bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–10–19
53 papers selected by
Christian Frezza, Universität zu Köln
  1. Aged mice exhibit widespread metabolic changes but preserved major fluxes.
  2. SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
  3. MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
  4. Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
  5. Nutrient allocation fuels T cell-mediated immunity.
  6. NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
  7. Normal circadian period length requires repression of Npas2 by REV-ERB nuclear receptors.
  8. Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
  9. Spatial metabolic gradients in the liver and small intestine.
  10. Now you serine, now you don't.
  11. Activation of a FOXO3-induced cell cycle arrest regulates ferroptosis.
  12. Power and Poison: The intersections of H2S and O2 metabolism.
  13. Towards a reference cell atlas of liver diversity over the human lifespan.
  14. POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
  15. HIFα isoform specific activities drive cell-type specificity of VHL-associated oncogenesis.
  16. Interplay between malic enzyme 2, de novo serine synthesis, and the malate-aspartate shuttle drives metabolic adaptation in triple-negative breast cancer.
  17. The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
  18. Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.
  19. Activation and regulation of cGAS-STING signaling in cancer cells.
  20. Purine metabolism: a pan-cancer metabolic dysregulation across circulation and tissues.
  21. Cell-death networks.
  22. Global conformation of the Rag GTPase heterodimer governs eukaryotic amino acid sensing.
  23. CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
  24. Metabolic Regulation of Copper Homeostasis Governs the Sec61-Dependent Protein Translocation Process in Saccharomyces cerevisiae.
  25. Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.
  26. HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.
  27. Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.
  28. From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
  29. Lysosomal Immunoprecipitation (LysoIP) from Cells and Tissues for Metabolomic and Proteomic Analyses.
  30. TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors.
  31. Exploiting metabolic cell death for cancer therapy.
  32. ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma.
  33. STBD1 mediates the crosstalk between glycogen and lipid droplets in clear cell renal cell carcinoma.
  34. Metabolites in the extracellular tumor microenvironment and the shaping of macrophage function.
  35. Age Deceleration and Reversal Gene Patterns in Dauer Diapause.
  36. Structural basis of potent inhibition of the human CAD dihydroorotase domain by 5-aminoorotic acid.
  37. Cholesterol sensing by the SCAP-FAM134B complex regulates ER-phagy and STING innate immunity.
  38. BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment.
  39. Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation.
  40. Productive mRNA chromatin escape is promoted by PRMT5 activity.
  41. Detection methods for mitochondrial DNA heteroplasmy and their potential single-cell applications in cancer.
  42. Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.
  43. Decoding tumor heterogeneity: A spatially informed pan-cancer analysis of the tumor microenvironment.
  44. Mechanism and importance of ferroptosis in clear cell renal cell carcinoma treatment.
  45. Information and the living tree of life A theory of measurement grounded in biology.
  46. Epigenetic alterations facilitate transcriptional and translational programs in hypoxia.
  47. Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
  48. A Roadmap for the Future of Systems Biology in Cancer Research.
  49. Astroimmunology: the effects of spaceflight and its associated stressors on the immune system.
  50. NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy.
  51. Genetic determinants and genomic consequences of non-leukemogenic somatic point mutations.
  52. Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function.
  53. Increased nucleotide metabolism alleviates Alzheimer's disease pathology.
  1. Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]
    Aged mice exhibit widespread metabolic changes but preserved major fluxes.
    Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.
      Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.
    Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
  2. Mol Cell. 2025 Oct 10. pii: S1097-2765(25)00703-8. [Epub ahead of print]
    SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
    Marilia M Dias, Martin S King, Engy Shokry, Sergio Lilla, Nikki Paul, Peter Thomason, Sara Zanivan, David Sumpton, Edmund R S Kunji, Thomas MacVicar.
      Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signaling pathways. Disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism, but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier 25A45 (SLC25A45) is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilizes the carrier by limiting its proteolytic degradation and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key amino acid derivative, carnitine. SLC25A45 is therefore an essential mediator of compartmentalized methylated amino acid metabolism.
    Keywords:  SLC25; carnitine; metabolism; metabolite transport; methylated amino acids; mitochondria; solute carriers
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.018
  3. Nat Cell Biol. 2025 Oct;27(10): 1708-1724
    MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
    Mai Nguyen, Jack J Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J Milnerwood, Sidong Huang, Michel Desjardins, Heidi M McBride.
      Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.
    DOI:  https://doi.org/10.1038/s41556-025-01774-y
  4. Cell Metab. 2025 Oct 10. pii: S1550-4131(25)00434-6. [Epub ahead of print]
    Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
    Artem Khan, Frederick S Yen, Gokhan Unlu, Nicole L DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R Gamazon, Gary J Patti, Kıvanç Birsoy.
      Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.
    Keywords:  SLC25A45; SLC45A4; UNC93A; acetylglucosamine; carnitine synthesis; fasting; metabolomic GWAS; mitochondrial metabolism; polyamines; solute carrier transporters
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.015
  5. Cell Metab. 2025 Oct 15. pii: S1550-4131(25)00393-6. [Epub ahead of print]
    Nutrient allocation fuels T cell-mediated immunity.
    Joseph Longo, McLane J Watson, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism in vivo and ex vivo highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.
    Keywords:  T cells; adaptive immunity; effector function; glucose; immunometabolism; nutrient allocation
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.008
  6. Nat Metab. 2025 Oct 13.
    NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
    Kasper T Vinten, Maria M Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E Janssens, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01387-7
  7. Cell Rep. 2025 Oct 14. pii: S2211-1247(25)01208-2. [Epub ahead of print]44(10): 116437
    Normal circadian period length requires repression of Npas2 by REV-ERB nuclear receptors.
    Michael C Tackenberg, Kristina M Heliodoro, Lily C Melink, Yifan Liu, Kun Zhu, Mitchell A Lazar.
      REV-ERB nuclear receptors are integrated into the molecular circadian clock present in most mammalian cells. Loss of REV-ERBs (REV-ERB DKO) within the suprachiasmatic nucleus (SCN) in vivo leads to a marked shortening of the circadian period, but it remains unclear whether REV-ERB regulation of circadian period is tissue autonomous, if it is conserved across tissues, and how it is established. Here, we show that period shortening in the absence of REV-ERBs is tissue autonomous, is consistent between brain and liver, and is brought about through derepression of clock transcription factors NPAS2 and CLOCK. Thus, in addition to disruption of synchrony with the external environment, our results demonstrate that the circadian impacts of REV-ERB loss also include the alteration of core circadian properties with tissue-specific consequences.
    Keywords:  CP: Metabolism; CP: Neuroscience
    DOI:  https://doi.org/10.1016/j.celrep.2025.116437
  8. Biochim Biophys Acta Mol Basis Dis. 2025 Oct 10. pii: S0925-4439(25)00418-1. [Epub ahead of print]1872(2): 168070
    Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
    Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Marta Zaninello, Esther Barth, Matteo Veronese, Richard Rodenburg, Elena I Rugarli, Susanne Brodesser, Susanne Arnold, Ulrich Brandt.
      Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, how molecular causes ultimately present as a clinical phenotype is poorly understood. To address this conundrum starting from the molecular defect, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40 % of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ∙mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.
    Keywords:  Active/deactive transition; Complex I; Complexome profiling; Mitochondria; Mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168070
  9. Nature. 2025 Oct 15.
    Spatial metabolic gradients in the liver and small intestine.
    Laith Z Samarah, Clover Zheng, Xi Xing, Won Dong Lee, Amichay Afriat, Uthsav Chitra, Michael R MacArthur, Wenyun Lu, Connor S R Jankowski, Cong Ma, Craig J Hunter, Michael Neinast, Daniel R Weilandt, Benjamin J Raphael, Joshua D Rabinowitz.
      The properties of mammalian cells depend on their location within organs. Gene expression in the liver varies between periportal and pericentral hepatocytes1-3, and in the intestine from crypts to villus tips4,5. A key element of tissue spatial organization is probably metabolic, but direct assessments of spatial metabolism remain limited. Here we map spatial metabolic gradients in the mouse liver and intestine. We develop an integrated experimental-computational workflow using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), isotope tracing and deep-learning artificial intelligence. Most measured metabolites (>90%) showed significant spatial concentration gradients in the liver lobules and intestinal villi. In the liver, tricarboxylic acid (TCA)-cycle metabolites and their isotope labelling from both glutamine and lactate localized periportally. Energy-stress metabolites, including adenosine monophosphate (AMP), also localized periportally, consistent with a high periportal energy demand. In the intestine, the TCA intermediates malate (tip) and citrate (crypt) showed opposite spatial patterns, aligning with higher glutamine catabolism in tips and lactate oxidation in crypts based on isotope tracing. Finally, we mapped the fate of the obesogenic dietary sugar fructose. In the intestine, oral fructose was catabolized faster in the villus bottom than in the tips. In the liver, fructose-derived carbon accumulated pericentrally as fructose-1-phosphate and triggered pericentral adenosine triphosphate (ATP) depletion. Thus, we both provide foundational knowledge regarding intestine and liver metabolic organization and identify fructose-induced focal derangements in liver metabolism.
