bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–08–31
fifty-six papers selected by
Christian Frezza, Universität zu Köln
  1. RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.
  2. A closer look at how cells sense dietary nutrients.
  3. Structural basis for the dynamic regulation of mTORC1 by amino acids.
  4. Mechanical confinement governs phenotypic plasticity in melanoma.
  5. Mitochondria and lysosomes in T cell immunometabolism.
  6. Class I histone deacetylases catalyze lysine lactylation.
  7. Investigating metabolic changes in single embryos during early development in Drosophila.
  8. α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
  9. Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer.
  10. An age-related decrease in leptin contributes to CD8+ T cell aging in the tumor microenvironment.
  11. Multifaceted role of the vitamin B6 pathway in cancer: metabolism, immune interaction, and temporal and spatial regulation.
  12. Endocytosis is essential for cysteine-deprivation-induced ferroptosis.
  13. Tamoxifen induces PI3K activation in uterine cancer.
  14. Targeting cancer metabolism: Therapeutic potential of the fatty acid synthase (FASN) inhibitors.
  15. STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD.
  16. Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy.
  17. Cancer as a failed response to renegade mitochondria.
  18. Repeated heatwaves can age you as much as smoking or drinking.
  19. Biogenesis and function of the mitochondrial solute carrier (SLC25) family in yeast.
  20. Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer.
  21. From Microbial Switches to Metabolic Sensors: Rewiring the Gut-Brain Kynurenine Circuit.
  22. Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.
  23. MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition.
  24. Mitochondrial Transfer Between Cancer and T Cells: Implications for Immune Evasion.
  25. Is mitochondrial function at the heart of ribosome-related diseases?
  26. Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain.
  27. Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
  28. Quantitative imaging of lipid transport in mammalian cells.
  29. Axonal injury is a targetable driver of glioblastoma progression.
  30. A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma.
  31. Distinct metabolic and genetic alterations in tumors from early-onset versus late-onset colorectal cancer.
  32. A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response.
  33. C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer.
  34. Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.
  35. Fetal nutrient flux and oxidative metabolism during hypoxia: adaptive responses to defend fetal growth.
  36. De novo synthesis of peroxisomes: How they are born.
  37. Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH.
  38. mGem: Revisiting bacterial overflow metabolism.
  39. Mitochondria transfer.
  40. The evolution of cancer and ageing: a history of constraint.
  41. Targeting spermine metabolism to overcome immunotherapy resistance in pancreatic cancer.
  42. Metabolomics using anion-exchange chromatography mass spectrometry for the analysis of cells, tissues and biofluids.
  43. Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis.
  44. Transient Nutrient Sensing Shapes T Cell Exhaustion.
  45. TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation.
  46. Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.
  47. The impact of p53 on the urea cycle and nitrogen metabolism enzymes: Mechanisms and implications for cancer development.
  48. Haematopoietic ageing in health and lifespan.
  49. STAT3 sustains tumorigenicity following mutant KRAS ablation.
  50. A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia.
  51. Cysteine metabolism at the crossroads of ferroptosis and cancer therapy.
  52. How did life get multicellular? Five simple organisms could have the answer.
  53. Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma.
  54. A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.
  55. Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism.
  56. Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.
  1. EMBO J. 2025 Aug 26.
    RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.
    Monika Oláhová, Rachel M Guerra, Jack J Collier, Juliana Heidler, Kyle Thompson, Chelsea R White, Paulina Castañeda-Tamez, Alfredo Cabrera-Orefice, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Alexander Galkin, Ilka Wittig, David J Pagliarini, Robert W Taylor.
      A biochemical deficiency of mitochondrial complex I (CI) underlies approximately 30% of cases of primary mitochondrial disease, yet the inventory of molecular machinery required for CI assembly remains incomplete. We previously characterised patients with isolated CI deficiency caused by segregating variants in RTN4IP1, a gene that encodes a mitochondrial NAD(P)H oxidoreductase. Here, we demonstrate that RTN4IP1 deficiency causes a CI assembly defect in both patient fibroblasts and knockout cells, and report that RTN4IP1 is a bona fide CI assembly factor. Complexome profiling revealed accumulation of unincorporated ND5-module and impaired N-module production. RTN4IP1 patient fibroblasts also exhibited defective coenzyme Q biosynthesis, substantiating a second function of RTN4IP1. Thus, our data reveal RTN4IP1 plays necessary and independent roles in both the terminal stages of CI assembly and in coenzyme Q metabolism, and that pathogenic RTN4IP1 variants impair both functions in patients with mitochondrial disease.
    Keywords:  Coenzyme Q; Complex I Assembly; Complexome Profiling; Mitochondria; RTN4IP1
    DOI:  https://doi.org/10.1038/s44318-025-00533-x
  2. Nature. 2025 Aug 27.
    A closer look at how cells sense dietary nutrients.
      
    Keywords:  Cell biology; Metabolism; Structural biology
    DOI:  https://doi.org/10.1038/d41586-025-02694-5
  3. Nature. 2025 Aug 20.
    Structural basis for the dynamic regulation of mTORC1 by amino acids.
    Max L Valenstein, Maximilian Wranik, Pranav V Lalgudi, Karen Y Linde-Garelli, Yuri Choi, Raghu R Chivukula, David M Sabatini, Kacper B Rogala.
      The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability1-5. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. 6-9). GATOR2 forms an octagonal cage, with its distinct WD40 domain β-propellers interacting with GATOR1 and the leucine sensors Sestrin1 and Sestrin2 (SESN1 and SESN2) and the arginine sensor CASTOR1 (ref. 10). The mechanisms through which these sensors regulate GATOR2 and how they detach from it upon binding their cognate amino acids remain unknown. Here, using cryo-electron microscopy, we determined the structures of a stabilized GATOR2 bound to either Sestrin2 or CASTOR1. The sensors occupy distinct and non-overlapping binding sites, disruption of which selectively impairs the ability of mTORC1 to sense individual amino acids. We also resolved the apo (leucine-free) structure of Sestrin2 and characterized the amino acid-induced structural rearrangements within Sestrin2 and CASTOR1 that trigger their dissociation from GATOR2. Binding of either sensor restricts the dynamic WDR24 β-propeller of GATOR2, a domain essential for nutrient-dependent mTORC1 activation. These findings reveal the allosteric mechanisms that convey amino acid sufficiency to GATOR2 and the ensuing structural changes that lead to mTORC1 activation.
    DOI:  https://doi.org/10.1038/s41586-025-09428-7
  4. Nature. 2025 Aug 27.
    Mechanical confinement governs phenotypic plasticity in melanoma.
    Miranda V Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P Koche, Richard M White.
      Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.
    DOI:  https://doi.org/10.1038/s41586-025-09445-6
  5. Trends Immunol. 2025 Aug 22. pii: S1471-4906(25)00181-4. [Epub ahead of print]
    Mitochondria and lysosomes in T cell immunometabolism.
    Erienne G Norton, Nicole M Chapman, Hongbo Chi.
      Metabolic reprogramming and signaling are key orchestrators of T cell immunity. Recent studies have illustrated important roles for intracellular organelles, especially mitochondria and lysosomes, in enforcing T cell metabolism and signaling in response to various extracellular cues. As such, mitochondrial and lysosomal function contributes to adaptive immunity by regulating T cell activation, differentiation, and functional adaptation. In this Review, we discuss how the interplay between organelle biology and metabolism instructs T cell-mediated immunity, with a particular focus on mitochondria and lysosomes. We also summarize how mitochondria and lysosomes, or their crosstalk with other organelles, orchestrate downstream signaling processes and functional reprogramming of T cells. We conclude with a discussion of the pathophysiological outcomes associated with dysregulation of these organelles.
    Keywords:  T cells; immunometabolism; lysosomes; metabolic signaling; mitochondria; organelle crosstalk
    DOI:  https://doi.org/10.1016/j.it.2025.07.014
  6. J Biol Chem. 2025 Aug 18. pii: S0021-9258(25)02453-6. [Epub ahead of print] 110602
    Class I histone deacetylases catalyze lysine lactylation.
    Michelangelo B Gonzatti, Jordi C J Hintzen, Isha Sharma, Mohd Altaf Najar, Takeshi Tsusaka, Mariola M Marcinkiewicz, Claudia Veronica Da Silva Crispim, Nathaniel W Snyder, George M Burslem, Emily L Goldberg.
      Metabolism and post-translational modifications (PTMs) are intrinsically linked and the number of identified metabolites that can covalently modify proteins continues to increase. This metabolism/PTM crosstalk is especially true for lactate, the product of anaerobic metabolism following glycolysis. Lactate forms an amide bond with the ε-amino group of lysine, a modification known as lysine lactylation, or Kla. Multiple independent mechanisms have been proposed in the formation of Kla, including p300/CBP-dependent transfer from lactyl-CoA, a reactive intermediate lactoylglutathione species that non-enzymatically lactylates proteins, and several enzymes are reported to have lactyl transferase capability. We recently discovered that class I histone deacetylases (HDACs) 1, 2, and 3 can all reverse their canonical chemical reaction to catalyze lysine β-hydroxybutyrylation. Here we tested the hypothesis that HDACs can also catalyze Kla formation. Using biochemical, pharmacological, and genetic approaches, we found that HDACs are sufficient to catalyze Kla formation and that HDACs are a major driver of lysine lactylation. Dialysis experiments confirm this is a reversible reaction that depends on lactate concentration. We also directly quantified intracellular lactyl-CoA and found that Kla abundance can be uncoupled from lactyl-CoA levels. Therefore, we propose a model in which the majority of Kla is formed through enzymatic addition of lactate by HDACs 1, 2, and 3.
