Med. 2025 Sep 02. pii: a035782. [Epub ahead of print]15(9):
    A History of Cancer Research: Cancer Cell Growth and Metabolism.
    Joseph Lipsick.
      Dysregulation of cell growth and metabolic changes are a feature of tumorigenesis. Studies over the past 50 years have mapped the pathways that control cell growth and metabolism and revealed how these are altered in cancer. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks at how we got here-from early work on insulin and growth factor receptor signaling to the discovery of phosphatidyl inositol 3-kinase (PI 3-kinase), the identification of mTOR as the target of rapamycin, and the unexpected finding that tumors can produce novel "oncometabolites."
    DOI:  https://doi.org/10.1101/cshperspect.a035782
  12. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2427125122
    Lysosomal reduced thiols are essential for mouse embryonic development.
    Charles H Adelmann, Avanthika Venkatachalam, Lingjuan Huang, Michelle Liu, Sharon Germana, Stefan A Harry, Paul C Rosen, Joshua Herron, Pei-Chieh Tien, Liron Bar-Peled, David M Sabatini, David E Fisher.
      While it has been appreciated for decades that lysosomes can import cysteine, its significance for whole-organism physiology has remained uncertain. Recent work identified MFSD12 as a transmembrane protein required for cysteine import into lysosomes (and melanosomes), enabling genetic interrogation of this pathway. Here, we show that Mfsd12 knockout mice die between embryonic days 10.5 and 12.5, indicating that MFSD12 is essential for organogenesis. Mfsd12 loss results in the expression of genes involved in cellular stress and thiol metabolism and likely disproportionately affects the erythroid, myeloid, and neuronal lineages. Within lysosomes, imported cysteine is largely oxidized to cystine, which is exported to the cytosol by the cystinosin (CTNS) transporter. However, unlike Mfsd12, loss of Ctns is compatible with viability, suggesting that the essential role of MFSD12 lies not in supplying cystine to the cytosol, but in providing reduced cysteine within the lysosomal lumen. Supporting this model, maternal treatment with cysteamine-a lysosome-penetrant thiol-rescued the development of Mfsd12 knockout embryos, yielding viable adult offspring. These findings establish lysosomal thiol import as a critical metabolic pathway and provide genetic tools to further clarify its physiological and biochemical roles.
    Keywords:  MFSD12; cysteine; lysosome; redox
    DOI:  https://doi.org/10.1073/pnas.2427125122
  13. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2502483122
    Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
    Haowen Jiang, Sarah Jane Tiche, Clifford Jiajun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert M Li, Anh T Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J Svensson, Daniel J Cuthbertson, Florette K Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.
      Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
    Keywords:  differentiation; mitochondria; neuroblastoma; retinoic acid; uncoupler
    DOI:  https://doi.org/10.1073/pnas.2502483122
  14. Nat Rev Nephrol. 2025 Aug 29.
    Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
    Ellen F Carney.
      
    DOI:  https://doi.org/10.1038/s41581-025-01002-8
  15. Nat Commun. 2025 Aug 30. 16(1): 8118
    Knowledge and data-driven two-layer networking for accurate metabolite annotation in untargeted metabolomics.
    Haosong Zhang, Xinhao Zeng, Yandong Yin, Zheng-Jiang Zhu.
      Metabolite annotation in untargeted metabolomics remains challenging due to the vast structural diversity of metabolites. Network-based approaches have emerged as powerful strategies, particularly for annotating metabolites lacking chemical standards. Here, we develop a two-layer interactive networking topology that integrates data-driven and knowledge-driven networks to enhance metabolite annotation. A comprehensive metabolic reaction network is curated using graph neural network-based prediction of reaction relationships, enhancing both coverage and network connectivity. Experimental data are pre-mapped onto this network via sequential MS1 matching, reaction relationship mapping, and MS2 similarity constraints. The generated networking topology enables interactive annotation propagation with over 10-fold improved computational efficiency. In common biological samples, it annotates over 1600 seed metabolites with chemical standards and >12,000 putatively annotated metabolites through network-based propagation. Notably, two previously uncharacterized endogenous metabolites absent from human metabolome databases have been discovered. Overall, this strategy significantly improves the coverage, accuracy, and efficiency of metabolite annotation and is freely available as MetDNA3.
    DOI:  https://doi.org/10.1038/s41467-025-63536-6
  16. J Exp Clin Cancer Res. 2025 Aug 28. 44(1): 257
    TRAP1 expression elicits pro-tumoral functions in macrophages associated to malignant peripheral nerve sheath tumor cells.
    Francesca Scantamburlo, Alessia Rubini, Margherita Toffanin, Maria Egle Castorina, Francesco Ciscato, Sofia Tomasoni, Paolo Finotti, Ranieri Verin, Valentina Zappulli, Marco Fantuz, Camilla Bean, Andrea Rasola, Ionica Masgras.
       BACKGROUND: Metabolic adaptations can sustain the pro-neoplastic functions exerted by macrophages in the tumor microenvironment. Malignant peripheral nerve sheath tumors (MPNSTs), aggressive and incurable sarcomas that develop either sporadically or in the context of the genetic syndrome Neurofibromatosis type 1, are highly infiltrated by macrophages, whose contribution to MPNST growth remains poorly characterized. Here, we analyze the role played by the molecular chaperone TRAP1, a regulator of mitochondrial metabolic pathways, in shaping the pro-tumoral activity of macrophages associated to MPNST cells.