    DOI:  https://doi.org/10.1038/s41586-025-09616-5
  10. Trends Pharmacol Sci. 2025 Oct 11. pii: S0165-6147(25)00225-1. [Epub ahead of print]
    Now you serine, now you don't.
    Robert B Cameron, Nia G Hammond, Brandon Faubert.
      Cancer cells alter metabolic programs to support uncontrolled growth and proliferation. A new study from Scott and colleagues directly examined tumor metabolism in glioblastoma patients and discovered increased import of the amino acid serine. Excitingly, limiting serine uptake enhanced the effectiveness of chemoradiation in preclinical models of glioblastoma.
    Keywords:  glioblastoma; metabolism; stable isotope tracing
    DOI:  https://doi.org/10.1016/j.tips.2025.10.001
  11. Cell Death Discov. 2025 Oct 16. 11(1): 465
    Activation of a FOXO3-induced cell cycle arrest regulates ferroptosis.
    Huanjie Huang, Matthias van Sligtenhorst, Alida M M Smits, Can Gulersonmez, Edwin Stigter, Tobias B Dansen, Boudewijn M T Burgering.
      FOXO transcription factors act downstream of PI3K signaling, and FOXO transcriptional activity is inhibited through nuclear exclusion by PKB/AKT-mediated phosphorylation. Many studies have shown FOXO to contribute to organismal homeostasis by mitigating (extra)cellular stress to prevent cell death (reviewed in [1]). Here we show that FOXO3 activation protects cells from ferroptosis, an iron-dependent form of non-apoptotic cell death. In untransformed hTERT-RPE-1 cells, FOXO3 activation reduces ferroptosis in a multilayered manner. First, FOXO3 mediates protection from ferroptosis in part through a p27-induced G1 cell cycle arrest. Second, FOXO3 activation reduces cellular H2O2 levels, thereby limiting substrate availability for the Fenton reaction, which fuels hydroxyl radical formation for lipid peroxidation. Third, FOXO3 activation lowers cellular iron content by reducing TFR1 expression, which, combined with the lowering of cellular H2O2 levels, likely further reduces the formation of hydroxyl radicals through the Fenton reaction. Finally, FOXO3 activation reduces expression of long-chain-fatty-acid-CoA ligase 4 (ACSL4) and Peroxisomal targeting signal 1 receptor (PEX5), proteins involved in lipid metabolism and protection against ferroptosis. Taken together, we show that FOXO3 activation results in protection from ferroptosis, adding to the repertoire of FOXO-controlled cell protection programs.
    DOI:  https://doi.org/10.1038/s41420-025-02760-x
  12. J Biol Chem. 2025 Oct 13. pii: S0021-9258(25)02662-6. [Epub ahead of print] 110810
    Power and Poison: The intersections of H2S and O2 metabolism.
    Joseph Brake, Ruma Banerjee.
      The metabolic interaction between hydrogen sulfide (H2S) and O2 exemplifies the interplay between chemical power and poison at the electron transport chain as these gases influence the conversion of nutrient energy to cellular currency. H2S is a product of mammalian and microbial metabolism and is both an inorganic nutrient and a respiratory poison. In its former role, H2S transfers its reducing power to coenzyme Q as it is oxidized by sulfide quinone oxidoreductase in the inner mitochondrial membrane. As a respiratory poison, H2S inhibits complex IV and profoundly influences intracellular O2 levels with pleiotropic effects on hypoxia sensing and signaling, and on cellular metabolism, glimpses of which are only just beginning to emerge. The high concentration of luminal sulfide in the lower gut combined with the steep radial O2 gradient, ranging from a virtually anoxic lumen to a highly vascular lamina propria, raises many questions about how the interaction between these gases plays out with local and long-range impacts on biology. Their interaction is equally germane in other hypoxic tissues where endogenous H2S production and/or constitutively low sulfide oxidation capacity could potentially dial up O2 availability. Importantly, H2S oxidation can prevail even when its concentration rises to levels that poison complex IV, and is enabled by rerouting electrons through complex II, using fumarate as a terminal electron acceptor. Methodological advancements that support the quantitative analysis of in vivo models will be critical for broadening our understanding of the metabolic and physiological import of the O2-H2S interplay.
    Keywords:  Hydrogen sulfide; butyrate; fumarate; gut dysbiosis; gut microbiome; hypoxia; hypoxia inducible factor; oxygen metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2025.110810
  13. Nat Rev Gastroenterol Hepatol. 2025 Oct 13.
    Towards a reference cell atlas of liver diversity over the human lifespan.
    Sarah A Taylor, Gary D Bader, Sonya MacParland, Alan C Mullen, Tallulah Andrews, Alex G Cuenca, Ramanuj DasGupta, Adam J Gehring, Dominic Grün, Martin Guilliams, Aliya Gulamhusein, Neil C Henderson, Gideon Hirschfield, Stacey S Huppert, Shalev Itzkovitz, Z Gordon Jiang, Georg M Lauer, Ian McGilvray, Krupa R Mysore, Carlos J Pirola, Gerald Quon, Mohammad Rahbari, Aviv Regev, Amanda Ricciuto, Charlotte L Scott, Ankur Sharma, Silvia Sookoian, Michelle M Tana, Sarah A Teichmann, Ludovic Vallier, Ioannis S Vlachos, Bruce Wang, Mei Zhen.
      The goal of the Human Liver Cell Atlas (HLiCA) is to create a comprehensive map that defines the normal functions of diverse liver cell types and their spatial relationships over the human lifespan. This project fits within the goals of the Human Cell Atlas to create comprehensive reference maps of all human cells as a basis for both understanding human health and diagnosing, monitoring and treating disease. Through collection of samples from diverse individuals, data integration across technologies and overcoming liver-specific challenges for experimental methods, the HLiCA will map as many cell types and states as possible in healthy human livers from individuals across all ages and many ancestries. Establishing this HLiCA of healthy livers is a critical step to begin to understand perturbations in disease. The HLiCA will be available on an open-access platform to facilitate data sharing and dissemination. We expect that creation of the HLiCA will help to lay the foundation for new research initiatives to advance our understanding of liver disease, improve methods of tissue engineering, and identify novel prognostic biomarkers and therapies to improve patient outcomes. We describe key experimental and computational challenges to overcome in building the atlas and the potential impact of the atlas on disease research.
    DOI:  https://doi.org/10.1038/s41575-025-01114-3
  14. Life Sci Alliance. 2025 Dec;pii: e202302563. [Epub ahead of print]8(12):
    POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
    Maria Miranda, Andrea Mesaros, Nathalie Scrima, Louise Pérard, Irina Kuznetsova, Martin Purrio, Ilian Atanassov, Aleksandra Filipovska, Arnaud Mourier, Nils-Göran Larsson, Inge Kühl.
      POLRMT is the sole RNA polymerase in human mitochondria, where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mtDNA to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice overexpressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT levels did not result in any pathological phenotype but led to increased exercise performance in male mice under stress conditions. Polrmt overexpression increased mtDNA transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of Polrmt and Lrpprc, which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.
    DOI:  https://doi.org/10.26508/lsa.202302563
  15. Nat Commun. 2025 Oct 16. 16(1): 9185
    HIFα isoform specific activities drive cell-type specificity of VHL-associated oncogenesis.
    Joanna D C C Lima, Madeleine Hooker, Ran Li, Ayslan B Barros, Norma Masson, Christopher W Pugh, David R Mole, Julie Adam, Peter J Ratcliffe, Samvid Kurlekar.
      Cancers arising from dysregulation of generally operative signaling pathways are often tissue specific, but the mechanisms underlying this paradox are poorly understood. Based on striking cell-type specificity, we postulated that these mechanisms must operate early in cancer development and set out to study them in a model of von Hippel Lindau (VHL) disease. Biallelic mutation of the VHL ubiquitin ligase leads to constitutive activation of hypoxia inducible factors HIF1A and HIF2A and is generally a truncal event in clear cell renal carcinoma. We used an oncogenic tagging strategy in which VHL-mutant cells are marked by tdTomato, enabling their observation, retrieval, and analysis early after VHL-inactivation. Here, we reveal markedly different consequences of HIF1A and HIF2A activation, but that both contribute to renal cell-type specific consequences of VHL-inactivation in the kidney. Early involvement of HIF2A in promoting proliferation within the proximal tubular epithelium supports therapeutic targeting of HIF2A early in VHL disease.