    Keywords:  glycolysis; histone deacetylase (HDAC); lactate; lactic acid; lysine lactylation; macrophage; post-translational modification (PTM); protein acylation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110602
  7. Nat Metab. 2025 Aug 22.
    Investigating metabolic changes in single embryos during early development in Drosophila.
      
    DOI:  https://doi.org/10.1038/s42255-025-01375-x
  8. Nat Chem Biol. 2025 Aug 22.
    α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
    Wen Mi, Yun Xue, Haohang Yan, Yurou Zhang, Xinlei Cai, Shuyuan Zhang, Ruiping He, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Yifan Liang, Chongwen Cao, Yi Xu, Junfeng Bi, Guanlin Wang, Li Chen, Dan Ye, Fei Li, Ruobing Ren, Pingyu Liu, Hongbin Ji, Fuming Li.
      The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment.
    DOI:  https://doi.org/10.1038/s41589-025-02013-z
  9. Dev Cell. 2025 Aug 25. pii: S1534-5807(25)00499-X. [Epub ahead of print]
    Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer.
    Deli Hong, Ying Lyu, Richa Nayak, Justin S Becker, Matthew A Booker, Keita Masuzawa, Zoe Devos, Tianchu Wang, Shin Saito, Qi Liu, Yixiang Li, Zhaorong Li, Eric H Knelson, Tran Thai, Leslie Duplaquet, Yasmin N Laimon, Gabriel Roberti De Oliveira, Sabina Signoretti, John G Doench, David A Barbie, Michael Y Tolystorukov, Jun Qi, Bradley E Bernstein, Yejing Ge, Matthew G Oser.
      Small cell lung cancer (SCLC) is a highly aggressive malignancy that lacks effective targeted therapies, in part due to frequent loss-of-function mutations in tumor suppressors and the absence of recurrent oncogenic drivers. Approximately 15% of SCLCs harbor inactivating mutations in NOTCH1 or NOTCH2, and most neuroendocrine-high SCLCs exhibit low NOTCH activity. Using CRISPR-Cas9 screening in primary cell lines derived from NOTCH1/2-isogenic SCLC genetically engineered mouse models, we identified TRIM28 as a synthetic lethal dependency in NOTCH2-inactivated SCLCs. Loss of TRIM28 in this context robustly induced expression of endogenous retroviruses (ERVs), activated viral sensing pathways, and triggered a type I interferon response. Mechanistically, NOTCH2 inactivation increased reliance on TRIM28-mediated ERV silencing, creating a hyperdependence on TRIM28 via the STING-MAVS-TBK1 axis. Notably, TRIM28 was essential for tumor growth only in the setting of NOTCH2 loss. These findings identify TRIM28 as a potential therapeutic target in NOTCH2-deficient or low-NOTCH2-expressing SCLC.
    Keywords:  CRISPR-Cas9 screening; NOTCH2; TRIM28; endogenous retroviruses; small cell lung cancer; synthetic lethality; viral sensing
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.023
  10. Cell Rep Med. 2025 Aug 20. pii: S2666-3791(25)00383-0. [Epub ahead of print] 102310
    An age-related decrease in leptin contributes to CD8+ T cell aging in the tumor microenvironment.
    Feixiang Wang, Rujuan Bao, Shuiyu Xu, Wenyan Li, Haiyan Huang, Runchang Li, Xinyu Ding, Yuerong Zhang, Xiaoyan Yu, Qiaoqiao Han, Xian Du, Jie Wan, Song Li, Yichuan Xiao, Ren Zhao, Xingang Cui, Youqiong Ye, Jiayuan Sun, Junke Zheng, Guo-Qiang Chen, Qiang Zou.
      T cell dysfunction with age underlies an increased incidence of cancer in elderly individuals; however, how T cell aging is triggered in the tumor microenvironment is unclear. Here, we show that an age-associated reduction in adipocyte-derived leptin contributes to the accumulation of tumor-infiltrating senescent CD8+ T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8+ T cells increases with age, leading to a weak antitumor effect. Moreover, decreased levels of adipocyte-derived leptin are an indispensable factor for CD8+ T cell aging. Leptin signaling prevents p38-dependent CD8+ T cell senescence. Furthermore, plasma leptin levels are negatively related to intratumoral CD8+ T cell senescence in cancer patients. Our findings identify an unappreciated interplay between metabolic perturbation and T cell aging and suggest that modulating adipocyte-derived leptin levels may be a promising therapeutic strategy for older cancer patients.
    Keywords:  CD8(+) T cells; T cell senescence; aging; antitumor immunity; leptin
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102310
  11. Genes Dev. 2025 Aug 22.
    Multifaceted role of the vitamin B6 pathway in cancer: metabolism, immune interaction, and temporal and spatial regulation.
    Sushanta Kumar Mishra, Bo Li, Ana S H Costa, Linda Van Aelst, Lingbo Zhang.
      Vitamin B6 is a metabolic cofactor that underpins critical regulatory pathways, including amino acid flux, one-carbon pathways, redox homeostasis, and neurotransmitter biosynthesis. Emerging evidence suggests that vitamin B6 deficiency or its metabolic dysregulation perturbs these core metabolic pathways, driving oncogenic programs in both solid tumors and hematologic malignancies. Moreover, vitamin B6-dependent processes can modulate several tumorigenic processes, such as proliferation, oncogenic signaling, immune regulation, and adaptive metabolic reprogramming. The tumor-specific spatiotemporal dynamics of vitamin B6 metabolism uncover context-dependent metabolic vulnerabilities that are tightly regulated by cellular state and tumor niche. This review addresses emerging mechanistic insights into the multifaceted functions of vitamin B6 in tumorigenesis. Furthermore, it proposes dynamic vitamin B6 metabolism as a promising therapeutic axis, offering novel opportunities for tumor-specific targeted intervention.
    Keywords:  cancer; immune regulation; metabolism; temporal and spatial specificity; vitamin B6
    DOI:  https://doi.org/10.1101/gad.352770.125
  12. Mol Cell. 2025 Aug 19. pii: S1097-2765(25)00656-2. [Epub ahead of print]
    Endocytosis is essential for cysteine-deprivation-induced ferroptosis.
    Xuesong Liu, Zechuan Zhao, Zhixuan Bian, Fahad A Benthani, Yingying Hu, Deguang Liang, Xuejun Jiang.
      Ferroptosis is a form of cell death caused by iron-dependent phospholipid peroxidation and subsequent membrane rupture. Autophagic degradation of the iron-storage protein ferritin promotes ferroptosis by increasing cytosolic bioactive iron, presumably explaining how lysosomal inhibitors suppress ferroptosis. Surprisingly, we found that lysosomal inhibitors suppress cysteine-deprivation-induced (CDI) ferroptosis, even in autophagy-defective cells, and subsequently discovered that clathrin-mediated endocytosis (CME) of transferrin is essential for CDI ferroptosis. Blocking lysosomal proteolytic activity failed to inhibit ferroptosis, whereas disrupting endosomal acidification and eliminating the endocytic protein AP2M1 both impeded ferroptosis. Conversely, replenishing cellular iron with ferric ammonium citrate, but not with transferrin, restored CDI ferroptosis in endocytosis-deficient cells. Unexpectedly, abolishing endosomal acidification, CME, and the associated increase in cellular labile iron could not prevent ferroptosis triggered by direct inhibition of the ferroptosis-suppressing enzyme glutathione peroxidase-4 (GPX4). Together, this study reveals the essential role of endocytosis, specifically for CDI ferroptosis.
    Keywords:  AP2M1; GPX4; autophagy; cysteine deprivation; endocytosis; endosome; ferroptosis; iron; lysosome; transferrin
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.006
  13. Nat Genet. 2025 Aug 22.
    Tamoxifen induces PI3K activation in uterine cancer.
    Kirsten Kübler, Agostina Nardone, Shankara Anand, Daniel Gurevich, Jianjiong Gao, Marjolein Droog, Francisco Hermida-Prado, Tara Akhshi, Ariel Feiglin, Avery S Feit, Gabriella Cohen Feit, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, Sebastian Gregoricchio, Mirthe Lanfermeijer, Sten Cornelissen, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra M Nederlof, Quang-Dé Nguyen, Marian J E Mourits, Milan Radovich, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, Rinath Jeselsohn.
      Mutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis.
    DOI:  https://doi.org/10.1038/s41588-025-02308-w
  14. Crit Rev Oncol Hematol. 2025 Aug 20. pii: S1040-8428(25)00298-7. [Epub ahead of print]214 104910
    Targeting cancer metabolism: Therapeutic potential of the fatty acid synthase (FASN) inhibitors.
    Pier Vitale Nuzzo, Silvia Rodrigues, Caroline Fidalgo Ribeiro, Isadora Ferrari Teixeira, Giuseppe Nicolo' Fanelli, Sara Bleve, Francesco Ravera, Hubert Pakula, Filippo Pederzoli, David M Nanus, Massimo Loda.
      Metabolic rewiring is a hallmark of cancer, enabling tumor cells to proliferate rapidly and survive under adverse conditions. Fatty acid synthase (FASN), a key enzyme in de novo lipogenesis, is significantly upregulated in various cancers and is associated with poor prognosis and increased tumor aggressiveness. This review examines the crucial role of FASN in cancer metabolism and evaluates the therapeutic potential of FASN inhibitors. We explore the metabolic pathways critically regulated by FASN and outline its structure, function, and regulatory mechanisms. Overexpression of FASN occurs in cancers such as lung, colon, brain, breast, and prostate, where clinical trials have either been conducted or are ongoing. Pharmacologic inhibition of FASN disrupts lipid biosynthesis, leading to accumulation of metabolic intermediates, induction of metabolic stress, and cell cycle arrest/apoptosis in cancer cells. Denifanstat (TVB-2640), the first-in-class selective FASN inhibitor with favorable pharmacokinetic properties, has demonstrated robust antitumor activity in preclinical models and encouraging results in early-phase clinical studies. Clinical evidence suggests that FASN blockade not only impairs tumor growth but also potentiates the efficacy of existing treatments, including chemotherapy and targeted agents, thereby supporting its integration into combination regimens. Future clinical optimization will require the identification of predictive biomarkers to guide patient selection and treatment stratification.