    METHODS: We have studied the phenotypic changes elicited by a MPNST cell-conditioned medium in macrophages with or without TRAP1, and their subsequent ability to support MPNST cell growth and migration and endothelial cell angiogenesis.
    RESULTS: The presence of TRAP1 is required in both naive and M2-like macrophages for eliciting phenotypic changes that lead to the acquisition of pro-neoplastic features. TRAP1-expressing macrophages become able to sustain MPNST cell growth and migration and to exert pro-angiogenic properties on endothelial cells through accumulation of the metabolite succinate and the ensuing activation of a HIF-1α-dependent transcriptional program.
    CONCLUSIONS: Our data provide evidence of a molecular crosstalk between MPNST cellular components, in which soluble factors released by cancer cells drive phenotypic changes in macrophages that in turn enhance pro-tumoral biological routines in both MPNST and endothelial cells. TRAP1-dependent metabolic rewiring in macrophages is mandatory for sustaining this interplay, as a TRAP1-succinate-HIF-1α signaling axis orchestrates their acquisition of tumor-promoting features.
    Keywords:  Angiogenesis; HIF-1α; MPNST; Macrophages; TRAP1
    DOI:  https://doi.org/10.1186/s13046-025-03525-1
  17. Nat Cancer. 2025 Aug 28.
    MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation.
    Michael Cangkrama, Huan Liu, Xiaoyu Wu, Josephine Yates, James Whipman, Christoph G Gäbelein, Mai Matsushita, Luca Ferrarese, Sibilla Sander, Francesc Castro-Giner, Simran Asawa, Magdalena K Sznurkowska, Manfred Kopf, Jörn Dengjel, Valentina Boeva, Nicola Aceto, Julia A Vorholt, Sabine Werner.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies.
    DOI:  https://doi.org/10.1038/s43018-025-01038-6
  18. bioRxiv. 2025 Aug 20. pii: 2025.08.19.671117. [Epub ahead of print]
    Renalase activates mitochondrial leak metabolism in response to cellular stress and to repair damage after injury.
    Xiaojia Guo, Rongmin Chen, Christine Shugrue, Fei-Fei Shang, Rolando Garcia Milian, Haley Moller, Pawel Licznerski, Tian-Min Chen, Richard Kibbey, Ons M'Saad, Yuan Tian, Joerg Bewersdorf, Frank Giordano, Fred S Gorelick, Robert Safirstein, Elizabeth A Jonas, Gary V Desir.
      A variety of mechanisms enhance cell stress response and repair; however, the role of mitochondria in this activity is unclear. Here we show that exogenous renalase (RNLS), an intracellular flavin-dependent NADH oxidase, activates intramitochondrial RNLS activity to promote cell survival. RNLS interacts with the ATP synthase alpha and beta subunits (ATP5α and ATP5β) and opens the ATP synthase c-subunit leak channel to increase complex I and II activities and protein synthesis rate. RNLS causes a selective, sustained, time-dependent increase in cellular protein synthesis without affecting cell proliferation, whereas RNLS deletion or direct inhibition of the mitochondrial leak blocks RNLS-mediated protein synthesis. Functional analysis of newly and differentially synthesized proteins over 24 hours reveals rapid changes in one-carbon metabolism and ribosomal biogenesis pathways as early as one hour after RNLS exposure. Mitochondrial injury is more severe in the RNLS KO kidney after acute stress, related to decreased protein synthesis rate and increased mitophagy. RNLS KO mice exposed to the stress of chronic cardiac pressure overload fail to develop cardiac hypertrophy, the physiological response, and die of heart failure and cardiac rupture. These data highlight the critical role RNLS has in activating mitochondrial leak metabolism to induce selective protein synthesis and protect against acute and chronic stress.
    HIGHLIGHTS: Renalase interacts with the ATP synthase alpha and beta subunitsRenalase activates mitochondrial leak metabolismRenalase and leak metabolism increase complex I and II activitiesLeak metabolism increases protein synthesis rateRenalase protects against cell stress and organ injury.
    DOI:  https://doi.org/10.1101/2025.08.19.671117
  19. Cell Metab. 2025 Aug 22. pii: S1550-4131(25)00357-2. [Epub ahead of print]
    Homocysitaconate controls inflammation through reshaping methionine metabolism and N-homocysteinylation.
    Moubin Lin, Juan Wang, Yongshuai Chai, Xin Chen, Danyang Zhao, Zhangdan Xie, Jiebang Jiang, Hong Li, Li Huang, Siwei Xing, Dashi Qi, Xinyu Mei.