    DOI:  https://doi.org/10.1038/s41467-025-64214-3
  16. Cancer Metab. 2025 Oct 14. 13(1): 42
    Interplay between malic enzyme 2, de novo serine synthesis, and the malate-aspartate shuttle drives metabolic adaptation in triple-negative breast cancer.
    Jin Heon Jeon, Mark D Slayton, Ben Krinkel, Olamide Animasahun, Ajay Shankaran, Fulei Wuchu, Minal Nenwani, Zackariah Farah, Julia Burke, Abhinav Achreja, Brisilda Nilaj, Kerslee Kohagen, Yi-Hsien Eu, Alyssa Rosenfeld, Mason Collard, Liwei Bao, Xu Cheng, Celina Kleer, Christopher Squire, Kerry Loomes, Deepak Nagrath, Sofia D Merajver.
      
    DOI:  https://doi.org/10.1186/s40170-025-00410-5
  17. Nat Commun. 2025 Oct 13. 16(1): 9071
    The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
    Shicong Xie, Shuyuan Zhang, Gustavo de Medeiros, Prisca Liberali, Jan M Skotheim.
      Cell growth and division must be coordinated to maintain a stable cell size, but how this coordination is implemented in multicellular tissues remains unclear. In unicellular eukaryotes, autonomous cell size control mechanisms couple cell growth and division with little extracellular input. However, in multicellular tissues we do not know if autonomous cell size control mechanisms operate the same way or whether cell growth and cell cycle progression are separately controlled by cell-extrinsic signals. Here, we address this question by tracking single epidermal stem cells growing in the mouse ear. We find that a cell-autonomous size control mechanism, dependent on the RB pathway, sets the timing of S phase entry based on the cell's current size. Cell-extrinsic variations in the cellular microenvironment affect cell growth rates but not this autonomous coupling. Our work reassesses long-standing models of cell cycle regulation in complex animal tissues and identifies cell-autonomous size control as a critical mechanism regulating cell division.
    DOI:  https://doi.org/10.1038/s41467-025-64150-2
  18. Nat Metab. 2025 Oct 14.
    Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.
    Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard.
      Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress.
    DOI:  https://doi.org/10.1038/s42255-025-01388-6
  19. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00735-X. [Epub ahead of print]85(20): 3807-3822
    Activation and regulation of cGAS-STING signaling in cancer cells.
    Abraham Shim, Yanyang Chen, John Maciejowski.
      Genomic instability is a defining feature of cancer that fuels transformation, tumor evolution, and therapeutic resistance. However, genomic instability also incurs an immunological liability by generating cytosolic DNA, a potent trigger of cGAS-STING signaling. In this review, we summarize recent advances in our understanding of the sources of immunostimulatory cytosolic DNA in genomically unstable cancer cells. We examine how newly identified regulatory mechanisms, including chromatin-mediated cGAS suppression, influence the immune-activating potential of cytosolic DNA generated by genomic instability. We also highlight how key regulators, such as the exonuclease TREX1, may be co-opted to shield genomically unstable cancer cells from immune surveillance. By synthesizing these recent advances in our understanding of cGAS-STING activation and regulation in cancer, we aim to highlight emerging therapeutic strategies that leverage cGAS signaling to bolster antitumor immunity.
    Keywords:  STING; TREX1; autophagy; cGAS; cancer; ecDNA; genomic instability; micronuclei
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.030
  20. Mol Cancer. 2025 Oct 14. 24(1): 255
    Purine metabolism: a pan-cancer metabolic dysregulation across circulation and tissues.
    Mengjie Yu, Cheng Liu, Minmin Cao, Dou Yang, Tongshan Wang, Jing Xu, Danxia Zhu, Guangji Wang, Jiye Aa, Wei Zhu.
      Tumors function as organ-like entities within complex ecosystems, interacting with diverse components of their microenvironment, including blood and lymphatic vessels, neurons, immune cells, metabolites, and cytokines, to drive tumorigenesis and progression. Our pan-cancer study investigated the universal tumor hallmarks, integrating metabolite characteristics with molecular mechanisms. Metabolomic profiling on plasma from 2,561 patients across 20 cancer types and 604 healthy controls in two clinical centers, identified three biomarkers in pan cancers: elevated levels of hypoxanthine and reduced levels of cysteine and pyruvic acid. Given the profound significance of hypoxanthine, we further discovered 33 core purine metabolism-related genes in The Cancer Genome Atlas (TCGA) pan-cancer tissues, and their influences on immunomodulation and overall survival. Lastly, candidate therapeutic compounds, intervening purine metabolism, were proposed based on pharmaco-transcriptomics and pharmaco-proteomics analysis. Through interdisciplinary multi-omics investigations, such approaches may enhance insight into antitumor immunotherapy by targeting cancer metabolic reprogramming.
    Keywords:  Circulation; Hypoxanthine; Metabolomics; Pan-cancer; Purine metabolism
    DOI:  https://doi.org/10.1186/s12943-025-02482-9
  21. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00788-9. [Epub ahead of print]85(20): 3890-3890.e1
    Cell-death networks.
    Hamid Kashkar, Manolis Pasparakis.
      Cells can undergo death through various genetically regulated pathways, each leading to distinct tissue outcomes. Emerging evidence suggests that these pathways are molecularly interconnected, indicating that the mode of death is determined not only by apical signals but by the availability of terminal executioners/substrates. This evolving understanding challenges the traditional rigid classification of cell death and has important implications for its therapeutic targeting in diseases.
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.028
  22. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2517050122
    Global conformation of the Rag GTPase heterodimer governs eukaryotic amino acid sensing.
    Dylan D Doxsey, Kuang Shen.
      The Rag GTPase heterodimer is a central mediator of amino acid sensing in eukaryotic cells. When amino acids are abundant, it binds to the mechanistic target of rapamycin complex 1 to activate cellular programs for growth and proliferation. In its functional cycle, besides local conformational changes near the nucleotides that are commonly observed in monomeric signaling GTPases, the relative positioning of the two Rag subunits, i.e., the global conformation, is unique due to the heterodimeric architecture. Although various global conformations have been captured in static structural models, dynamic transitions between these conformations and their biological relevance remain unclear. Here, we visualize the global conformation of the Rag GTPase heterodimer using single-molecule Förster resonance energy transfer. By tracking the movement of individual protein molecules, we found that the two subunits explore a wide conformational space, which is strictly dictated by the bound nucleotides, regulators, and mutations. Additionally, we demonstrate that proper modulation of the global conformation is crucial for correctly interpreting amino acid signals. Our results defined a checkpoint of amino acid sensing in eukaryotic cells.
    Keywords:  Rag GTPase; amino acid sensing; mTORC1; protein conformation; single-molecule FRET
    DOI:  https://doi.org/10.1073/pnas.2517050122
  23. Cell Rep. 2025 Oct 13. pii: S2211-1247(25)01183-0. [Epub ahead of print]44(10): 116412
    CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
    Alison Galloway, Katarzyna Knop, Carolina Gomez-Moreira, Vanessa Xavier, Sarah Thomson, Harunori Yoshikawa, Olga Suska, Radoslaw Lukoszek, Aneesa Kaskar, Angus I Lamond, Thomas MacVicar, Victoria H Cowling.
      During T cell activation, mitochondrial biogenesis and cellular metabolism are altered to meet the elevated energy demands of protein synthesis, rapid proliferation, and effector T cell function. The mechanisms coupling mitochondrial dynamics to T cell status are unclear. Here, we report that RNA cap methyltransferase 1 (CMTR1) is induced in activated T cells, methylating the first nucleotide on mRNA and U2 small nuclear RNA (snRNA), a component of the spliceosome. Using transcriptomic analyses, we identify a functional splicing module regulating mitochondrial dynamics in T cells, which alters the isoforms of proteins controlling mitochondrial fission and fusion. Through epitranscriptomic control of U2 snRNA and splicing, CMTR1 directs protein isoform selection during T cell activation to promote the development of longer mitochondria with increased respiratory capacity. Thus, CMTR1 upregulation supports the energetic demands of T cell activation, survival, and immune responses.