    Keywords:  Cancer Metabolism; De Novo Lipogenesis (DNL); Denifanstat (TVB-2640); Fatty Acid Synthase (FASN) inhibitors; Lipid Biosynthesis; Metabolic Reprogramming
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104910
  15. Nature. 2025 Aug 20.
    STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD.
    Konstantinos Kelepouras, Julia Saggau, Debora Bonasera, Christine Kiefer, Federica Locci, Hassan Rakhsh-Khorshid, Louisa Grauvogel, Ana Beatriz Varanda, Martin Peifer, Elena Loricchio, Antonella Montinaro, Marijana Croon, Aleksandra Trifunovic, Giusi Prencipe, Antonella Insalaco, Fabrizio De Benedetti, Henning Walczak, Gianmaria Liccardi.
      Conditional deletion of Caspase-8 in epidermal keratinocytes (Casp8E-KO) causes necroptosis-driven lethal dermatitis1-7. Here, we discover that Casp8 loss leads to accumulation of cytosolic DNA responsible for the activation of a cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) gene (STING)-mediated transcriptional program. Genetic and biochemical evidence indicate that STING upregulates both Z-DNA binding protein-1 (ZBP1), and mixed lineage kinase domain-like (MLKL). Combined Casp8-deficiency- and STING-activation-driven accumulation of Z-nuclei acids, activates ZBP1 and triggers formation of a ZBP1-RIPK1-RIPK3 complex independently of FADD-RIPK1-RIPK3 complex enabling necroptosis execution. Genetically, we reveal a functional overlap between STING and ZBP1 as drivers of lethal dermatitis independently of TNFR1, uncovering a novel aetiology of necroptotic inflammation. Since gain-of-function mutations in human STING cause STING-Associated Vasculopathy with onset in Infancy (SAVI), we assessed the role of STING-induced necroptosis in SAVI's aetiology. Chronic activation of STING in patients orchestrates a necroptotic transcriptional program which is confirmed in the N153S-SAVI preclinical mouse model where immune cell-driven pathology and lethality are remarkably rescued by RIPK3 co-deletion. These findings establish STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism in both Casp8-deficient inflammation and SAVI and suggest that targeting the ZBP1-RIPK3-MLKL axis holds therapeutic potential for interferonopathies characterised by excessive necroptosis.
    DOI:  https://doi.org/10.1038/s41586-025-09536-4
  16. Nature. 2025 Aug 20.
    Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy.
    Erez N Baruch, Frederico O Gleber-Netto, Priyadharsini Nagarajan, Xiayu Rao, Shamima Akhter, Tuany Eichwald, Tongxin Xie, Mohammad Balood, Adebayo Adewale, Shorook Naara, Hinduja N Sathishkumar, Shajedul Islam, William McCarthy, Brandi J Mattson, Renata Ferrarotto, Michael K Wong, Michael A Davies, Sonali Jindal, Sreyashi Basu, Karine Roversi, Amin Reza Nikpoor, Maryam Ahmadi, Ali Ahmadi, Catherine Harwood, Irene Leigh, Dennis Gong, Paulino Tallón de Lara, Derrick L Tao, Tara M Davidson, Nadim J Ajami, Andrew Futreal, Kunal Rai, Veena Kochat, Micah Castillo, Preethi Gunaratne, Ryan P Goepfert, Sharia D Hernandez, Nikhil I Khushalani, Jing Wang, Stephanie S Watowich, George A Calin, Michael R Migden, Mona Yuan, Naijiang Liu, Yi Ye, William L Hwang, Paola D Vermeer, Nisha J D'Silva, Yuri L Bunimovich, Dan Yaniv, Jared K Burks, Javier Gomez, Patrick M Dougherty, Kenneth Y Tsai, James P Allison, Padmanee Sharma, Jennifer A Wargo, Jeffrey N Myers, Sebastien Talbot, Neil D Gross, Moran Amit.
      Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.
    DOI:  https://doi.org/10.1038/s41586-025-09370-8
  17. Exp Cell Res. 2025 Aug 20. pii: S0014-4827(25)00321-0. [Epub ahead of print]451(2): 114721
    Cancer as a failed response to renegade mitochondria.
    John Hartung.
      In 1948, before the word 'mitochondrion' gained common parlance in the lexicon of cell biologists, Cyril Darlington published The Plasmagene Theory of the Origin of Cancer without referring to mitochondria per se. Reconsideration of Darlington's theory is warranted today because discoveries about the extraordinary capacities of mitochondria - the organelles that house Darlington's "plasmagenes" - have grown exponentially. If Darlington was right, if intracellular competition between mutant and wild-type mitochondria is the first cause of cancer, it may be the case that a general cure for cancer will include injection of: (A) nanoparticles carrying wild-type mitochondrial genes, and (B) copious amounts of wild-type mitochondria.
    Keywords:  Apoptosis; Cancer; Evolution; Experiment; Heteroplasmic; Homoplasmic; Mitochondria; Mitochondrial transfer; Mitophagy; Reproductive competition; Reversible reaction
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114721
  18. Nature. 2025 Sep;645(8079): 19-20
    Repeated heatwaves can age you as much as smoking or drinking.
    Freda Kreier.
      
    Keywords:  Ageing; Climate change; Public health
    DOI:  https://doi.org/10.1038/d41586-025-02729-x
  19. Biol Chem. 2025 Jun 24.
    Biogenesis and function of the mitochondrial solute carrier (SLC25) family in yeast.
    Celina Nauerz, Ophry Pines, Johannes M Herrmann.
      The mitochondrial solute carrier family, also called SLC25 family, comprises a group of structurally and evolutionary related transporters that are embedded in the mitochondrial inner membrane. About 35 and 53 mitochondrial carrier proteins are known in yeast and human cells, respectively, which transport nucleotides, metabolites, amino acids, fatty acids, inorganic ions and cofactors across the inner membrane. They are proposed to function by a common rocker-switch mechanism, alternating between conformations that expose substrate-binding pockets to the intermembrane space (cytoplasmic state) and to the matrix (matrix state). The substrate specificities of both states differ so that carriers can operate as antiporters, symporters or uniporters. Carrier proteins share a characteristic structure comprising six transmembrane domains and expose both termini to the intermembrane space. Most carriers lack N-terminal presequences but use carrier-specific internal targeting signals that direct them into mitochondria via a specific import route, known as the 'carrier pathway'. Owing to their hydrophobicity and aggregation-prone nature, the mistargeting of carriers can lead to severe proteotoxic stress and diseases. In this review article, we provide an overview about the structure, biogenesis and physiology of carrier proteins, focusing on baker's yeast where their biology is particularly well characterized.
    Keywords:  TIM22 complex; membrane transport; metabolism; mitochondria; protein translocation
    DOI:  https://doi.org/10.1515/hsz-2025-0152
  20. Sci Adv. 2025 Aug 22. 11(34): eadt1798
    Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer.
    Otto Kauko, Mikko Turunen, Päivi Pihlajamaa, Antti Häkkinen, Rayner M L Queiroz, Mirva Pääkkönen, Sami Ventelä, Massimiliano Gaetani, Susanna L Lundström, Antonio Murgia, Biswajyoti Sahu, Johannes Routila, Gong-Hong Wei, Heikki Irjala, Julian L Griffin, Kathryn S Lilley, Teemu Kivioja, Sampsa Hautaniemi, Jussi Taipale.
      Mutations in numerous genes contribute to human cancer, with different oncogenic lesions prevalent in different cancer types. However, the malignant phenotype is simple, characterized by unrestricted cell growth, invasion, and often metastasis. One possible hypothesis explaining this dichotomy is that cancer genes regulate common targets, which then function as master regulators of essential cancer phenotypes. To identify mechanisms that drive the most fundamental feature shared by all tumors-unrestricted cell proliferation-we used a multiomic approach, which identified translation and ribosome biogenesis as common targets of major oncogenic pathways across cancer types. Proteomic analysis of tumors and functional studies of cell cultures established nucleolar and coiled-body phosphoprotein 1 as a key node, whose convergent regulation, both transcriptionally and posttranslationally, is critical for tumor cell proliferation. Our results indicate that lineage-specific oncogenic pathways regulate the same set of targets for growth control, revealing key downstream nodes that could be targeted for therapy or chemoprevention.
    DOI:  https://doi.org/10.1126/sciadv.adt1798
  21. Biomedicines. 2025 Aug 19. pii: 2020. [Epub ahead of print]13(8):
    From Microbial Switches to Metabolic Sensors: Rewiring the Gut-Brain Kynurenine Circuit.
    Masaru Tanaka, László Vécsei.