      Inflammation and its metabolic-network interactions generate novel regulatory molecules with translational implications. Here, we identify the immunometabolic crosstalk that generates homocysitaconate, a metabolite formed by homocysteine and itaconate adduction catalyzed by S-adenosyl-L-homocysteine hydrolase (AHCY). Homocysitaconate increases 152-fold during inflammation and exhibits anti-inflammatory effects. Mechanistically, homocysitaconate binds to the D312 residue of the pro-inflammatory protein methionyl-tRNA synthetase (MARS), inhibiting its function and reshaping methionine metabolism to feedback-brake the early activation of the N-homocysteinylation pathway. This metabolic switch facilitates NLR family pyrin domain-containing 3 (NLRP3) ubiquitination to control inflammation. Homocysitaconate demonstrates therapeutic effects in sepsis, high-fat-diet-induced inflammation, and colitis models. Boosting endogenous homocysitaconate synthesis through nicotinamide adenine dinucleotide (NAD+)-dependent AHCY activation (using nicotinamide riboside and pyruvate) also inhibits inflammation by targeting the MARS/NLRP3-N-homocysteinylation cascade. This study establishes homocysitaconate as an anti-inflammatory metabolite that serves as a homeostatic governor by reprogramming protein modification switches, introducing both metabolic timing regulation and clinical strategies to manage inflammatory complications.
    Keywords:  AHCY; Hci; Hcy; MARS1; N-Hcy; N-homocysteinylation; NAD+; NLR family pyrin domain-containing 3; NLRP3; S-adenosyl-L-homocysteine hydrolase; homocysitaconate; homocysteine; itaconate; methionyl-tRNA synthetase; nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.1016/j.cmet.2025.08.001
  20. bioRxiv. 2025 Aug 30. pii: 2025.05.19.654973. [Epub ahead of print]
    Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
    Luisa F Castillo, Katarina E Heyden, Abigail R Williamson, Wenxia Ma, Olga V Malysheva, Nathaniel M Vacanti, Anna E Thalacker-Mercer, Martha S Field.
       OBJECTIVES: Vitamin B12 plays a vital role in folate-mediated one-carbon metabolism (FOCM), a series of one-carbon transfer reactions that generate nucleotides (thymidylate (dTMP) and purines) and methionine. Inadequate levels of B12 impair FOCM, depressing de novo thymidylate (dTMP) synthesis, which in turn leads to uracil accumulation in DNA. This phenomenon has been well documented in nuclear DNA. Our previous work in liver tissue has shown that mitochondrial DNA (mtDNA) is more sensitive to FOCM impairments in that mtDNA exhibits elevated uracil levels before uracil concentrations in nuclear DNA change. However, the functional consequences of uracil accumulation in mtDNA are largely unknown. The purpose of this study was to determine how a functional B12 deficiency (induced by reduced levels of the B12-dependent enzyme methionine synthase (MTR)) and dietary B12 deficiency affects mtDNA integrity and mitochondrial function in energetic and mitochondria-rich tissues such as skeletal muscle.
    METHODS: Male Mtr+/+ and Mtr+/- mice were weaned to either an AIN93G-based control (C) diet containing 25 μ/kg vitamin B12 or a B12-deficient (-B12) diet containing 0 μ/kg vitamin B12 to explore the effects of functional (Mtr+/-) and dietary B12 deficiency on muscle weight, uracil content in mtDNA, mtDNA content, and oxidative phosphorylation complex capacity in skeletal muscle. Aged (20-22mo) male C57BL6/N mice were acclimated to an AIN93G control diet four weeks, then received either weekly injections of saline (vehicle control [30 uL 0.9% NaCl]) or B12 (0.65mg per 30uL 0.9% NaCl) in each of two hindleg muscles [1.25 mg B12 total]) for 8 weeks.
    RESULTS: The tibialis anterior (TA) muscle from Mtr+/- mice exhibited lowered maximal respiratory capacity of complex I, II, and IV of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B12 diet lowered maximal capacity of complex I in red, mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) (p=0.02). Levels of uracil accumulation in mtDNA in red muscle and gastrocnemius were elevated ~10 fold with exposure to -B12 diet (p=0.04 and p<0.001, respectively). In aged mice gastrocnemius complex IV activity increased with intramuscular B12 supplementation (p=0.04).
    CONCLUSIONS: Exposure to a B12-deficient diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in two different types of skeletal muscle. B12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice.
    DOI:  https://doi.org/10.1101/2025.05.19.654973
  21. Nat Aging. 2025 Sep 01.
    REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3-CD38 axis.
    Jiyeon Lee, Ryeonghwa Kang, Sohui Park, Ibrahim O Saliu, Minsoo Son, Jaymie R Voorhees, Julie M Dimitry, Elsa I Quillin, Lauren N Woodie, Brian V Lananna, Li Gan, Young-Ah Goo, Guoyan Zhao, Mitchell A Lazar, Thomas P Burris, Erik S Musiek.
      Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD+ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD+ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD+ via control of the NAD+-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD+-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD+ levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD+ and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD+ in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα-NFIL3-CD38 pathway controlling brain NAD+ metabolism and neurodegeneration.
    DOI:  https://doi.org/10.1038/s43587-025-00950-x
  22. bioRxiv. 2025 Aug 31. pii: 2025.08.26.672471. [Epub ahead of print]
    Loss of the Y chromosome drives cancer metabolic reprogramming.
    Boopathi Subramaniyan, Bipul R Acharya, Prince Anand, Saravana Kumar Kailasam Mani, Saswat Mohapatra, Xingyu Chen, Fangyuan Qu, Yesai Fstkchyan, Corazon Gutierrez, Hany Abdel-Hafiz, Jim Costello, Dan Theodorescu.