    Keywords:  CMTR1; CP: Immunology; CP: Metabolism; MFF; RNA cap; RNA methylation; T cell; T lymphocyte; metabolism; mitochondria; snRNA; splicing
    DOI:  https://doi.org/10.1016/j.celrep.2025.116412
  24. Mol Cell Biol. 2025 Oct 14. 1-30
    Metabolic Regulation of Copper Homeostasis Governs the Sec61-Dependent Protein Translocation Process in Saccharomyces cerevisiae.
    Vandana Anjana, Smriti Anand, Prateeksha Thakur, Rajshree Pal, Santoshi Acharjee, Sugandh Sharma, Sharayu Subhash Awachat, Ritika Manjhi, Devika Rejidev, Ranu Singh, Raghuvir Singh Tomar.
      The concentration of cellular labile pool of copper must be strictly regulated because disruption in copper homeostasis results in diseases. In Saccharomyces cerevisiae, elevated levels of labile copper impair cell viability by inhibiting Sec61-mediated protein translocation into the endoplasmic reticulum. We investigated how metabolic pathways, specifically mitochondrial respiration and autophagy, contribute to copper homeostasis and the translocation of secretory proteins. We show that copper selectively inhibits protein translocation in yeast cells grown in minimal medium but not in a rich medium, highlighting a critical role of nutrients in modulating copper toxicity. Supplementation of specific amino acids suppresses the copper-induced defects in protein translocation and cell death, identifying amino acids as suppressors of the copper toxicity. Using a panel of gene deletion mutants affecting mitochondrial functions, autophagy, peroxisomes, and lipid droplets, we demonstrate that metabolic pathways regulate subcellular concentration of copper and translocation of secretory proteins. Further, disruption of redox and pH homeostasis, and pharmacological inhibition of respiration, reveals that correct subcellular concentration of copper is essential to prevent inhibitory effects on protein translocation. Together, our findings provide mechanistic insights into how metabolic status influences cellular copper homeostasis and the secretory pathway of proteins, with broader implications for understanding diseases of copper metabolism.
    Keywords:  Copper; amino acids; autophagy; copper homeostasis; mitochondria; protein translocation
    DOI:  https://doi.org/10.1080/10985549.2025.2569577
  25. ACS Chem Neurosci. 2025 Oct 16.
    Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.
    Richard S McCain, Gerardo G Piroli, Holland H Smith, Aman S Sumal, Paul A Grimsrud, William E Cotham, Michael D Walla, Norma Frizzell.
      The Ndufs4-/- mouse is a model of mitochondrial Complex I deficiency that contributes to altered production of the tricarboxylic acid cycle metabolites. We hypothesized that l-2-hydroxyglutarate (l-2-HG) levels would be elevated in the pathologically affected regions of the Ndufs4-/- mouse brain in parallel with metabolic acidosis. We employed a stable isotope dilution method for the concurrent quantification of l-lactate and the distinct 2-HG enantiomers in isolated mouse brain regions. While lactate levels were elevated, as expected in the Ndufs4-/- brain, the levels of l-2-HG and the enantiomer d-2-HG were markedly reduced in a region-specific manner, and this decrease was also reproduced in the Ndufs4-/- serum. The specific and reproducible decreases in 2-HG quantified in Complex I deficiency may have utility as a unique disease biomarker. Quantitative analysis of the mitochondrial proteome of the Ndufs4-/- mouse brainstem indicated an increased abundance of l-2-HG dehydrogenase, suggesting that 2-HG enantiomers are metabolized in the Ndufs4-/- mouse yielding FADH2 to alleviate the bioenergetic deficit.
    Keywords:  2-hydroxyglutarate; brainstem; lactate; mass spectrometry; mitochondrial disease; neurometabolic
    DOI:  https://doi.org/10.1021/acschemneuro.5c00628
  26. Cell Rep. 2025 Oct 09. pii: S2211-1247(25)01153-2. [Epub ahead of print]44(10): 116382
    HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.
    Takayuki Ikeda, Sungki Hong, Shota Yoshida, Swayam Prakash Srivastava, Abhiram Kunamneni, Yao Yao, Om Khuperkar, Venkatesha Basrur, Henry Kuang, Maureen Kachman, Abraham Raskind, Heidi Baum, Arya Joshi, Vinamra Swaroop, Aaron Thurman, Oliviamae Kopasz-Gemmen, Siddharth Kandukuri, F N U Pradeepa, Hideto Yonekura, Jiandie D Lin, Ken Inoki.
      The mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of cell growth, is activated by Rheb small GTPase. Our recent studies have demonstrated that polyubiquitinated Rheb enhances its interaction with mTORC1, resulting in the activation of mTORC1. Here, we demonstrate that the HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1), an E3 ubiquitin ligase, preferentially interacts with ubiquitinated Rheb and facilitates Rheb's binding to mTORC1 and its subsequent activation. The ablation of HUWE1 results in reduced ubiquitination of Rheb and decreased mTORC1 activity in cultured cells and mouse liver. HUWE1 is also necessary for Rheb to interact with carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase (CAD), a key enzyme in pyrimidine biosynthesis, and for CAD activation through the activation of the mTORC1-S6K1 pathway. Moreover, HUWE1 maintains CAD expression by increasing its transcript in cells and liver tissues. Therefore, HUWE1 acts as a key organizer of the ubiquitinated Rheb complex, playing a vital role in enhancing mTORC1 activity and pyrimidine synthesis by increasing both CAD activity and expression.
    Keywords:  CAD; CP: Cell biology; CP: Molecular biology; HUWE1; Rheb; mTOR; mTORC1; pyrimidine; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2025.116382
  27. Cancer Res. 2025 Oct 15.
    Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.
    Horacio Cardenas, Yinu Wang, Guangyuan Zhao, Delan Xingyue Hao, Ana Maria Isac, Vanessa Hernandez, Ujin Kim, Wenan Qiang, Hao F Zhang, Daniela Matei.
      Ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy. Metabolic adaptations can play a pivotal role in therapy resistance. Here, we aimed to identify key metabolic pathways that regulate platinum response and represent potential therapeutic targets. Transcriptomic and metabolomic analyses in cisplatin sensitive and resistant ovarian cancer cells identified enrichment of pyrimidine metabolism related to upregulated de novo pyrimidine synthesis. 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in cisplatin resistant cells. Targeting this pathway using brequinar (BRQ), an inhibitor of the key enzyme dihydroorotate dehydrogenase (DHODH), decreased cell viability, delayed G2/M cell cycle progression, and altered expression of genes related to mitochondrial electron transport in resistant cells. Under basal conditions, cisplatin resistant cells had a lower oxygen consumption rate (OCR) and spare respiratory capacity (SRC) than sensitive cells. BRQ suppressed OCR in both sensitive and resistant but only inhibited SRC in resistant cells. In cell line-derived and patient-derived xenograft models, BRQ attenuated the growth of cisplatin resistant ovarian tumors and enhanced the inhibitory effects of carboplatin. Together, these results identify metabolic reprogramming in cisplatin resistant ovarian cancer that induces an acquired dependency on de novo pyrimidine synthesis, which can be targeted to sensitize tumors to chemotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0043
  28. Mol Cell Biol. 2025 Oct 17. 1-27
    From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
    Phoebe J Leeming, Julia Mercuri-Svik, Diana Stojanovski.
      Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.
    Keywords:  Mitochondria; mitochondrial disease; protein import; protein quality control
    DOI:  https://doi.org/10.1080/10985549.2025.2566671
  29. Methods Mol Biol. 2026 ;2976 85-102
    Lysosomal Immunoprecipitation (LysoIP) from Cells and Tissues for Metabolomic and Proteomic Analyses.
    Nouf N Laqtom, Monther Abu-Remaileh.
      Lysosomes, known for degrading biomolecules and damaged cellular components, are now recognized as signaling hubs for nutrient sensing and metabolic adaptation, and their dysfunction is implicated in diseases including cancer and neurodegeneration. To understand the composition of the lysosome, the dynamic behavior of its contents, and its specific roles in health and disease, we describe a lysosomal immunoprecipitation method, termed "LysoIP," that enables the isolation of intact lysosomes from cultured cells and mouse tissues. This method utilizes a lysosome-localized 3xHA epitope tag (LysoTag) and a simple, yet robust organelle immunoprecipitation workflow. Isolated lysosomes are extracted with optimized buffers to allow the efficient retrieval of lysosomal proteins, polar metabolites, and lipids, maintaining compatibility with downstream liquid chromatography and mass spectrometry (LC-MS) analyses.
    Keywords:  LC-MS analyses; LysoIP; LysoTag; LysoTag mouse; Lysosomes; Metabolomics; Proteomics; TMEM192
    DOI:  https://doi.org/10.1007/978-1-0716-4844-5_8
  30. Cancer Cell. 2025 Oct 16. pii: S1535-6108(25)00403-9. [Epub ahead of print]
    TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors.