      The kynurenine (KYN) metabolic pathway sits at the crossroads of immunity, metabolism, and neurobiology, yet its clinical translation remains fragmented. Emerging spatial omics, wearable chronobiology, and synthetic microbiota studies reveal that tryptophan (Trp) metabolism is regulated by distinct cellular "checkpoints" along the gut-brain axis, finely modulated by sex differences, circadian rhythms, and microbiome composition. However, current interventions tackle single levers in isolation, leaving a key gap in the precision control of Trp's fate. To address this, we drew upon an extensive body of the primary literature and databases, mapping enzyme expression across tissues at single-cell resolution and linking these profiles to clinical trials investigating dual indoleamine 2,3-dioxygenase 1 (IDO1)/tryptophan 2,3-dioxygenase (TDO) inhibitors, engineered probiotics, and chrono-modulated dosing strategies. We then developed decision-tree algorithms that rank therapeutic combinations against biomarker feedback loops derived from real-time saliva, plasma, and stool metabolomics. This synthesis pinpoints microglial and endothelial KYN hotspots, quantifies sex-specific chronotherapeutic windows, and identifies engineered Bifidobacterium consortia and dual inhibitors as synergistic nodes capable of reducing immunosuppressive KYN while preserving neuroprotective kynurenic acid. Here, we highlight a framework that couples lifestyle levers, bio-engineered microbes, and adaptive pharmaco-regimens into closed-loop "smart protocols." By charting these intersections, this study offers a roadmap for biomarker-guided, multidisciplinary interventions that could recalibrate KYN metabolic activity across cancer, mood, neurodegeneration, and metabolic disorders, appealing to clinicians, bioengineers, and systems biologists alike.
    Keywords:  chronotherapy; circadian rhythm; indoleamine 2,3-dioxygenase; kynurenine; microbiotal brain–gut axis; precision medicine; probiotics; tryptophan; tryptophan 2,3-dioxygenase
    DOI:  https://doi.org/10.3390/biomedicines13082020
  22. Nat Commun. 2025 Aug 20. 16(1): 7757
    Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.
    Myeong-Gyun Kang, Sanghee Shin, Dong-Gi Jang, Ohyeon Kwon, Song-Yi Lee, Pratyush Kumar Mishra, Minkyo Jung, Ji Young Mun, Jung-Min Kee, Jong-Seo Kim, Hyun-Woo Rhee.
      Proximity labeling with engineered ascorbate peroxidase (APEX) has been widely used to identify proteomes within various membrane-enclosed subcellular organelles. However, constructing protein distribution maps between two non-partitioned proximal spaces remains challenging with the current proximity labeling tools. Here, we introduce a proximity labeling approach using isotope-coded phenol probes for APEX labeling (ICAX) that enables the quantitative analysis of the spatial proteome at nanometer resolution between two distinctly localized APEX enzymes. Using this technique, we identify the spatial proteomic architecture of the mitochondrial intracristal space (ICS), which is not physically separated from the peripheral space. ICAX analysis further reveals unexpected dynamics of the mitochondrial spatiome under mitochondrial contact site and cristae organizing system (MICOS) complex inhibition and mitochondrial uncoupling, respectively. Overall, these findings highlight the importance of ICS for mitochondrial quality control under dynamic stress conditions.
    DOI:  https://doi.org/10.1038/s41467-025-62756-0
  23. Cell Rep. 2025 Aug 22. pii: S2211-1247(25)00951-9. [Epub ahead of print]44(9): 116180
    MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition.
    Gregor A Lueg, James Zhang, Monica Faronato, Andrii Gorelik, Wouter W Kallemeijn, Francesco Falciani, Josephine Walton, Jack W Houghton, Silvia Vannini, Evon Poon, Barbara M Costa, Roberto Solari, Robin Carr, Andrew S Bell, Edward J Bartlett, Bernadette Brzezicha, Martin Janz, Louis Chesler, Dinis P Calado, Edward W Tate.
      Human N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic rationale for targeted therapy. Here, we screened 245 cancer cell lines against IMP-1320, a potent NMT inhibitor (NMTi), and conducted pathway-level analyses to identify that deregulated MYC increases cancer cell sensitivity to NMTis. Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I. This is concurrent with loss of myristoylation and degradation of the complex I assembly factor NDUFAF4, and induction of mitochondrial dysfunction, driven by MYC or MYCN-deregulation. NMTis eliminated or suppressed MYC- and MYCN-driven tumors in vivo without overt toxicity, suggesting that this constitutive co-translational protein modification can be targeted in MYC-driven cancers.
    Keywords:  CP: Cancer; CP: Molecular biology; Complex I; MYC; MYCN; N-myristoylation; N-myristoyltransferase; NDUFAF4; NMT
    DOI:  https://doi.org/10.1016/j.celrep.2025.116180
  24. Antioxidants (Basel). 2025 Aug 18. pii: 1008. [Epub ahead of print]14(8):
    Mitochondrial Transfer Between Cancer and T Cells: Implications for Immune Evasion.
    Soohyun Chun, Jin An, Man S Kim.
      Intercellular mitochondrial transfer in the tumor microenvironment (TME) is a paradigm-shifting process that redefines cancer-T cell crosstalk. This review explores its dual nature as both a tumor immune evasion strategy and a promising therapeutic avenue. Crucially, oxidative stress acts as a key regulator, inducing tunneling nanotube (TNT) formation to facilitate this organelle exchange. Tumors exploit this by transferring dysfunctional, reactive oxygen species (ROS) generating mitochondria to T cells to induce senescence while simultaneously hijacking healthy mitochondria from T cells to empower their own metabolism. This directional exchange, quantified by computational tools like mitochondrial-enabled reconstruction of cellular interactions (MERCI), is linked to poor clinical outcomes. Transfer occurs via TNTs, extracellular vesicles, and direct contact. Conversely, the therapeutic transfer of healthy mitochondria from sources like mesenchymal stromal cells can revitalize exhausted T cells, improving chimeric antigen receptor T (CAR-T) cell efficacy. Clinical translation is guided by emerging biomarkers, including circulating mitochondrial DNA (mtDNA), mitochondrial haplogroups, and the tumor mitochondrial transfer (TMT) score. Harnessing this biological axis for next-generation immunotherapies requires overcoming challenges in transfer efficiency and standardization to effectively modulate the tumor redox landscape and immune response.
    Keywords:  MERCI methodology; T cell exhaustion; cancer metabolism; immune evasion; immunotherapy; mitochondrial transfer; oxidative stress; single-cell analysis; tumor microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.3390/antiox14081008
  25. Trends Cell Biol. 2025 Aug 26. pii: S0962-8924(25)00175-8. [Epub ahead of print]
    Is mitochondrial function at the heart of ribosome-related diseases?
    Qiuxia Zhao, Elif Sarinay Cenik.
      Defects in ribosomal machinery cause ribosomopathies such as Diamond Blackfan anemia, classically linked to impaired protein synthesis. However, emerging evidence places mitochondrial dysfunction as a critical downstream consequence of ribosomal insufficiency. Thus, is impaired energy metabolism, rather than translation alone, a key driver of ribosomopathies such as Diamond Blackfan anemia? This insight could reframe our understanding of disease mechanisms and could identify metabolic pathways as promising therapeutic targets.
    Keywords:  mitochondrial function; mitochondriopathies; ribosome biogenesis; ribosomopathies
    DOI:  https://doi.org/10.1016/j.tcb.2025.07.007
  26. Cell Rep. 2025 Aug 19. pii: S2211-1247(25)00936-2. [Epub ahead of print]44(9): 116165
    Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain.
    Zehao Zhang, Alexander Epstein, Chloe Schaefer, Abdulraouf Abdulraouf, Weirong Jiang, Wei Zhou, Junyue Cao.
      Caloric restriction (CR) is a well-studied intervention that extends lifespan and slows cognitive decline across species, yet the specific cell populations and molecular pathways involved remain elusive. In this study, we profiled >500,000 cells from 36 control and CR mouse brains across three age groups with EasySci single-nucleus transcriptomics and performed imaging-free IRISeq spatial transcriptomics on twelve brain sections from CR and control aged mice. We thereby explored the impact of CR in >300 cellular states and 11 brain regions. CR delayed expansion of inflammatory cell populations, preserved neural precursor cells, and broadly reduced the expression of aging-associated genes involved in cellular stress, senescence, inflammation, and DNA damage. CR restored the expression of region-specific genes linked to cognitive function, myelin maintenance, and circadian rhythm. In summary, we provide a high-resolution spatiotemporal map of the aging mouse brain's response to CR, detailing precise cellular and molecular mechanisms behind its neuroprotective effects.
    Keywords:  CP: Genomics; CP: Metabolism; brain aging; caloric restriction; cellular senescence; neurogenesis; neuroinflammation; rejuvenation; single-cell transcriptomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116165
  27. Nat Commun. 2025 Aug 26. 16(1): 7934
    Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
    Xinzhu Li, Ying Zhu, Ting Li, Xinyi Tu, Shiyu Zhu, Lingzhi Wang, Fei Li, Chenglong Sun, Xin Li, Haiyi Zhao, Tang Tang, Qingce Zang, Ruiping Zhang, Zeper Abliz.
      Organs collaborate to maintain metabolic homeostasis in mammals. Spatial metabolomics makes strides in profiling the metabolic landscape, yet can not directly inspect the metabolic crosstalk between tissues. Here, we introduce an approach to comprehensively trace the metabolic fate of 13C-nutrients within the body and present a robust computational tool, MSITracer, to deep-probe metabolic activity in a spatial manner. By discerning spatial distribution differences between isotopically labeled metabolites from ambient mass spectrometry imaging-based isotope tracing data, this approach empowers us to characterize fatty acid metabolic crosstalk between the liver and heart, as well as glutamine metabolic exchange across the kidney, liver, and brain. Moreover, we disclose that tumor burden significantly influences the host's hexosamine biosynthesis pathway, and that the glucose-derived glutamine released from the lung as a potential source for tumor glutamate synthesis. The developed approach facilitates the systematic characterization of metabolic activity in situ and the interpretation of tissue metabolic communications in living organisms.
    DOI:  https://doi.org/10.1038/s41467-025-63243-2
  28. Nature. 2025 Aug 20.
    Quantitative imaging of lipid transport in mammalian cells.