      Metabolic reprogramming promotes cancer aggressiveness and an immune-suppressive tumor microenvironment. Loss of the Y chromosome (LOY) drives both phenotypes in bladder cancer (BC). We investigated the hypothesis that LOY leads to metabolic reprogramming using untargeted metabolomic profiling of human BC cells and analysis of pan-cancer transcriptomic datasets. This revealed that aerobic glycolysis is activated in LOY BC cells. Since prior work showed that expression of collagen receptor DDR2 drives BC progression and DDR2 is a regulator of tumor metabolism, we investigated if DDR2 is implicated in metabolic reprogramming of LOY-tumors. Analysis of scRNAseq data from 251 patients with 12 tumor types found that LOY and DDR2 expression promote aerobic glycolysis, and this was confirmed by metabolomics. Deletion of DDR2 in LOY BC cells reduced glycolytic flux, inhibited cell proliferation, reduced EMT and stemness features, and promoted apoptosis. Our data provide a rationale for using LOY as a tumor selection biomarker for DDR2 targeted therapeutics.
    DOI:  https://doi.org/10.1101/2025.08.26.672471
  23. Semin Oncol. 2025 Sep 02. pii: S0093-7754(25)00101-0. [Epub ahead of print]52(6): 152409
    Purine metabolism in tumorigenesis and its clinical implications.
    Zerui Lu, Jiayi Li, Ying Liu, Hui Li, Ying Sun, Rui Geng, Jiahang Song, Jinhui Liu.
      Metabolic reprogramming constitutes a hallmark of malignant neoplasms. Purine metabolism emerges as a pivotal regulator in cellular metabolic networks through multiple mechanisms, including dysregulation of de novo biosynthesis/salvage pathway coordination, adenosine-mediated immunosuppressive microenvironment formation, and collective contributions to tumorigenesis and malignant progression. During metastatic progression, purine metabolism reinforces tumor cell plasticity through mitochondrial energy regulation and modulation of cell cycle checkpoints (eg, G1/S transition). These mechanistic revelations have positioned purine metabolism-targeting strategies as promising oncotherapeutic candidates. This review methodically analyzes (1) purine metabolic pathways and their regulatory dynamics, (2) adenosine-mediated pathophysiological interactions, and (3) the synergistic impacts of these pathways in malignant transformation. We propose a unified mechanistic framework that clarifies oncogenic purine metabolic rewiring while evaluating translational potential through three clinical dimensions: pathogenesis elucidation, diagnostic biomarker discovery, and targeted therapeutic development. This comprehensive synthesis aims to advance precision oncology through mechanistic insights and therapeutic innovation.
    Keywords:  Immune evasion; Metabolic reprogramming; Purine metabolism; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152409
  24. Nat Commun. 2025 Sep 04. 16(1): 7033
    Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue.
    Manuela Sánchez-Feutrie, Montserrat Romero, Sónia R Veiga, Núria Borràs-Ferré, Nick Berrow, Martina Ràfols, Noemí Giménez, Andrea Rodgers-Furones, Alba Sabaté-Pérez, Ángela Rodríguez Pérez, Luis Rodrigo Cataldo, Hans Burghardt, David Sebastián, Natàlia Plana, Vanessa Hernández, Laura Isabel Alcaide, Óscar Reina, Maria J Monte, José Juan G Marin, Manuel Palacín, Remy Burcelin, Per Antonson, Jan-Ake Gustafsson, Antonio Zorzano.
      Brown adipose tissue (BAT) plays a key role in metabolic homeostasis through its thermogenic effects and the secretion of regulatory molecules. Here we report that RAP250 haploinsufficiency stimulates BAT in mice, thus contributing to a decrease in fat accumulation. Local in vivo AAV-mediated RAP250 silencing in BAT reduces body weight and fat mass and enhances glucose oxidation, thereby indicating that RAP250 participates in the regulation of BAT metabolic activity. Analysis of the mechanisms led to the finding that Neuritin 1 is produced and released by brown adipocytes, it plays a key metabolic role, and it participates in the enhanced BAT metabolic activity under RAP250 deficiency. Forced overexpression of Neuritin 1 in UCP1-expressing cells markedly decreases fat mass and body weight gain in mice and induces the expression of thermogenic genes in BAT. Neuritin 1-deficient brown adipocytes also shows a reduced β-adrenergic response. We demonstrate a metabolic role of BAT-derived Neuritin 1 acting through an autocrine/paracrine mechanism. Based on our results, Neuritin-1 emerges as a potential target for the treatment of metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-62255-2
  25. Cell Metab. 2025 Aug 22. pii: S1550-4131(25)00360-2. [Epub ahead of print]
    Effect of ultra-processed food consumption on male reproductive and metabolic health.
    Jessica M Preston, Jo Iversen, Antonia Hufnagel, Line Hjort, Jodie Taylor, Clara Sanchez, Victoria George, Ann N Hansen, Lars Ängquist, Susan Hermann, Jeffrey M Craig, Signe Torekov, Christian Lindh, Karin S Hougaard, Marcelo A Nóbrega, Stephen J Simpson, Romain Barrès.