    Shelley Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared Gilliam, Milan Radovich, Padmanee Sharma.
      Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients and 25,064 colorectal adenocarcinoma patients, TET2-mutant CH is associated with improved outcome specifically with ICT. This study proposes a role for Tet2+/mut antigen presenting macrophages in shaping antitumor immunity and identifies TET2-mutant CH as a potential biomarker for improved response to ICT in patients with solid tumors.
    Keywords:  TET2; antigen presentation; clonal hematopoiesis; cross-priming; immune checkpoint therapy; tumor immunology
    DOI:  https://doi.org/10.1016/j.ccell.2025.09.011
  31. Nat Rev Cancer. 2025 Oct 15.
    Exploiting metabolic cell death for cancer therapy.
    Chao Mao, Dadi Jiang, Albert C Koong, Boyi Gan.
      Resistance to cell death is a hallmark of cancer, driving tumour progression and limiting therapeutic efficacy. Metabolic cell death pathways have been identified as unique vulnerabilities in cancer, with ferroptosis being the most extensively studied, alongside the more recently discovered pathways of cuproptosis and disulfidptosis - each triggered by distinct metabolic perturbations. In this Review, we examine the molecular mechanisms and regulatory networks that govern these forms of metabolic cell death in cancer cells. We further examine the potential crosstalk between these pathways and discuss how insights gained and challenges encountered from extensive studies on ferroptosis can guide future research and therapeutic strategies targeting cuproptosis and disulfidptosis in cancer treatment. We highlight the complexity and dual roles of metabolic cell death in cancer and offer our perspective on how to leverage these cell death processes to develop innovative, targeted cancer therapies.
    DOI:  https://doi.org/10.1038/s41568-025-00879-8
  32. Hum Mutat. 2025 ;2025 8856239
    ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma.
    Lei Xiao, Zicheng Zhang, Tong Li, Yuyin Jiang, Yuanxin Liu, Jia Wang, Wei Tang.
      While hypoxia-driven nucleolar stress (NS) has been recognized as a critical modulator of the immunosuppressive tumor microenvironment in clear cell renal cell carcinoma (ccRCC), its mechanistic contribution to disease progression remains poorly defined. To address this gap, we systematically mapped NS-associated molecular landscapes through integrated spatial transcriptomics and single-cell RNA sequencing of ccRCC specimens. Our analysis stratified tumors into two distinct NS subtypes, revealing that high-NS tumors exhibit aggressive clinical behavior, elevated expression of immunosuppressive checkpoints, and significantly reduced survival. At single-cell resolution, high-NS malignant cells displayed enhanced proliferative activity, glycolytic metabolic reprograming, and marked chromosomal instability. Mechanistic investigations demonstrated that hypoxia-induced ETS1 activation orchestrates NS via the MYC/NPM1/DDX17 signaling axis, directly promoting tumor proliferation and metabolic adaptation in preclinical models. Spatial multiomics further uncovered coordinated niche formation between high-NS cells and OLR1+ macrophages, with ligand-receptor profiling identifying the EDN1-EDNRA-OLR1 axis as a central mediator of this immunosuppressive crosstalk. Functional validation in syngeneic mouse models confirmed that ETS1 overexpression accelerates tumor growth while enriching OLR1+ macrophages with immunosuppressive phenotypes. Clinically, high OLR1+ macrophage infiltration correlated with shorter survival across independent cohorts. These findings establish a hypoxia-ETS1-NS-macrophage axis as a key mechanism sustaining ccRCC progression and highlight actionable targets for disrupting protumorigenic immune niches through modulation of the NS pathway.
    Keywords:  ETS1; OLR1+ macrophages; clear cell renal cell carcinoma; immunosuppressive microenvironment; nucleolar stress
    DOI:  https://doi.org/10.1155/humu/8856239
  33. Cell Rep. 2025 Oct 15. pii: S2211-1247(25)01200-8. [Epub ahead of print]44(10): 116429
    STBD1 mediates the crosstalk between glycogen and lipid droplets in clear cell renal cell carcinoma.
    Hao Wang, Tong Xiao, Hao Zhuang, Yi Liu, Kexing Jin, Jing Li, Jun Li, Yan Gao, Dan Yue, Wei Cui, Qingxia Xu, Jingxuan Pan, Kangdong Liu, Yong Wang, Ruibing Chen, Hongle Li.
      The accumulation of lipid droplets (LDs) and glycogen is a major hallmark of clear cell renal cell carcinoma (ccRCC), yet their interplay remains unclear. By proteomic profiling of 50 ccRCC tumors, we observe activation of glycogen- and LD-related pathways. Using proximity labeling of the LD proteome, we identify starch-binding domain-containing protein 1 (STBD1), a glycogen-binding protein involved in glycophagy, as a novel LD component. Further mechanistic investigation shows that STBD1 targets LDs via N-terminal myristoylation and mediates glycogen-LD colocalization. Its depletion decreases LD abundance and impairs both glycophagy and lipophagy, suggesting a critical role of STBD1 in both the biogenesis and autophagic degradation of LDs. Furthermore, STBD1 knockdown alters lipid composition, enhances ferroptosis sensitivity, and suppresses tumor growth both in vitro and in vivo. Collectively, our findings establish STBD1 as a critical mediator of glycogen-LD crosstalk and highlight its potential as a therapeutic target in ccRCC.
    Keywords:  CP: Cancer; CP: Metabolism; STBD1; clear cell renal cell carcinoma; ferroptosis; glycogen; glycophagy; lipid droplets; lipophagy; metabolic reprogramming; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.116429
  34. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00776-2. [Epub ahead of print]85(20): 3779-3792
    Metabolites in the extracellular tumor microenvironment and the shaping of macrophage function.
    Sara Lamorte, Matthew Bianca, Zhe Qi Liu, Tracy L McGaha.
      It has been a century since it was discovered that cancer cells have a distorted metabolism compared to healthy cells and tissues. It is now universally accepted that the abnormal metabolic state of cancers is essential for proliferation and survival in the harsh environment of most solid tumors. However, the impact of the altered metabolite pools generated from this rewiring is complex and has been challenging to functionally disentangle. Macrophages are innate immune cells and a major cellular constituent of the tumor microenvironment (TME). Macrophages are functionally plastic and highly sensitive to changes in metabolite exposure, with the potential to change the TME in a profound, disease-altering fashion. However, it was not until the recent advent of sensitive, high-dimensional analysis that the impact of metabolites on tumor macrophage diversity and function was fully appreciated. In this review, we discuss recent developments in our knowledge of how altered metabolites, resulting from metabolic reprogramming in the TME, influence macrophage phenotype and the implications for tumor development and progression. Furthermore, we examine emerging therapeutic strategies aimed at targeting tumor-metabolite crosstalk to improve disease outcomes.
    Keywords:  immunity; macrophage; metabolism; metabolites; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.016
  35. Aging Cell. 2025 Oct 17. e70253
    Age Deceleration and Reversal Gene Patterns in Dauer Diapause.
    Khrystyna Totska, João C V V Barata, Walter Sandt, David H Meyer, Björn Schumacher.
      The aging process is characterized by a general decrease in physical functionality and poses the biggest risk factor for a variety of diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders among others. Understanding the naturally evolved mechanisms that slow aging and rejuvenate an animal could reveal important concepts on how to prevent age-associated diseases and even revert aging. The C. elegans dauer stage is a robust and long-lived alternative developmental state that, after dauer exit, has a normal adult lifespan with fully retained fecundity. To understand how longevity during dauer and rejuvenation following dauer exit is mediated, we characterized the gene expression changes during dauer and upon exit. We assessed how biological age, as determined via BiT Age, a transcriptome aging clock, is affected during dauer and upon dauer exit. During the dauer stage, we measured a decelerated increase in age compared to the chronological age and an age reversal following dauer exit. Transcriptomic analyses revealed major metabolic shifts and enhanced biomolecular degradation that are reversed during exit. Moreover, we show that transcription-blocking lesions can induce lasting transcription stress in dauers that is rapidly resolved by transcription-coupled nucleotide excision repair during dauer exit. Our data provide new insights into the underlying mechanisms of naturally occurring age deceleration and rejuvenation.
    DOI:  https://doi.org/10.1111/acel.70253
  36. Biochem Biophys Res Commun. 2025 Oct 13. pii: S0006-291X(25)01520-7. [Epub ahead of print]787 152804
    Structural basis of potent inhibition of the human CAD dihydroorotase domain by 5-aminoorotic acid.