    Juan M Iglesias-Artola, Kristin Böhlig, Kai Schuhmann, Katelyn C Cook, H Mathilda Lennartz, Milena Schuhmacher, Pavel Barahtjan, Cristina Jiménez López, Radek Šachl, Vannuruswamy Garikapati, Karina Pombo-Garcia, Annett Lohmann, Petra Riegerová, Martin Hof, Björn Drobot, Andrej Shevchenko, Alf Honigmann, André Nadler.
      Eukaryotic cells produce over 1,000 different lipid species that tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unclear, owing to the difficulty of imaging lipid transport in cells3. Here we measured the retrograde transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high-resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting, in contrast to the slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between energy-dependent lipid flipping and non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids, while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09432-x
  29. Nature. 2025 Aug 20.
    Axonal injury is a targetable driver of glioblastoma progression.
    Melanie Clements, Wenhao Tang, Zan Florjanic Baronik, Holly Simpson Ragdale, Roger Oria, Dimitrios Volteras, Ian J White, Gordon Beattie, Imran Uddin, Tchern Lenn, Rachel Lindsay, Sara Castro Devesa, Saketh R Karamched, Mark F Lythgoe, Vahid Shahrezaei, Valerie M Weaver, Ryoichi Sugisawa, Federico Roncaroli, Samuel Marguerat, Ciaran S Hill, Simona Parrinello.
      Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death3, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration4, was sufficient to break this tumour-promoting feedforward loop, leading to the development of less advanced terminal tumours and prolonged survival in mice. Thus, targeting the tumour-induced injury microenvironment may supress progression from latent to advanced disease, thereby providing a potential strategy for GBM interception and control.
    DOI:  https://doi.org/10.1038/s41586-025-09411-2
  30. Neoplasia. 2025 Aug 23. pii: S1476-5586(25)00102-2. [Epub ahead of print]68 101223
    A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma.
    Jiang Zhou, Xinxin Chai, Yi Zhu, Zhi Huang, Tingting Lin, Zhen Hu, Guangdi Chen, Chi Luo, Rutao Cui, Jinghao Sheng.
      The BRAFV600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAFV600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAFV600E downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1α, a master regulator of mitochondrial metabolism, enabling melanoma cells to sustain oxidative metabolism and survive BRAFV600E-targeted therapies. Blocking this H3K27 methyl-to-acetyl switch disrupted metabolic adaptation and sensitized melanoma cells to BRAFV600E inhibition. In conclusion, we revealed an epigenetic and metabolic reprogramming mechanism that enables melanoma to survive the treatment with BRAFV600E inhibitors, presenting druggable targets within the H3K27 modification pathway that could enhance the efficacy of BRAF-targeted therapies in melanoma patients.
    Keywords:  BRAF(V600E); H3K27; KDM6A; Melanoma; Mitochondrial Metabolism; PGC1α
    DOI:  https://doi.org/10.1016/j.neo.2025.101223
  31. Free Radic Biol Med. 2025 Aug 25. pii: S0891-5849(25)00939-6. [Epub ahead of print]
    Distinct metabolic and genetic alterations in tumors from early-onset versus late-onset colorectal cancer.
    Allison Janak, Abhishek Jain, Rolando Garcia-Milian, Oladimeji Aladelokun, Xiaomei Ma, Philip B Paty, Sajid A Khan, Caroline H Johnson.
      Early-onset colorectal cancer (EO-CRC) occurring in individuals under age 50 is rapidly increasing globally, while the incidence of late-onset colorectal cancer (LO-CRC) has decreased over recent years. Previous studies have identified metabolites linked to CRC biology, however tumor-specific differences between EO-CRC and LO-CRC have not been explored. This study aimed to compare the tumor metabolome of EO-CRC and LO-CRC patients to reveal the unique biochemical state of EO-CRC. Mass spectrometry-based untargeted metabolomics was performed on tumor and patient-matched normal tissues from EO-CRC (n=53) and LO-CRC (n=314) patients to identify metabolites significantly altered in tumors (q≤0.05). Metabolite set enrichment analysis, metabolic pathway, and network analyses were performed, to identify the relationship between the altered metabolites and biological function. Analysis revealed 156 metabolites significantly altered between normal and tumor tissues. Homovanillic acid (HVA), a metabolite of dopamine, was uniquely downregulated in EO-CRC. Despite shared changes to HVA-metabolizing genes between EO- and LO-CRC the disruption in catecholamine metabolism may be specific to EO-CRC biology. Pathway and network analysis, supported by gene expression validation, showed that PD-L1 was uniquely decreased in EO-CRC suggesting immunosuppression. Additionally, phospholipid signaling was favored in EO-CRC, whereas LO-CRC tumors showed alterations to EGFR signaling and oxidative stress-related genes. In summary, this study reveals the metabolic nuances in tumor tissues from patients with EO-CRC and LO-CRC, indicating catecholamine metabolism, phospholipid signaling and immunosuppression in the biology of EO-CRC. These findings provide new insight into the metabolism of EO-CRCs that may inform new therapeutic strategies for this group of CRC patients.
    Keywords:  early-onset colorectal cancer; tumor tissues; untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.052
  32. Mol Cell. 2025 Aug 19. pii: S1097-2765(25)00659-8. [Epub ahead of print]
    A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response.
    Jinhua Li, Yansong Zhang, Jingyu Peng, Wei Yang, Yanzhe Pan, Ying Xu, Jiayi Yao, Siyuan Lin, Yizhi Li, Xinran Gu, Wei Dong, Xiang Yu, Ming Ge, Min Liu, Alan Jian Zhu.
      Recent studies highlight the antioxidant role of lipid droplets (LDs) in shielding unsaturated lipids from peroxidation. While LDs accumulate during oxidative stress, the underlying mechanism remains unclear. Our previous research revealed that intracellular amino acids directly bind to and activate the E3 ubiquitin ligase Ubr1 to degrade Plin2, an LD protein inhibiting lipolysis. Here, we unexpectedly find that Ubr1's ability to bind to amino acids is inhibited during oxidative stress. Mechanistically, oxidative stress-induced lipid peroxidation blocks the activity of Hsc70-4, an ATPase that maintains the amino-acid-binding ability of Ubr1. 4-hydroxynonenal, a reactive product of lipid peroxidation, covalently modifies and inactivates Hsc70-4, leading to Ubr1 inactivation, Plin2 stabilization, and LD accumulation. Increased LDs minimize lipid peroxidation, thus protecting cells from oxidative damage and cell death. Together, we identify a regulator of amino acid sensing with redox-dependent activity, bridging the gap in understanding how lipid peroxidation stimulates LD-dependent antioxidant responses.
    Keywords:  4-hydroxynonenal; HSPA8; Hsc70-4; Plin2; Ubr1; amino acid sensing; antioxidant response; lipid droplet; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.009
  33. Cell Rep. 2025 Aug 19. pii: S2211-1247(25)00934-9. [Epub ahead of print]44(9): 116163
    C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer.
    Ran Liu, Meng Zhao, Xinrui Zhang, Hao Wu, Li Ren, Junqiang Lv, Zhe Liu, Quan Wang, Zhi Yao.
      Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is a hallmark of cancer, yet the mechanisms driving aerobic glycolysis are unclear. In this study, we identified chromosome 19 open reading frame 12 (C19orf12), a gene associated with neurodegeneration, as upregulated in non-small cell lung cancer (NSCLC). Elevated C19orf12 expression is associated with poor prognosis and enhanced metastatic potential in NSCLC cells. High C19orf12 levels repress mitochondrial respiration and decrease glucose flux through the tricarboxylic acid cycle. Mechanistically, C19orf12 interacts with and suppresses the biological function of leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) and downregulates the expression of mitochondrial electron transport chain (ETC) genes. Moreover, C19orf12 increases NSCLC cell sensitivity to the tumoricidal effects of metformin by synergistically inhibiting mitochondrial respiration. These findings highlight C19orf12 as a regulator of mitochondrial metabolism in NSCLC and suggest that its elevated expression could serve as a biomarker to predict improved responses to metformin therapy.
    Keywords:  C19orf12; CP: Cancer; CP: Metabolism; LRPPRC; NSCLC; glycolysis; metastasis; metformin; mitochondrial function
    DOI:  https://doi.org/10.1016/j.celrep.2025.116163
  34. Nat Commun. 2025 Aug 20. 16(1): 7438
    Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.
    Jeremy Williams, Roman Camarda, Serghei Malkov, Lisa J Zimmerman, Suzanne Manning, Dvir Aran, Andrew Beardsley, Daniel Van de Mark, Rachel Nakagawa, Yong Chen, Charles Berdan, Sharon M Louie, Celine Mahieu, Daphne Superville, Juliane Winkler, Elizabeth Willey, Erica J Hutchins, John D Gagnon, Seda Kilinc Avsaroglu, Kosaku Shinoda, Matthew Gruner, Hiroshi Nishida, K Mark Ansel, Zena Werb, Daniel K Nomura, Shingo Kajimura, Atul J Butte, Melinda E Sanders, Daniel C Liebler, Hope S Rugo, Gregor Krings, John A Shepherd, Andrei Goga.
      A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 (GJB3) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer.
    DOI:  https://doi.org/10.1038/s41467-025-62486-3
  35. Philos Trans R Soc Lond B Biol Sci. 2025 Aug 21. 380(1933): 20240176
    Fetal nutrient flux and oxidative metabolism during hypoxia: adaptive responses to defend fetal growth.
    Hannah M Kyllo, Stephanie R Wesolowski.