      Consumption of ultra-processed food is associated with increased caloric intake and impaired health. Here, we conducted a nutrition trial (NCT05368194) with controlled, 2 × 2 crossover design and tested whether ultra-processed food impairs reproductive and metabolic fitness, with further aggravation by excess caloric intake. Comparing the response from an unprocessed to ultra-processed diet identified increased body weight and low-density lipoprotein (LDL):high-density lipoprotein (HDL) ratio, independent of caloric load. Several hormones involved in energy metabolism and spermatogenesis were affected, including decreased levels of growth/differentiation factor 15 and follicle-stimulating hormone. Sperm quality trended toward impairment, with a decrease in total motility. Differential accumulation of pollutants between the discordant diets were detected, such as decreased plasma lithium and a trend for increased levels of the phthalate mono(4-methyl-7-carboxyheptyl)phthalate (cxMINP) in serum, following the ultra-processed diet. Alteration in caloric load alone had distinct effects on the measured outcomes. This study provides evidence that consumption of ultra-processed food is detrimental for cardiometabolic and reproductive outcomes, regardless of excessive caloric intake.
    Keywords:  body weight management; cholesterol; depression score; diet intervention; hormones; phthalates; pollutants; reproduction; sperm quality; ultra-processed diet
    DOI:  https://doi.org/10.1016/j.cmet.2025.08.004
  26. Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01005-8. [Epub ahead of print]44(9): 116234
    Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
    Shuang Ma, Jianhua Qin, Yao Zhang, Jing Luan, Na Sun, Guoyuan Hou, Jiyuan He, Yang Xiao, Wei Zhang, Minghui Gao.
      Ferroptosis is a regulated necrosis driven by iron-dependent lipid peroxidation. Mitochondria play vital roles in ferroptosis. Mitochondrial dynamics is critical for the health of mitochondria and cells. But how this process regulates ferroptosis is not fully understood. Here, we found that mitochondrial fission is induced during ferroptosis. Disruption of mitochondrial dynamics by impeding the expression of the central players of mitochondrial dynamics control, dynamin-related protein 1 (DRP1) and Mitofusion1/2, or modifying the expression of optic atrophy 1 (OPA1) inhibits ferroptosis. Mechanistically, a defect in mitochondrial dynamics homeostasis increases the ratio of [AMP+ADP]/[ATP], thus activating AMP-activated protein kinase (AMPK), which further phosphorylates nuclear factor erythroid 2-related factor 2 (NRF2) and promotes NRF2 nuclear translocation. Subsequently, NRF2 triggers ferroptosis suppressor 1 (FSP1) upregulation, which renders the cells resistant to ferroptosis. Importantly, mitochondrial fusion promoter M1 can mitigate the chemotoxicity induced by doxorubicin without compromising its anti-cancer efficacy. Collectively, the results of this study demonstrate the crucial role of mitochondrial dynamics in ferroptosis and indicate a potential therapeutic protective approach for chemotoxicity.
    Keywords:  AMPK; CP: Immunology; CP: Metabolism; FSP1; NRF2; chemotoxicity; ferroptosis; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116234
  27. Cell Rep. 2025 Sep 01. pii: S2211-1247(25)00910-6. [Epub ahead of print]44(9): 116139
    SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer.
    Xiaojun Zhou, Genxin Wang, Yuhang Wu, Mingzhi Wu, Xiang Zhai, Chenhui Tian, Edward V Prochownik, Congqing Jiang, Youjun Li.
      Tumor metabolic reprogramming is critical for providing energy to support proliferation and resistance to stress-induced cell death. However, the regulatory mechanisms linking these processes remain incompletely understood. Here, using untargeted metabolomics, we demonstrate that creatine potently induces ferroptosis in colorectal cancer (CRC). Mechanistically, creatine binds extracellular signal-regulated kinase 2 (ERK2), impairing its activation by mitogen-activated protein kinase kinase 1 (MEK1). Inhibiting the creatine transporter SLC6A8 reduces creatine uptake and activates ERK2. Activated ERK2 then binds, phosphorylates ferroptosis suppressor protein 1 (FSP1) at Thr109, and stabilizes it to inhibit ferroptosis. Creatine supplementation suppresses tumor growth, enhances CD8+ T cell infiltration, and sensitizes tumors to anti-programmed cell death protein 1 (PD-1) immunotherapy. Our study identifies ERK2 as a creatine sensor regulating FSP1 stability and ferroptosis resistance, highlighting the therapeutic potential of creatine supplementation in combination cancer immunotherapy.
    Keywords:  CP: Cancer; CP: Metabolism; creatine; ferroptosis; mmune checkpoint blockade; tumor metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.celrep.2025.116139
  28. Nat Metab. 2025 Sep 01.
    ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.
    Olivia I Coleman, Adam Sorbie, Alessandra Riva, Miriam von Stern, Stephanie Kuhls, Denise M Selegato, Luisa Siegert, Isabel Keidel, Nikolai Köhler, Jakob Wirbel, Tim Kacprowski, Andreas Dunkel, Josch K Pauling, Johannes Plagge, Diego Mediel-Cuadra, Sophia J Wagner, Ines Chadly, Sandra Bierwith, Tingying Peng, Thomas Metzler, Xin Li, Mathias Heikenwälder, Clemens Schafmayer, Sebastian Hinz, Christian Röder, Christoph Röcken, Michael Zimmermann, Philip Rosenstiel, Katja Steiger, Moritz Jesinghaus, Gerhard Liebisch, Josef Ecker, Christina Schmidt, Georg Zeller, Klaus-Peter Janssen, Dirk Haller.