    Yen-Hua Huang, Tsai-Ying Huang, Man-Cheng Wang, Cheng-Yang Huang.
      Dihydroorotase (DHOase) catalyzes the reversible conversion of N-carbamoyl-L-aspartate to dihydroorotate in de novo pyrimidine biosynthesis. In humans, DHOase (huDHOase) is part of the CAD enzyme complex and contains a flexible loop that alternates between loop-in and loop-out conformations. Here, we identify 5-aminoorotic acid (5-AOA), previously known as a dihydroorotate dehydrogenase inhibitor, as a potent huDHOase inhibitor. Enzyme assays showed strong inhibition by 5-AOA (IC50 = 9.87 μM) compared with weaker inhibition by 5-fluoroorotic acid (5-FOA; IC50 = 191.59 μM). To elucidate the mechanism, we determined the crystal structures of huDHOase bound to 5-AOA (1.83 Å; PDB ID: 9WIC) and to 5-FOA (1.55 Å; PDB ID: 9WIN) for direct comparison. Structural analysis revealed distinct binding modes: 5-AOA bound in the loop-in conformation, forming extensive stabilizing interactions, whereas 5-FOA bound in the loop-out state with fewer contacts. Consistently, the T1562A mutation decreased the binding affinity of 5-AOA from 18.6 μM to 53.4 μM, an approximately threefold reduction, confirming the role of the loop in inhibitor recognition. These findings establish 5-AOA as a dual inhibitor in pyrimidine biosynthesis and highlight a loop-in binding mechanism for huDHOase inhibition.
    Keywords:  5-Aminoorotic acid; 5-Fluoroorotic acid; CAD; Dihydroorotase; Dynamic loop
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152804
  37. Nat Cell Biol. 2025 Oct;27(10): 1739-1756
    Cholesterol sensing by the SCAP-FAM134B complex regulates ER-phagy and STING innate immunity.
    Boran Li, Dongheng Zhou, Xinyi Wang, Xiao Jiang, Yongjuan Sang, Youjing Dai, Yu Yao, Yi Zhang, Chen Chen, Shulin Li, Wang Ni, Quan Zhou, Aifu Lin, Xinyang Hu, Liang Ge, Zhiying Wu, Pinglong Xu, Dante Neculai, Wei Liu, Qiming Sun.
      The endoplasmic reticulum (ER) is central to cholesterol biosynthesis and trafficking, yet paradoxically maintains low cholesterol levels, enabling it to sense fluctuations that impact various signalling pathways. However, the role of ER cholesterol in cellular signalling remains unclear. Here we show that the ER-phagy receptor FAM134B interacts directly with both cholesterol and SCAP, a key regulator of cholesterol biosynthesis. When ER cholesterol is high, FAM134B and SCAP are sequestered by cholesterol-tightened interactions, halting ER-phagy, STING activation and cholesterol synthesis. Under low cholesterol conditions, FAM134B dissociates from SCAP, allowing SCAP to activate SREBP2 and upregulate cholesterol synthesis, while FAM134B either facilitates ER-phagy through oligomerization or aids STING trafficking to activate innate immune responses. These findings reveal that the SCAP-FAM134B complex senses ER cholesterol levels, regulating both ER-phagy and immune signalling, with implications for diseases linked to cholesterol imbalance.
    DOI:  https://doi.org/10.1038/s41556-025-01766-y
  38. Elife. 2025 Oct 15. pii: RP102097. [Epub ahead of print]13
    BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment.
    Emilio Rios-Jimenez, Anoek Zomer, Raphael Collot, Mario Barrera Román, Sandra F Archidona, Hendrikus Ariese, Ravian van Ineveld, Michiel Kleinnijenhuis, Nils Bessler, Hannah Johnson, Caleb A Dawson, Anne Rios, Maria Alieva.
      Intravital microscopy (IVM) enables live imaging of animals at single-cell level, offering essential insights into cancer progression. This technique allows for the observation of single-cell behaviors within their natural 3D tissue environments, shedding light on how genetic and microenvironmental changes influence the complex dynamics of tumors. IVM generates highly complex datasets that often exceed the analytical capacity of traditional uni-parametric approaches, which can neglect single-cell heterogeneous in vivo behavior and limit insights into microenvironmental influences on cellular behavior. To overcome these limitations, we present BEHAV3D Tumor Profiler (BEHAV3D-TP), a computational framework that enables unbiased single-cell classification based on a range of morphological, environmental, and dynamic single-cell features. BEHAV3D-TP integrates with widely used 2D and 3D image processing pipelines, enabling researchers without advanced computational expertise to profile cancer and healthy cell dynamics in IVM data from mouse models. Here, we apply BEHAV3D-TP to study diffuse midline glioma (DMG), a highly aggressive pediatric brain tumor characterized by invasive progression. By extending BEHAV3D-TP to incorporate tumor microenvironment (TME) data from IVM or fixed correlative imaging, we demonstrate that distinct migratory behaviors of DMG cells are associated with specific TME components, including tumor-associated macrophages and vasculature. BEHAV3D-TP enhances the accessibility of computational tools for analyzing the complex behaviors of cancer cells and their interactions with the TME in IVM data.
    Keywords:  cancer biology; cell migration; computational biology; confocal microscopy; image analysis; mouse; systems biology
    DOI:  https://doi.org/10.7554/eLife.102097
  39. Nat Aging. 2025 Oct 17.
    Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation.
    David Ezuz, Heba Ombashe, Lana Watad, Akmaral Rakhymzhanova, Satyarth Pandey, Orna Atar, Esther G Meyron-Holtz, Noga Ron-Harel.
      Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with immune and stromal cells. Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging. Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice. This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging.
    DOI:  https://doi.org/10.1038/s43587-025-00981-4
  40. Mol Cell. 2025 Oct 13. pii: S1097-2765(25)00781-6. [Epub ahead of print]
    Productive mRNA chromatin escape is promoted by PRMT5 activity.
    Joseph D DeAngelo, Maxim I Maron, Jacob S Roth, Subray Hegde, Aliza M Silverstein, Varun Gupta, Stephanie Stransky, Joel Basken, Joey Azofeifa, Charles C Query, Simone Sidoli, Matthew J Gamble, David Shechter.
      Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric arginine dimethylation (Rme2s) of RNA-binding proteins and influences RNA splicing and gene expression. However, how PRMT5 couples splicing to productive transcript output remains unclear. We show that a major function of PRMT5 is to promote chromatin escape of mRNAs, designated as genomically retained incompletely processed polyadenylated transcripts (GRIPPs). Using nascent and spike-in normalized fractionated transcriptomics with proteomics, we find that PRMT5 inhibition in mammalian cells causes polyadenylated mRNA and Smith antigen (Sm) protein accumulation on chromatin. These retained transcripts are intron rich and splice slowly. PRMT5 inhibition and isogenic SNRPB mutants demonstrate that Sm tail methylation is essential to prevent RNA detention on chromatin. Biochemical assays reveal that the SMN Tudor domain competes with nucleic acid binding of methylated Sm tails. We conclude that PRMT5 ensures mRNA processing and nuclear export by preventing aberrant chromatin retention, highlighting arginine methylation as a key regulator of RNA-chromatin dynamics.
    Keywords:  CLNS1A; PRMT5; RIOK1; Rme2s; SDMA; SMN; SNRPB; SNRPD1; SNRPD3; pICln
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.021
  41. Biochim Biophys Acta Rev Cancer. 2025 Oct 10. pii: S0304-419X(25)00214-8. [Epub ahead of print] 189472
    Detection methods for mitochondrial DNA heteroplasmy and their potential single-cell applications in cancer.
    Tianguang Cheng, Min Pan, Yi Qiao, Jing Tu.
      Mitochondrial DNA (mtDNA) is crucial for cellular metabolism, oxidative stress responses, and genomic stability, with mutations linked to cancer progression and therapeutic resistance. Mitochondrial heteroplasmy, the coexistence of wild-type and mutant mtDNA within a cell or across populations, plays a key role in mitochondrial dysfunction, tumor heterogeneity, and disease pathogenesis. Advances in single-cell technologies like quantitative PCR (qPCR), digital droplet PCR (ddPCR), next-generation sequencing (NGS), and long-read sequencing (TGS) have enabled precise mapping of heteroplasmic variants, providing insights into their role in cancer. This review evaluates current detection methods, discussing their strengths, limitations, and relevance to cancer research. We also explore the biological implications of heteroplasmy in cellular dynamics, nuclear mitochondrial DNA segments (NUMTs), and cancer pathogenesis, highlighting emerging technologies and future directions for studying mtDNA mutations at single-cell resolution in cancer. Ultimately, this review provides a critical synthesis of how single-cell mtDNA heteroplasmy analysis is reshaping our understanding of tumorigenesis and identifies key methodological and challenges that must be addressed to realize its full potential in precision oncology.