      Fetal oxidative metabolism, the primary determinant of growth, depends on oxygen and nutrient supply. Fetuses with fetal growth restriction (FGR) are exposed to hypoxia and an altered nutrient milieu. Here, we examine hypoxia-associated metabolic adaptations in FGR fetuses and explore how these adaptations may function to maintain rates of oxidative metabolism to enable the fetus to defend its growth rate. We highlight adaptations related to oxygen, glucose, lactate, pyruvate and amino acid flux and metabolism. Given limited human data, we present data from ovine models of chronic placental insufficiency (PI) and sustained maternal hypoxia in late gestation (HOX). These data demonstrate that PI fetuses have lower oxygen consumption rates, increased hepatic glucose production, lower glutamine-glutamate shuttling with the placenta, increased lactate production and accelerated lactate-pyruvate shuttling with the placenta. HOX fetuses have many of these metabolic responses yet have maintained oxygen consumption rates and growth. Thus, hypoxia during gestation may initiate these adaptations to enable the FGR fetus to defend its rate, albeit lower, of oxidative metabolism. During PI, with constraints from chronic hypoxia and nutrient deficiencies across gestation, we speculate that FGR fetuses develop a lower metabolic set point with these metabolic adaptations to ensure survival in utero.This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.
    Keywords:  fetus; glucose; hypoxia; lactate
    DOI:  https://doi.org/10.1098/rstb.2024.0176
  36. J Biochem. 2025 Aug 26. pii: mvaf048. [Epub ahead of print]
    De novo synthesis of peroxisomes: How they are born.
    Ayumu Sugiura.
      Peroxisomes are dynamic organelles found in almost all eukaryotic cells and play a central role in intracellular metabolism. The number of peroxisomes is maintained through the balance of peroxisome biogenesis and degradation. Peroxisomes multiply by growth and division from preexisting peroxisomes but have also been shown to be synthesized de novo under experimental conditions. During de novo synthesis, pre-peroxisome vesicles mature in a stepwise process into functional peroxisomes. While the growth and division cycle is well studied, de novo synthesis, including whether it physiologically occurs, remains poorly understood. Although studies using several models have been proposed, the origin of the membranes required for peroxisome assembly remain controversial. This review provides an overview of the studies on de novo synthesis of peroxisomes in multiple organisms and discusses the evolutionary insights and biological meanings of peroxisome de novo synthesis.
    Keywords:   de novo synthesis; endoplasmic reticulum; mitochondria; peroxisomes; pre-peroxisome vesicles
    DOI:  https://doi.org/10.1093/jb/mvaf048
  37. Nat Commun. 2025 Aug 26. 16(1): 7972
    Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH.
    Dhanya Thamaraparambil Jayaram, Pranav Sivaram, Pranjal Biswas, Yue Dai, Elizabeth A Sweeny, Dennis J Stuehr.
      Heme is an iron-containing cofactor generated in mitochondria that must leave this organelle to reach protein targets in other cell compartments. Because mitochondrial heme binding by cytosolic GAPDH enables its distribution in cells, we sought to uncover how heme reaches GAPDH. Experiments utilizing two human cell lines and a GAPDH reporter protein whose heme binding can be followed by fluorescence reveal that the mitochondrial protein FLVCR1b provides heme to GAPDH in concert with a rise and fall in their association. An absence of FLVCR1b diminishes GAPDH association with mitochondria and prevents GAPDH and cell hemeproteins from receiving heme. GAPDH heme procurement also requires the TANGO2 protein, which interacts with FLVCR1b to presumably support heme export. In isolated mitochondria, GAPDH associates with FLVCR1b to trigger heme release and delivery to client hemeproteins. Identifying FLVCR1b as the source of mitochondrial heme for GAPDH reveals a path by which this essential cofactor can reach multiple protein targets within eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41467-025-62819-2
  38. mBio. 2025 Aug 25. e0119325
    mGem: Revisiting bacterial overflow metabolism.
    Niaz Bahar Chowdhury, Wheaton L Schroeder, Lummy Monteiro, Kristin E Burnum-Johnson.
      Bacterial overflow metabolism, where cells perform oxidative fermentation despite the availability of ample oxygen and carbon sources, remains a long-standing paradox in microbial metabolism. Traditional explanations attribute this phenomenon to bacterial physiology, including rapid growth, redox imbalances, competitive advantages in microbiomes, and catabolite repression. However, recent advances in systems biology have revealed additional contributing factors, such as thermodynamic constraints, proteome allocation efficiency, bioenergetics, and the membrane real estate hypothesis. Despite these insights, a comprehensive commentary that critically examines these perspectives is still lacking. In this mGem, we summarize key drivers of overflow metabolism, examine state-of-the-art theories, and identify unresolved questions in current understanding. By evaluating multiple viewpoints, we aim to provide a cohesive analysis of bacterial overflow metabolism and contribute to a broader understanding of microbial physiology, regulatory networks, and evolutionary adaptations shaping metabolic strategies.
    Keywords:  bioenergetics; overflow metabolism; proteome allocation; thermodynamic
    DOI:  https://doi.org/10.1128/mbio.01193-25
  39. Nat Metab. 2025 Aug 27.
    Mitochondria transfer.
    Navdeep S Chandel, Marni J Falk, Janine H Santos, Jonathan R Brestoff, Ana V Lechuga-Vieco, Yasemin S Sancak, Quan Chen, Alvaro A Elorza, Rubén Quintana-Cabrera.
      
    DOI:  https://doi.org/10.1038/s42255-025-01364-0
  40. Nat Rev Cancer. 2025 Aug 26.
    The evolution of cancer and ageing: a history of constraint.
    João Pedro de Magalhães.
      Ageing and cancer are ubiquitous in animals. They are fundamental and generally intrinsic to multicellular life. Nonetheless, ageing and cancer rates vary widely across species and understanding their evolution and interaction is of great biological interest. Although cancer arises from uncontrolled cell proliferation, ageing involves cell loss and degeneration, making them seemingly opposite yet interconnected processes. Because cancer can affect young individuals, natural selection will favour the evolution of cancer resistance over processes that maintain health in later life. As such, I propose that species evolve longer lifespans under the constraints imposed by the need to reduce cancer risk. Mechanisms that suppress cancer, such as telomere shortening and cellular senescence, may inadvertently promote ageing by limiting cell proliferation and tissue regeneration. Selection for tumour suppression may also impact stem cell ageing and contribute to the limited ability of adult tissues to regenerate. Overall, although cancer resistance is essential for the evolution of longevity, tumour suppression mechanisms may also contribute to ageing-related tissue degeneration and functional decline. Studying the trade-offs between the evolution of tumour suppression processes and their impact later in life may provide important insights into ageing processes.
    DOI:  https://doi.org/10.1038/s41568-025-00861-4
  41. Nat Commun. 2025 Aug 22. 16(1): 7827
    Targeting spermine metabolism to overcome immunotherapy resistance in pancreatic cancer.
    Hanshen Yang, Xiaozhen Zhang, Sirui Zhang, Yanqing Yang, Yan Chen, Yangwei Jiang, Qingsong Lu, Lingyue Liu, Mengyi Lao, Weiran Du, Kang Sun, Lihong He, Jiatao Shi, Xinyuan Liu, Jinyuan Song, Na Lu, Junming Huang, Jinyan Huang, Ruhong Zhou, Xiongbin Lu, Tingbo Liang, Xueli Bai.
      While dysregulation of polyamine metabolism is frequently observed in cancer, it is unknown how polyamines alter the tumor microenvironment (TME) and contribute to therapeutic resistance. Analysis of polyamines in the plasma of pancreatic cancer patients reveals that spermine levels are significantly elevated and correlate with poor prognosis. Using a multi-omics approach, we identify Serpinb9 as a vulnerability in spermine metabolism in pancreatic cancer. Serpinb9, a serine protease inhibitor, directly interacts with spermine synthase (SMS), impeding its lysosome-mediated degradation and thereby augmenting spermine production and secretion. Mechanistically, the accumulation of spermine in the TME alters the metabolic landscape of immune cells, promoting CD8+ T cell dysfunction and pro-tumor polarization of macrophages, thus creating an immunosuppressive microenvironment. Small peptides that disrupt the Serpinb9-SMS interaction significantly enhance the efficacy of immune checkpoint blockade therapy. Together, our findings suggest that targeting spermine metabolism is a promising strategy to improve pancreatic cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-63146-2
  42. Nat Protoc. 2025 Aug 22.
    Metabolomics using anion-exchange chromatography mass spectrometry for the analysis of cells, tissues and biofluids.
    Rachel Williams, John Walsby-Tickle, Ingvild Comfort Hvinden, Isabelle Legge, Tereza Kacerova, KyoungEun Vicky Lee, Mariya Misheva, David Hauton, Judith B Ngere, John D Sidda, Elisabete Pires, Tom Cadoux-Hudson, James S O McCullagh.
      The direct coupling of ion-exchange chromatography with mass spectrometry using electrochemical ion suppression creates a hyphenated technique with selectivity and specificity for the analysis of highly polar and ionic compounds. The technique has enabled new applications in environmental chemistry, food chemistry, forensics, cell biology and, more recently, metabolomics. Robust, reproducible and quantitative methods for the analysis of highly polar and ionic metabolites help meet a longstanding analytical need in metabolomics. Here, we provide step-by-step instructions for both untargeted and semi-targeted metabolite analysis from cell, tissue or biofluid samples by using anion-exchange chromatography-high-resolution tandem mass spectrometry (AEC-MS/MS). The method requires minimal sample preparation and is robust, sensitive and selective. It provides comprehensive coverage of hundreds of metabolites found in primary and secondary metabolic pathways, including glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, purine and pyrimidine metabolism, amino acid degradation and redox metabolism. An inline electrolytic ion suppressor is used to quantitatively neutralize OH- ions in the eluent stream, after chromatographic separation, enabling AEC to be directly coupled with MS. Counter ions are also removed during this process, creating a neutral pH, aqueous eluent with a simplified matrix optimal for negative ion MS analysis. Sample preparation through to data analysis and interpretation is described in the protocol, including a guide to which metabolites and metabolic pathways are suitable for analysis by using AEC-MS/MS.