      Endoplasmic reticulum unfolded protein responses contribute to cancer development, with activating transcription factor 6 (ATF6) involved in microbiota-dependent tumorigenesis. Here we show the clinical relevance of ATF6 in individuals with early-onset and late colorectal cancer, and link ATF6 signalling to changes in lipid metabolism and intestinal microbiota. Transcriptional analysis in intestinal epithelial cells of ATF6 transgenic mice (nATF6IEC) identifies bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype labelling confirm ATF6-related enrichment of long-chain fatty acids in colonic tissue of humans, mice and organoids. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including Desulfovibrio fairfieldensis, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01350-6
  29. Annu Rev Microbiol. 2025 Sep 03.
    The Central Role of Gut Microbes in Host Purine Homeostasis.
    Heather L Emery, Robert L Kerby, Federico E Rey.
      Purines are ubiquitous metabolites that play evolutionarily conserved roles, including as precursors to molecules central to life. Purine synthesis is metabolically and energetically expensive; thus, under physiological conditions, intermediates of purine degradation are efficiently reused through salvage pathways. Excess purines are oxidized and eliminated via the kidneys and intestine. The efficient elimination of excess purines in humans is critical because the primary waste product of purine metabolism, uric acid, is proinflammatory and has been linked to multiple health conditions. Recent studies suggest that gut bacteria influence the purine pool locally and systemically. Bacteria can break down uric acid and other purines aerobically and anaerobically and may regulate their homeostasis. In this article, we provide an overview of purines and their metabolism, and we discuss our current understanding of the complex purine-dependent cross talk and cross-feeding between the host and the gut microbiome.
    DOI:  https://doi.org/10.1146/annurev-micro-041522-100126
  30. Mol Oncol. 2025 Sep 03.
    Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma.
    Johan Staaf, Daniel Ehinger, Hans Brunnström, Mats Jönsson, Frida Rosengren, Marija Kotevska, Anna Karlsson, Mattias Aine, Christian Frezza, Maria Planck, Elsa Arbajian.
      Squamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant cell metabolism is a hallmark of carcinogenesis. This study aimed to identify SqCC-specific key regulators that could eventually be used as new anticancer targets. Transcriptional and metabolomic data were gathered for a cohort of resected lung cancers. SqCC-specific differentially expressed genes were integrated with metabolic data. Findings were validated in cohorts of tumors, normal specimens, and cell lines. In situ protein expression of SLC6A8 was investigated. Differential gene expression analysis identified a subset of SqCC-specific genes with metabolic functions through the Reactome database, and/or correlated to specific metabolites through GEMs models. Metabolic profiling identified seven SqCC-specific metabolites, of which increased creatine levels, in particular, matched to SqCC-specific expression of SLC6A8. Expression of the gene appeared tumor cell-associated. Elevated creatine levels and overexpression of its transporter SLC6A8 appear a distinct metabolic feature of SqCC. Considering ongoing clinical trials in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.
    Keywords:  SLC6A8; creatine; lung cancer; metabolomics; squamous cell lung carcinoma
    DOI:  https://doi.org/10.1002/1878-0261.70121
  31. Nat Rev Cancer. 2025 Sep 01.
    3D chromatin architecture as a predictor of somatic mutations in cancer genomes.
    Karan Bansal, Aprotim Mazumder.
      
    DOI:  https://doi.org/10.1038/s41568-025-00875-y
  32. bioRxiv. 2025 Aug 27. pii: 2025.08.27.672715. [Epub ahead of print]
    Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
    Monil Shah, Ilika Ghosh, Luca Pishos, Valentina Villani, Tristano Pancani, Ryohei Yasuda, Chao Sun, Naomi Kamasawa, Vidhya Rangaraju.
      The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.
    DOI:  https://doi.org/10.1101/2025.08.27.672715
  33. Analyst. 2025 Sep 03.
    Unsupervised machine learning for mass spectrometry imaging data analysis with in vivo isotope labeling.
    Raven L Buckman Johnson, Vy T Tat, Young Jin Lee.
      Mass spectrometry imaging (MSI) has emerged as a powerful tool for spatial metabolomics, but untargeted data analysis has proven to be challenging. When combined with in vivo isotope labeling (MSIi), MSI provides insights into metabolic dynamics with high spatial resolution; however, the data analysis becomes even more complex. Although various tools exist for advanced MSI analyses, machine learning (ML) applications to MSIi have not been explored. In this study, we leverage Cardinal to process MSIi datasets of duckweeds labeled with either 13CO2 or D2O. We apply spatial shrunken centroid (SSC) segmentation, an unsupervised ML algorithm, to differentiate metabolite localizations and investigate isotope labeling of untargeted metabolites. In the SSC segmentation of three-day 13C-labeled duckweed dataset, five spatial segments were identified based on distinct lipid isotopologue distributions, in contrast to classification of only three tissue regions in previous manual analysis based on galactolipid isotopologues. Similarly, SSC segmentation of five-day D-labeled dataset revealed five spatial segments based on distinct metabolite and isotopologue profiles. Further, this untargeted segmentation analysis of MSIi dataset provided insights on tissue-specific relative flux of each metabolite by calculating the fraction of de novo biosynthesis in each segment. Overall, the application of unsupervised machine learning to MSIi datasets has proven to significantly reduce analysis time, increase throughput, and improve the clarity of spatial isotopologue distributions.