    Keywords:  Cancer metabolism; Heteroplasmy; Mitochondrial DNA; Sequencing; Single cell
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189472
  42. EMBO Mol Med. 2025 Oct 13.
    Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.
    Bauke V Schomakers, Adriana S Passadouro, Maria M Trętowicz, Pelle J Simpson, Yorrick R J Jaspers, Michel van Weeghel, Iman Man Hu, Cathelijne M E Lamboo, Denise Cloutier, Barry J Byrne, Jan Bert van Klinken, Paul M L Janssen, Sander R Piersma, Connie R Jimenez, Frédéric M Vaz, Gajja S Salomons, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard.
      Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.
    Keywords:  Barth Syndrome; Cardiac Tissue; Integrated Multi-omics; Mitochondrial Dysfunction
    DOI:  https://doi.org/10.1038/s44321-025-00320-5
  43. Cell Rep Med. 2025 Oct 10. pii: S2666-3791(25)00489-6. [Epub ahead of print] 102416
    Decoding tumor heterogeneity: A spatially informed pan-cancer analysis of the tumor microenvironment.
    Francesca Lodi, Sam Vanmassenhove, Duojiao Chen, Bram Boeckx, Lucas Ferreira Maciel, Frederik Peeters, Elena Donders, Heesoo Song, Luuk Harbers, Joanna Poźniak, Liselore Loverix, Yiduo Zhou, Michel Bila, Ayse Bassez, Sarah Cappuyns, Tom Venken, Siel Olbrecht, Amelie Franken, Pierre Van Mol, Rogier Schepers, Thomas van Brussel, Gino Philips, Hanne Vos, Machteld Keupers, Frederik De Smet, Sabine Tejpar, Oliver Bechter, Gabriele Bergers, Ann Smeets, Paul Clement, Els Wauters, Jeroen Dekervel, Toon Van Gorp, Junbin Qian, Jean-Christophe Marine, Diether Lambrechts.
      Pan-cancer single-cell atlases explore the heterogeneity of cell types residing within the tumor microenvironment (TME). So far, atlases focused on individual cell types, failing to capture the full complexity of the TME. Here, we present a single-cell atlas that simultaneously considers heterogeneity in 5 cell types, collected from 230 treatment-naive samples across 9 cancer types. We identify 70 pan-cancer single-cell subtypes, investigate their patterns of co-occurrence and show an enrichment of specific subtypes in certain TMEs, e.g., immune-reactive versus immune-suppressive TME. We observe two TME hubs of strongly co-occurring subtypes: one hub resembling tertiary lymphoid structures (TLSs), another consisting of immune-reactive PD1+/PD-L1+ immune-regulatory T cells and B cells, dendritic cells and inflammatory macrophages. Subtypes belonging to each hub are spatially co-localized, while their abundance associates with early and long-term checkpoint immunotherapy response. We publicly share our atlas using a Shiny app, allowing others to explore TME heterogeneity in different biological contexts.
    Keywords:  ICB; TLS; TME; immune checkpoint blockade; pan-cancer; scRNA-seq; single-cell RNA sequencing; tertiary lymphoid structure; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102416
  44. Exp Mol Pathol. 2025 Oct 15. pii: S0014-4800(25)00054-1. [Epub ahead of print]144 105004
    Mechanism and importance of ferroptosis in clear cell renal cell carcinoma treatment.
    Manvi Agarwal Neeraj, Songmi Noh, JeeHoon Chae, JunJeong Choi.
      Metabolic reprogramming is a common phenomenon that is observed in diverse cancer types. Clear cell renal cell carcinoma (ccRCC) is termed a metabolic disease due to its dysregulated lipid and glucose metabolism. Among kidney cancers, ccRCC is the most malignant form of cancer, defined by the large accumulation of lipid droplets. These lipid droplets, although they provide energy and induction of metastasis, also act as a buffer by preventing ferroptosis. Ferroptosis is an iron-dependent type of regulated cell death, which is characterized by the accumulation of toxic lipid peroxides. Ferroptosis has emerged to play an important part in tumor progression and cancer therapy. Due to a lack of diagnostic markers and resistance towards therapy, ccRCC is a difficult cancer type to overcome. However, studies have shown the importance of ferroptosis in ccRCC treatment by targeting various pathways. This paper helps in understanding the mechanism of ferroptosis and the evidence observed in ccRCC. This paper aims to understand the current trend of ferroptosis in ccRCC and produce a potential therapy for ccRCC through ferroptosis.
    Keywords:  Cancer therapy; Clear cell renal cell carcinoma; Epigenetic modifications; Ferroptosis; Metabolism
    DOI:  https://doi.org/10.1016/j.yexmp.2025.105004
  45. Biosystems. 2025 Oct 11. pii: S0303-2647(25)00220-5. [Epub ahead of print] 105610
    Information and the living tree of life A theory of measurement grounded in biology.
    Kevin Hudnall.
      We extend a formal framework that previously derived time from the multifractal structure of biological lineages (Hudnall & D'Souza, 2025). That work showed that time itself is multifractal - not a universal background dimension, but an observer-dependent geometry. Here we develop the corresponding theory of measurement: showing that a multifractal conception of time not only permits measurement, but grounds it more rigorously in the structure of biology. The tree of life is modeled as the outcome of stochastic, convex branching, and we show how information-theoretic and fractal measures render its multifractal geometry into measurable, observer-relative time intervals. At the core is a dilation equation that expresses relative time elapse between entities as dimensionless ratios. Operational standards such as the SI second remain valid, but our framework makes explicit their lineage-dependence. This framework unifies measurement theory with biological form, preserves full compatibility with established science, and provides a biologically grounded theory of observation. It enables comparative analyses of duration and kinematics across lineages, with predictions that are directly open to experimental validation.
    Keywords:  Random iterated function system; biokinematics; emergent time; fractal geometry; information theory; multifractal time; observer-relative measurement
    DOI:  https://doi.org/10.1016/j.biosystems.2025.105610
  46. Nat Cell Biol. 2025 Oct 16.
    Epigenetic alterations facilitate transcriptional and translational programs in hypoxia.
    Kathleen Watt, Bianca Dauber, Krzysztof J Szkop, Laura Lee, Predrag Jovanovic, Shan Chen, Ranveer Palia, Julia A Vassalakis, Tyler T Cooper, David Papadopoli, Laìa Masvidal, Michael Jewer, Kristofferson Tandoc, Hannah Plummer, Gilles A Lajoie, Ivan Topisirovic, Ola Larsson, Lynne-Marie Postovit.
      Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, by quantifying hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells, we show pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Notably, hypoxia-associated TSS switching was induced or reversed via pharmacological modulation of H3K4me3 in the absence of hypoxia, defining a role for H3K4me3 in TSS selection independent of HIF1-transcriptional programs. By remodelling 5'UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of messenger RNAs encoding pyruvate dehydrogenase kinase 1, which is essential for metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5'UTRome.
    DOI:  https://doi.org/10.1038/s41556-025-01786-8
  47. Sci Adv. 2025 Oct 17. 11(42): eadx8662
    Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
    Sofia La Vecchia, Saurav Doshi, Petros Antonoglou, Tanima Kundu, Wafa Al Santli, Kleopatra Avrampou, Matthew T Witkowski, Anna Pellattiero, Federico Magrin, Kristina Ames, Amit Verma, Kira Gritsman, Xiaoyang Su, Andrea Mattarei, Iannis Aifantis, Luca Scorrano, Christina Glytsou.
      Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.
    DOI:  https://doi.org/10.1126/sciadv.adx8662
  48. Cancer Res. 2025 Oct 15.
    A Roadmap for the Future of Systems Biology in Cancer Research.
    H Steven Wiley, Carlos F Lopez, Andrei S Rodin, Russell C Rockne, Thomas E Yankeelov, Herbert M Sauro, Ghmkin Hassan, Sandhya Prabhakaran, Emek Demir, Mengzhou Hu, Juan Fuxman Bass, Kimberly A Luddy, Hannah Newman, Jonathan P Mochel, James C Costello, Jianhua Xing, Said M Afify, Ahmet Acar, Melanie Hayden Gephart, Song Feng, Orion Banks, Jineta Banerjee, Ashley Clayton, David E Hill, Randy F Sweis, Maxine C Umeh-Garcia, Yapeng Su, Aaron S Meyer.