    DOI:  https://doi.org/10.1038/s41596-025-01222-z
  43. Sci Adv. 2025 Aug 29. 11(35): eadw9952
    Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis.
    Laura Boccuni, Frieda Marka, Manuel Salzmann, Alessia Schirripa, Elisabeth Ableitner, Magdalena Siller, Mira Brekalo, Patrick Haider, Stefan Stojkovic, Christoph Neumayer, Tiit Örd, Karoline Kollmann, Alice Assinger, Thomas Decker, Thomas Köcher, Michael B Fischer, Marion Mußbacher, Andreas Bergthaler, Christian Hengstenberg, Bruno K Podesser, Minna U Kaikkonen, Johann Wojta, Philipp J Hohensinner.
      Macrophage-to-foam cell transition is an integral part of atherosclerotic plaque progression. Particularly, oxidized low-density lipoprotein (oxLDL) is a driving factor in foam cell formation, altering macrophage function and metabolism. The aim of our research was to understand the impact of oxLDL-induced mitochondrial reactive oxygen species on macrophage-to-foam cell differentiation. We demonstrate that macrophage oxLDL-derived superoxide modulates mitochondrial metabolic reprogramming, facilitating foam cell formation. Mechanistically, mitochondrial superoxide drives signal transducers and activators of transcription 5 (STAT5) activation, leading to reduced tricarboxylic acid cycle activity. In parallel, mitochondrial superoxide enhances chromatin accessibility at STAT5 target genes, establishing a distinct STAT5 signaling signature in foam cells ex vivo and in human and mouse plaques in vivo. Inhibition of STAT5 during atherosclerosis progression prevents the differentiation of macrophages to mature Trem2hiGpnmbhi foam cells. Collectively, our data describe an oxLDL-induced, mitochondrial superoxide-dependent STAT5 activation that leads to a self-amplifying feedback loop of reciprocal mitochondrial superoxide production and STAT5 activation, ultimately driving macrophage-to-foam cell transition.
    DOI:  https://doi.org/10.1126/sciadv.adw9952
  44. Cancer Res. 2025 Aug 21.
    Transient Nutrient Sensing Shapes T Cell Exhaustion.
    Julian J Lum.
      The fate of CD8⁺ T cells is sculpted not only by antigenic stimulation and cytokine milieu but, increasingly, by metabolic context. In their recent Nature Immunology study, Sharma and colleagues report a previously underappreciated and temporally constrained nutrient-sensing mechanism where methionine (Met) availability during the earliest minutes of T cell receptor (TCR) engagement exerts durable control over T cell function, exhaustion, and anti-tumor efficacy. Their findings expose a critical metabolic window, within just 30 minutes of activation, during which extracellular Met shapes intracellular signaling and transcriptional fate decisions through a post-translational mechanism involving arginine methylation of the calcium-activated potassium channel KCa3.1. These findings open the door to timed interventions that modulate methionine and potentially enhance T cell responses.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3656
  45. Cell Rep. 2025 Aug 21. pii: S2211-1247(25)00957-X. [Epub ahead of print]44(9): 116186
    TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation.
    Wenqing Ren, Hui Jiang, Qianqian Song, Yiliang Chen, Chenxiao Tang, Fang Wang, Jing Zhu, Jingming Ren, Yaxing Zhao, Yuan He, Jin Cai, Tianle Zhang, Zhuhong Wang, Chenjie Zhu, Wen Xue, Ai Peng, Xiaona Feng, Yue Liu, Jianqiang Yu, Zheng-Gang Liu, Zhenyu Cai.
      Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identify regulators in glucose-starvation-induced cell death and find a group of genes in lysosomal pathway is enriched following glucose starvation. We focus on one candidate gene, Transcriptional Factor 25 (TCF25). We find TCF25 enhances lysosomal acidification by targeting V-ATPase, promoting autophagy and ATP generation under glucose starvation. However, prolonged glucose starvation constitutively activates ferritinophagy via TCF25, increasing lysosomal membrane permeability (LMP) and leading to lysosome-dependent cell death (LDCD). Knocking out TCF25 or V-ATPase components prevents cell death. Furthermore, TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury. Our findings identify TCF25 as a crucial nutrient sensor that regulates lysosomal activity, offering potential therapeutic targets for metabolic and ischemic disorders.
    Keywords:  CP: Cell biology; CP: Metabolism; TCF25; cell death; glucose starvation; lysosome; metabolic adaptation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116186
  46. Cell Metab. 2025 Aug 19. pii: S1550-4131(25)00356-0. [Epub ahead of print]
    Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.
    Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan.
      The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to diet in mice, while single-nucleotide polymorphisms (SNPs) associated with rhythmic gene expression are enriched in E-PIs in steatotic human livers and correlate with lipid metabolism traits. These findings reveal a previously underappreciated temporal aspect of genetics-environment interaction in regulating lipid metabolic traits, with implications for individual variations in obesity-associated disease susceptibility and personalized chronotherapy.
    Keywords:  3D enhancer-promoter interaction; diurnal rhythm; genetic variation; human metabolic traits; metabolic disorders
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.010
  47. Biochim Biophys Acta Mol Basis Dis. 2025 Aug 20. pii: S0925-4439(25)00372-2. [Epub ahead of print]1871(8): 168024
    The impact of p53 on the urea cycle and nitrogen metabolism enzymes: Mechanisms and implications for cancer development.
    Santhanagopalakrishnan Rajesh Iyer, Beata Schlichtholz.
      The tumour suppressor protein p53, encoded by the TP53 gene, is widely celebrated as the "guardian of the genome," yet its role in metabolic reprogramming, particularly nitrogen metabolism, remains underappreciated. This review highlights the emerging nexus between p53 and the urea cycle, a key pathway responsible for ammonia detoxification and the generation of biosynthetic precursors. By regulating the expression and activity of urea cycle enzymes, p53 exerts profound control over interconnected metabolic pathways, including the metabolism of polyamine, methionine, glutathione, and proline. Cancer cells, with their voracious nitrogen demand, co-opt urea cycle dysregulation to fuel tumour growth and survival. Here, we synthesise the latest insights into p53's role in nitrogen homeostasis, delineating its broader implications for cellular metabolism and carcinogenesis. Additionally, we propose the strategic targeting of urea cycle enzymes as novel prognostic biomarkers and therapeutic vulnerabilities in cancer. This work not only redefines the metabolic scope of p53 but also positions nitrogen metabolism at the forefront of cancer research, offering transformative avenues for therapeutic innovation.
    Keywords:  Ammonia detoxification; Cellular metabolic adaptation; Enzyme regulation; Glutathione; Methionine metabolism; Nitrogen metabolism; Polyamines; Urea cycle; p53
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168024
  48. Nat Cell Biol. 2025 Aug 25.
    Haematopoietic ageing in health and lifespan.
    Rebecca Andersson, Eva Mejia-Ramirez, Maria Carolina Florian.
      Ageing of the haematopoietic system is characterized by phenotypic and functional impairments that are driven by alterations of haematopoietic stem cells and of the bone marrow niche. Haematopoietic stem cells are responsible for the production of all the different cell types that constitute the blood, and their maintenance and differentiation must be tightly regulated during the whole life of an organism. Exciting new data emphasize that central aspects of blood ageing, ranging from inflammageing and immunosenescence to clonal haematopoiesis, are mechanistically linked to dysfunction and ageing of other tissues, supporting a central role for the haematopoietic system in this context. Here we review some of the recent findings with a focus on ageing of the haematopoietic system and provide an overview of its role in driving healthspan and lifespan of the whole organism.
    DOI:  https://doi.org/10.1038/s41556-025-01739-1
  49. EMBO Rep. 2025 Aug 26.
    STAT3 sustains tumorigenicity following mutant KRAS ablation.
    Stephen D'Amico, Varvara Kirillov, Jingxuan Liu, Zhijuan Qiu, Xinyuan Lei, Hong Qin, Brian S Sheridan, Nancy C Reich.
      Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological KRAS inactivation produces mixed outcomes and frequent relapse. Mechanisms of tumor resistance to KRAS inhibition remain poorly understood. We present evidence that STAT3 supports tumor growth following KRAS depletion. Using a conceptual framework of pancreatic ductal adenocarcinoma, we show that cancer cells that survive CRISPR-mediated ablation of mutant KRAS are dependent on STAT3 function to maintain tumorigenicity. Mechanistically, the combined loss of mutant KRAS and STAT3 disrupts a core transcriptional program of cancer cells critical to oncogenic competence. This in turn impairs tumor growth in mice and enhances immune rejection, leading to tumor clearance. We propose that the STAT3 transcriptional program operating in cancer cells enforces their malignant identity, rather than providing classical features of transformation, and shapes cancer persistence following KRAS inactivation. Our findings establish STAT3 as a critical enforcer of oncogenic identity in KRAS-ablated tumors, revealing a key vulnerability.
    Keywords:  KRAS; Oncogene Dependence; Pancreatic Cancer; STAT3
    DOI:  https://doi.org/10.1038/s44319-025-00563-w
  50. Nature. 2025 Aug 20.
    A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia.
    Jean Jacobs, Hristiana Lyubenova, Sven Potelle, Johannes Kopp, Isabelle Gerin, Wing Lee Chan, Miguel Rodriguez de Los Santos, Wiebke Hülsemann, Martin A Mensah, Valérie Cormier-Daire, Marieke Joosten, Hennie T Bruggenwirth, Kyra E Stuurman, Valancy Miranda, Philippe M Campeau, Lars Wittler, Julie Graff, Stefan Mundlos, Daniel M Ibrahim, Emile Van Schaftingen, Björn Fischer-Zirnsak, Uwe Kornak, Nadja Ehmke, Guido T Bommer.