    DOI:  https://doi.org/10.1039/d5an00649j
  34. J Clin Invest. 2025 Aug 28. pii: e191826. [Epub ahead of print]
    Clonal expansion of alveolar fibroblast progeny drives pulmonary fibrosis in mouse models.
    Christopher Molina, Tatsuya Tsukui, Imran S Khan, Xin Ren, Wenli Qiu, Michael Matthay, Paul Wolters, Dean Sheppard.
      Pulmonary fibrosis has been called a fibroproliferative disease but the functional importance of proliferating fibroblasts to pulmonary fibrosis has not been systematically examined. In response to alveolar injury, resting alveolar fibroblasts differentiate into fibrotic fibroblasts that express high levels of collagens. However, what role, if any, proliferation plays in the accumulation of fibrotic fibroblasts remains unclear. Through EdU incorporation, genetic lineage tracing, and single cell RNA sequencing, we resolve the proliferation dynamics of lung fibroblasts during post-injury fibrogenesis. Our data show substantial DNA replication in progeny of alveolar fibroblasts in two models of pulmonary fibrosis. By genetically labeling individual cells, we observe clonal expansion of alveolar fibroblast descendants principally in regions of fibrotic remodeling. The transcriptome of proliferating fibroblasts closely resembles that of fibrotic fibroblasts, suggesting that fibroblasts can first differentiate into fibrotic fibroblasts and then proliferate. Genetic ablation of proliferating fibroblasts and selective inhibition of cytokinesis in alveolar fibroblast descendants significantly mitigates pulmonary fibrosis and rescues lung function. Furthermore, fibroblasts in precision-cut lung slices from human fibrotic lungs exhibit higher proliferation rates than those in non-diseased lungs. This work establishes fibroblast proliferation as a critical driver of pulmonary fibrosis and suggests that specifically targeting fibroblast proliferation could be a new therapeutic strategy for fibrotic diseases.
    Keywords:  Cell biology; Fibrosis; Pulmonology
    DOI:  https://doi.org/10.1172/JCI191826
  35. Nature. 2025 Sep 03.
    Genetic suppression features ABHD18 as a Barth syndrome therapeutic target.
    Sanna N Masud, Anchal Srivastava, Patricia Mero, Victoria Saba Echezarreta, Eve Anderson, Lennard van Buren, Jiarun Wei, David Thomson Taylor, Adrian Granda Farias, Nicholas Mikolajewicz, Angela Shaw, Brandon M Murareanu, Michelle Lohbihler, Olivia Sniezek Carney, Simon van Heeringen, Linda Clijsters, Olga Sizova, Jeroen van Ameijde, Freya Nye, Andrea Habsid, Lucy Nedyalkova, Laura McDonald, Craig Simpson, Leanne Wybenga-Groot, Kevin R Brown, Nhi Nho, Radu M Suciu, Katherine Chan, Amy H Y Tong, Frédéric M Vaz, Bastiaan Evers, Robert Lesurf, Tanya Papaz, Lauryl M J Nutter, Stephanie Protze, Maximilian Billmann, Michael Costanzo, Brenda J Andrews, Chad L Myers, Seema Mital, Hilary Vernon, Thijn R Brummelkamp, Charles Boone, Ian C Scott, Micah J Niphakis, Douglas Strathdee, Sebastian M B Nijman, Vincent A Blomen, Jason Moffat.
      Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes electron transport chain protein complexes1. The final step in CL biosynthesis relates to its remodelling: the exchange of nascent acyl chains with longer, unsaturated chains1. However, the enzyme responsible for cleaving nascent CL (nCL) has remained elusive. Here, we describe ABHD18 as a candidate deacylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro, and its inactivation in cells and mice results in a shift to nCL in serum and tissues. Notably, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth syndrome. This rare genetic disease is characterized by the build-up of MLCL resulting from inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL-remodelling cascade1. We also identified a selective, covalent, small-molecule inhibitor of ABHD18 that rescues TAZ mutant phenotypes in fibroblasts from human patients and in fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.
    DOI:  https://doi.org/10.1038/s41586-025-09373-5
  36. Cell. 2025 Aug 25. pii: S0092-8674(25)00921-3. [Epub ahead of print]
    Hepatocyte metabolic adaptations during pregnancy and lactation.
    Li Yang, Yu Zhang, Xin-Xin Yu, Yu-Heng Zhou, Shuang He, Liu Yang, Tong-Yun Mao, Jun-Ge Yang, Ying Wu, Qi-Qi Zheng, Xun-Kai Li, Hou-Zao Chen, Cheng-Ran Xu.