      Cancer systems biology seeks to understand how cancer arises as a system of interconnected molecules, cells, and tissues, with the goal of understanding, predicting, and controlling the disease. In the last decade, the field has rapidly grown as advances in experimental, computational, and analytical technologies have improved our ability to capture and recapitulate the complexities of cancer at multiple scales. However, the field's promise to understand how specific molecular changes give rise to altered cancer outcomes remains incompletely fulfilled. Fortunately, an opportunity exists to accelerate progress by better coordinating modeling and data-gathering efforts across the cancer systems biology community. This will create the foundation for building accurate, multiscale cancer models that can better predict and identify improved therapeutic interventions. Here, we outline some of the current challenges in cancer systems biology research, how they can be addressed, and actions that the community can take to accelerate progress in the field.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0700
  49. Nat Rev Immunol. 2025 Oct 16.
    Astroimmunology: the effects of spaceflight and its associated stressors on the immune system.
    Daniel A Winer, Huixun Du, JangKeun Kim, Veronica Chang, Marissa Burke, Shawn Winer, Sylvain V Costes, Jean-Pol Frippiat, Clarence Sams, Amber M Paul, Honglu Wu, Oliver Ullrich, Sarah Baatout, Afshin Beheshti, Christopher E Mason, Alexander Choukér, Brian E Crucian.
      As humans embark on longer and deeper missions into space, it is crucial to understand how spaceflight impacts the immune system. Decades of discoveries, bolstered by recent multiomic analyses, have identified key immune processes that are affected by the spaceflight environment. These findings form the foundations of the emerging field of 'astroimmunology'. Spaceflight stressors - such as microgravity and galactic cosmic radiation - and other mission-associated variables, including psychological stress and abnormal circadian rhythms, can disrupt or adversely affect immune cell biology. In addition, spaceflight alters host-microbiome interactions, which can increase susceptibility to opportunistic pathogens and viral reactivation. Although ground-based analogues for human spaceflight have provided insights into these stressors individually, their combined effects during spaceflight remain less understood. This Review explores our current knowledge of the effects of spaceflight stressors on the immune system and the clinical implications for human space exploration. It also highlights current and developing countermeasures, including machine-learning approaches, advanced monitoring technologies and standardized biobanking, that can facilitate research into the impact of spaceflight on the immune system. Looking ahead, progressing from low Earth orbit missions to long-term missions to the Moon, Mars and beyond will introduce new challenges, including increased radiation, variable gravity and regolith exposure. We discuss these prospective challenges and outline potential preventive and mitigative strategies for sustaining immune health to enable safe and effective space exploration and habitation of distant worlds.
    DOI:  https://doi.org/10.1038/s41577-025-01226-6
  50. J Exp Clin Cancer Res. 2025 Oct 17. 44(1): 292
    NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy.
    Mohammed Moustapha Anwar, Salvador Meseguer, Néstor García-Rodríguez, Ewa Krupinska, Céleste Sele, Aida Rodríguez-Jiménez, Suraj Verma, Samna Sagadevan, Javier Ramon, Ramon Martí, Annalisa Occhipinti, Claudio Angione, Paloma Ordóñez-Morán, Wolfgang Knecht, Pablo Huertas, M Angeles Juanes.
      Human dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in pyrimidine de novo synthesis and represents a promising target for cancer therapy. However, current inhibitors of DHODH have limited clinical effectiveness and adverse effects. Herein, we report NK-A 17E-233I, a novel small-molecule inhibitor of the human DHODH enzyme, identified through a prospective virtual screening methodology. Molecular docking and biochemical assays show NK-A 17E-233I functions as a pure or partial competitive inhibitor with respect to the natural substrate, dihydroorotate (DHO). It adopts a distinct binding mode from classical inhibitors that target the flavin mononucleotide (FMN) binding cavity of the hydrophobic tunnel. NK-A 17E-233I exhibits selective cytotoxicity in both human cancer cell lines and patient-derived intestinal organoids, inducing DNA damage, S-phase arrest, and cell death. Unlike Brequinar, NK-A 17E-233I preserves mitochondrial respiration via complexes I and II and maintains ATP-linked basal respiration, avoiding the impairment of the electron transport chain (ETC). Our findings imply the aptitude of NK-A 17E-233I as a novel competitive inhibitor of human DHODH, representing a significant advancement in this field since the 1990s.
    Keywords:  Cancer; DHODH; NK-A 17E-233I; Pyrimidine de novo synthesis
    DOI:  https://doi.org/10.1186/s13046-025-03538-w
  51. Nat Commun. 2025 Oct 16. 16(1): 9194
    Genetic determinants and genomic consequences of non-leukemogenic somatic point mutations.
    Joshua S Weinstock, Sharjeel A Chaudhry, Maria Ioannou, Maria Viskadourou, Paula Reventun, Yasminka A Jakubek, L Alexander Liggett, Cecelia Laurie, Jai G Broome, Alyna Khan, Kent D Taylor, Xiuqing Guo, Patricia A Peyser, Eric Boerwinkle, Nathalie Chami, Eimear E Kenny, Ruth J Loos, Bruce M Psaty, Russell P Tracy, Jennifer A Brody, Jeong H Yun, Michael H Cho, Ramachandran S Vasan, Sharon L Kardia, Jennifer A Smith, Laura M Raffield, Aurelian Bidulescu, Emily C O'Brien, Mariza de Andrade, Jerome I Rotter, Stephen S Rich, Russell P Tracy, Yii Der Ida Chen, C Charles Gu, Chao A Hsiung, Charles Kooperberg, Bernhard Haring, Rami Nassir, Rasika Mathias, Alex Reiner, Vijay G Sankaran, Charles J Lowenstein, Thomas W Blackwell, Goncalo R Abecasis, Albert V Smith, Hyun M Kang, Pradeep Natarajan, Siddhartha Jaiswal, Alexander Bick, Wendy S Post, Paul Scheet, Paul Auer, Theodoros Karantanos, Alexis Battle, Marios Arvanitis.
      Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as leukemogenic point mutations or mosaic chromosomal alterations (mCAs), are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we use 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantify CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we develop a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We perform a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. We identify seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1).Functional analyses of SMC4 and NRIP1 implicated altered hematopoietic stem cell self-renewal and proliferation as the primary mediator of mutation burden in blood. We then perform comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we perform phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.
    DOI:  https://doi.org/10.1038/s41467-025-64236-x
  52. J Inflamm (Lond). 2025 Oct 14. 22(1): 45
    Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function.
    M Jedlička, T Feglarová, V Švubová, E Mašínová, V Graman, K Kuglerová, J Szabová, F Jahan, M Korhonen, K Kuželová, M Hortová-Kohoutková, J Frič.
       BACKGROUND: Natural killer (NK) cells are responsible for monitoring and eliminating malignant or virus-infected cells. To become activated, NK cells must upregulate oxidative phosphorylation and glycolysis to meet the high energetic demands associated with cytotoxic and effector functions. While glutamine can also fuel the tricarboxylic acid cycle through its conversion to alpha-ketoglutarate, the precise role of this pathway in NK-cell cytotoxic activity is unclear.
    RESULTS: To investigate NK-cell dependency on glutamine, we selectively inhibited kidney-type glutaminase to prevent glutamine metabolism. We analysed the metabolism and cytotoxicity of expanded primary NK cells, treated or not with glutaminase inhibitor. Glutaminase inhibition significantly reduced oxidative phosphorylation and led to a significant decrease in NK cell cytotoxic function. Furthermore, glutaminase inhibition reduced protein synthesis in activated NK cells. Meanwhile, supplementation with alpha-ketoglutarate rescued both the metabolic and cytotoxic capacities of primary expanded NK cells.
    CONCLUSIONS: Our findings highlight the importance of glutaminase activity in supporting NK cell respiratory metabolism and cytotoxic function, and the need for caution when combining glutaminase inhibitors with NK cell-based therapies.
    Keywords:  Alpha-ketoglutarate; Cell cytotoxicity; Glutaminase; Immunometabolism; Natural killer cell
    DOI:  https://doi.org/10.1186/s12950-025-00470-w
  53. Cell Death Dis. 2025 Oct 16. 16(1): 724
    Increased nucleotide metabolism alleviates Alzheimer's disease pathology.
    Yizhou Yu, Michael B Miller, August Yue Huang, Bryan Wei Zhi Tan, Ivana Celardo, Nuno Santos Leal, Samantha H Y Loh, L Miguel Martins.
      Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP‒ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is linked to a lower risk of developing AD. Our results suggest that enhancing nucleotide metabolism could improve DNA repair and serve as an adjunct therapy to delay AD progression.
    DOI:  https://doi.org/10.1038/s41419-025-08066-1
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