      Living cells depend on an intricate network of chemical reactions catalysed by enzymes, which sometimes make mistakes that lead to their inactivation. Here we report a metabolite-based mechanism for preserving enzyme function in an unfavourable environment. We found that the enzyme TGDS produces UDP-4-keto-6-deoxyglucose, a mimic of the reaction intermediate of the enzyme UXS1, which regenerates the essential cofactor NAD+ within the catalytic pocket of UXS1 by completing its catalytic cycle. Thus, the production of an 'enzyme-rescue metabolite' by TGDS represents a mechanism for maintaining the activity of an enzyme in a subcellular compartment where NAD+ is scarce. Using a combination of in vitro and in vivo studies, we demonstrate that the inability to produce sufficient amounts of this enzyme-rescue metabolite leads to the inactivation of UXS1, impairing the synthesis of specific glycans that are crucial for skeletal development. This provides an explanation for the development of the hereditary skeletal disorder Catel-Manzke syndrome in individuals with TGDS deficiency. Defects in similar protective layers might contribute to metabolic changes in other diseases that cannot be explained with common concepts in metabolic biochemistry.
    DOI:  https://doi.org/10.1038/s41586-025-09397-x
  51. Crit Rev Oncol Hematol. 2025 Aug 18. pii: S1040-8428(25)00294-X. [Epub ahead of print]215 104906
    Cysteine metabolism at the crossroads of ferroptosis and cancer therapy.
    Jaewang Lee, Jong-Lyel Roh.
      Cysteine metabolism plays a pivotal role in ferroptosis regulation by modulating antioxidant defense, lipid peroxidation, and iron homeostasis. Cancer cells exploit cysteine availability to evade ferroptotic cell death, contributing to tumor progression and therapy resistance. Despite growing interest in ferroptosis as a therapeutic vulnerability, a comprehensive understanding of cysteine metabolism in this process remains essential. This review explores key sources of intracellular cysteine, its roles in ferroptosis suppression, and therapeutic strategies targeting cysteine metabolism in cancer. We discuss systemic cysteine depletion, xCT inhibition, suppression of H2S biosynthesis, and GPX4-targeted therapies, along with promising drug combinations. While preclinical studies highlight the efficacy of these approaches, in vivo validation and clinical translation remain limited. Advancing cysteine-targeting therapies require further mechanistic insights, biomarker identification, and optimized delivery strategies. A deeper understanding of cysteine metabolism may pave the way for ferroptosis-based cancer treatments with improved precision and efficacy.
    Keywords:  Cancer therapy; Cyst(e)inases; Cysteine metabolism; Ferroptosis; XCT targeting
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104906
  52. Nature. 2025 Aug;644(8078): 856-859
    How did life get multicellular? Five simple organisms could have the answer.
    Alla Katsnelson.
      
    Keywords:  Cell biology; Evolution; Genetics; Microbiology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-025-02635-2
  53. Nat Commun. 2025 Aug 21. 16(1): 7582
    Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma.
    Margaret A Potts, Shinsuke Mizutani, Yexuan Deng, Srimayee Vaidyanathan, Keziah E Ting, Göknur Giner, Shruti Sridhar, Girija Shenoy, Yang Liao, Sarah T Diepstraten, Andrew J Kueh, Martin Pal, Geraldine Healey, Lin Tai, Zilu Wang, Christina König, Deeksha Kaloni, Lauren Whelan, Michael J G Milevskiy, Hannah D Coughlan, Giovanna Pomilio, Andrew H Wei, Jane E Visvader, Anthony T Papenfuss, Stephen Wilcox, Anand D Jeyasekharan, Wei Shi, Emily J Lelliott, Gemma L Kelly, Kristin K Brown, Andreas Strasser, Marco J Herold.
      Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC, which is abnormally highly expressed in ~70% of human cancers, we use a genome-wide CRISPR gene knockout screen in Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discover that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerates c-MYC-driven lymphoma development in mice. MYC-driven lymphomas lacking GATOR1 display constitutive mTOR pathway activation and are highly sensitive to mTOR inhibitors, both in vitro and in vivo. These findings identify GATOR1 suppression of mTORC1 as a tumor suppressive mechanism in MYC-driven lymphomagenesis and suggest an avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition.
    DOI:  https://doi.org/10.1038/s41467-025-62615-y
  54. Mol Cell. 2025 Aug 21. pii: S1097-2765(25)00646-X. [Epub ahead of print]
    A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.
    Julia Vorhauser, Theodoros I Roumeliotis, David Coupe, Jacky K Leung, Lu Yu, Kristin Böhlig, Thomas Zerjatke, Ingmar Glauche, André Nadler, Jyoti S Choudhary, Jörg Mansfeld.
      Reactive oxygen species (ROS) influence cell proliferation and fate decisions by oxidizing cysteine residues (S-sulfenylation) of proteins, but specific targets and underlying regulatory mechanisms remain poorly defined. Here, we employ redox proteomics to identify cell-cycle-coordinated S-sulfenylation events and investigate their functional role in proliferation control. Although ROS levels rise during cell cycle progression, the overall oxidation of the proteome remains constant, with dynamic S-sulfenylation restricted to a subset of cysteines. Among these, we identify a critical redox-sensitive cysteine residue (C41) in the cyclin-dependent kinase (CDK) inhibitor p21. C41 oxidation regulates the interaction of p21 with CDK2 and CDK4, controlling a double-negative feedback loop that determines p21 stability. When C41 remains reduced, p21's half-life increases in the G2 phase, resulting in more p21 inheritance to daughter cells, suppressing proliferation and promoting senescence after irradiation. Notably, we identify dynamic S-sulfenylation on further cell cycle regulators, implying coordination of cell cycle and redox control.
    Keywords:  CDKN1A; Cdk2; Cdk4; G2 phase; ROS; S-sulfenylation; cell cycle; cell cycle exit; decision-making; negative feedback loop; oxidation; p21; proliferation; reactive oxygen species; redox; redox proteomics; redox switch; reduction; senescence; sulfenic acid
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.023
  55. Cell. 2025 Aug 13. pii: S0092-8674(25)00863-3. [Epub ahead of print]
    Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism.
    Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova, Allen Yi-Lun Tsai, Yoshihiko Kuchitsu, Harrison Byron Chong, Tomoyoshi Kawakami, Jirio Fuse, Wei Han, Ryuhei Kudo, Tomoki Naito, Kota Sato, Toru Nakazawa, Yasunori Saheki, Akiyoshi Hirayama, Peter F Stadler, Mieko Arisawa, Kimi Araki, Liron Bar-Peled, Tomohiko Taguchi, Shinichiro Sawa, Kenji Inaba, Fan-Yan Wei.
      RNA contains diverse post-transcriptional modifications, and its catabolic breakdown yields numerous modified nucleosides requiring correct processing, but the mechanisms remain unknown. Here, we demonstrate that three RNA-derived modified adenosines, N6-methyladenosine (m6A), N6,N6-dimethyladenosine (m6,6A), and N6-isopentenyladenosine (i6A), are sequentially metabolized into inosine monophosphate (IMP) to mitigate their intrinsic cytotoxicity. After phosphorylation by adenosine kinase (ADK), they undergo deamination by adenosine deaminase-like (ADAL). In Adal knockout mice, N6-modified adenosine monophosphates (AMPs) accumulate and allosterically inhibit AMP-activated protein kinase (AMPK), dysregulating glucose metabolism. Furthermore, ADK deficiency, linked to human inherited disorders of purine metabolism, elevates levels of the three modified adenosines, resulting in early lethality in mice. Mechanistically, excessive m6A, m6,6A, and i6A impair lysosomal function by interfering with lysosomal membrane proteins, thereby disrupting lipid metabolism and causing cellular toxicity. Through this nucleotide metabolism pathway and mechanism, cells detoxify modified adenosines, linking modified RNA metabolism to human disease.
    Keywords:  ADAL; ADK; AMP-activated protein kinase; AMPK; Adenosine deaminase-like; Adenosine kinase; Lipid metabolism; Lysosome; Modified RNA metabolism; Purine metabolism; RNA modification; m(6)A
    DOI:  https://doi.org/10.1016/j.cell.2025.07.041
  56. Genes (Basel). 2025 Aug 13. pii: 957. [Epub ahead of print]16(8):
    Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.
    Jisu Jeong, Junghyun Kim, Man S Kim.
       BACKGROUND: The mitochondrial integrated stress response (ISR) represents a fundamental cellular adaptation mechanism with dual protective and pathological roles. We critically analyzed current literature on ISR mechanisms, focusing on recent paradigm shifts including the 2020 discovery of the OMA1-DELE1-HRI axis, emerging controversies over context-dependent activation patterns, and the January 2025 clinical trial failures that have reshaped the therapeutic landscape.
    METHODS: We reviewed recent literature (2020-2025) examining ISR mechanisms, clinical trials, and therapeutic developments through comprehensive database searches.
    RESULTS: The field has evolved from simple linear pathway models to recognition of complex, context-dependent networks. Recent findings reveal that ISR activation mechanisms vary dramatically based on cellular metabolic state, with distinct pathways operating in proliferating versus differentiated cells. The "dark microglia" phenotype in neurodegeneration and DR5-mediated apoptotic switches exemplify pathological ISR manifestations, while adaptive responses include metabolic reprogramming and quality control enhancement.
    CONCLUSIONS: The 2025 failures of DNL343 and ABBV-CLS-7262 in ALS trials underscore the need for precision medicine approaches that account for context-dependent ISR functions, temporal dynamics, and disease-specific mechanisms.
    Keywords:  cellular adaptation; eIF2α phosphorylation; integrated stress response; mitochondrial dysfunction; neurodegeneration; precision medicine
    DOI:  https://doi.org/10.3390/genes16080957
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