      The liver undergoes metabolic adaptations during gestation and lactation to meet evolving physiological demands, yet the precise processes, regulatory mechanisms, and functions remain unclear. Using high-resolution single-cell RNA sequencing, we systematically characterized hepatocyte adaptations in mice across pregnancy and postpartum stages. We discovered a cyclical hepatocyte trajectory ("pregnancy clock") that governs metabolic changes during gestation and postpartum recovery, reverting to pregestational states in non-lactating mice. Lactation induced a distinct branching trajectory characterized by elevated lipid synthesis and export. Deletion of glycoprotein 130 (gp130) disrupted hepatic adaptations during pregnancy, impairing fetal growth, whereas acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) deficiency postpartum impaired hepatic lipid biosynthesis and export, reducing milk lipid content and compromising offspring development. Comparative analysis with sheep highlighted conserved hepatic metabolic adaptation pathways despite genetic divergence between species. These insights clarify hepatocyte plasticity during pregnancy and lactation, identifying potential therapeutic targets to optimize maternal-fetal health and lactation performance, with implications for reproductive biology and livestock management.
    Keywords:  ACSS2; JAK/STAT signaling; gestation; gp130; hepatocyte adaptations; lactation; maternal liver function; pregnancy clock; sheep hepatocytes; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2025.08.007
  37. Nat Aging. 2025 Sep 02.
    Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
    Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li, Manish Mishra, Rihao Qu, Emily L Goldberg, Sviatoslav Sidorov, Payal Damani-Yokota, Stephen T Yeung, Camille Khairallah, David Gonzalez, Taverlyn M Shepard, Christina Camell, Maxim N Artyomov, Yuval Kluger, Kamal M Khanna, Vishwa Deep Dixit.
      Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38+ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.
    DOI:  https://doi.org/10.1038/s43587-025-00952-9
  38. bioRxiv. 2025 Aug 25. pii: 2025.08.21.671546. [Epub ahead of print]
    Quiescent OXPHOS-high triple-negative breast cancer cells that persist after chemotherapy depend on BCL-XL for survival.
    Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco D M Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea.
      The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.
    DOI:  https://doi.org/10.1101/2025.08.21.671546
  39. Nature. 2025 Sep 03.
    Single-cell transcriptomic and genomic changes in the ageing human brain.
    Ailsa M Jeffries, Tianxiong Yu, Jennifer S Ziegenfuss, Allie K Tolles, Christina E Baer, Cesar Bautista Sotelo, Yerin Kim, Zhiping Weng, Michael A Lodato.
      Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process1. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life2. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.
    DOI:  https://doi.org/10.1038/s41586-025-09435-8
  40. J Biol Chem. 2025 Sep 01. pii: S0021-9258(25)02513-X. [Epub ahead of print] 110661
    In situ metabolomics reveals intra-islet metabolite changes upon in vivo stimulation of insulin secretion.
    Yan Zhou, Nicolas Baez, Tingting Fu, Thierry Brun, Pierre Maechler.
      Upon glucose stimulation, metabolic pathways of pancreatic beta-cells promptly adapt metabolite levels inducing insulin secretion fine-tuned by mitochondrial glutamate dehydrogenase (GDH). Although well described in vitro, these responses cannot yet be captured in vivo due to the intrinsic nature of the islets scattered throughout the pancreas. Tested first in vitro, glutamate precursor glutamine enhanced glucose-stimulated insulin secretion without eliciting oxidative catabolism, as opposed to glucose. Then, to be as close as possible to the in vivo state, we collected the pancreas of mouse models in fasted versus fed states and at the peak of a glucose tolerance test, immediately followed by snap freezing before in situ analysis of metabolic pathways. On the same series of pancreatic cryosections, islets were identified by dithizone beta-cell staining for metabolic analyses combining spatial in situ redox enzymatic assay with targeted metabolomics using time-of-flight secondary ion MS high-resolution imaging. Direct measurements in cryopreserved pancreatic sections of control and beta-cell specific GDH knockout mice showed tight coupling between glycolysis and mitochondrial pathways favored by low lactate dehydrogenase activity and strong succinate dehydrogenase velocity. In response to regular feeding, intra-islet glutamate and glutamine levels were elevated, an effect dependent on beta-cell GDH. Acute in vivo glucose stimulation increased both alanine and glutamate intra-islet levels. Lack of beta-cell GDH abrogated the rise in glutamate and reduced insulin secretion without impacting alanine levels. Overall, the hallmark of in vivo beta-cell stimulation was a strong mitochondrial activity and GDH-dependent elevation of glutamate required for the full development of insulin secretion.
    Keywords:  beta-cell; glutamate dehydrogenase; insulin secretion; metabolomics; pancreatic islet
    DOI:  https://doi.org/10.1016/j.jbc.2025.110661
  41. Trends Endocrinol Metab. 2025 Aug 29. pii: S1043-2760(25)00170-5. [Epub ahead of print]
    The dual role of taurine in cancer and immune metabolism.
    Miaochun Xu, Yang Yu, Canhui Cao.
      Taurine is a conditionally essential amino acid with paradoxical roles in cancer, as both tumor and immune cells rely on it for vital functions. Here, we discuss the emerging context-dependent functions of taurine and propose therapeutic strategies that leverage or inhibit its metabolism to modulate cancer progression and immunity.
    Keywords:  CD8(+) T cell; SLC6A6; immunity; taurine; tumor metabolism
    DOI:  https://doi.org/10.1016/j.tem.2025.08.001
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