bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–11–09
sixty papers selected by
Christian Frezza, Universität zu Köln
  1. Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
  2. Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression.
  3. Targeting FSP1 triggers ferroptosis in lung cancer.
  4. NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
  5. Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
  6. Lymph node environment drives FSP1 targetability in metastasizing melanoma.
  7. An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
  8. Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
  9. Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release.
  10. Creatine kinase B regulates glycolysis and de novo lipogenesis pathways to control lipid accumulation during adipogenesis.
  11. Epigenetically driven and early immune evasion in colorectal cancer evolution.
  12. Mitochondrial ROS sources steer neuroinflammation.
  13. Mitochondrial metabolic alterations fuel bladder cancer initiation.
  14. Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.
  15. Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.
  16. Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis.
  17. A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis.
  18. Leveraging genetic and phenotypic variation to discover metabolite-protein interactions.
  19. Secretome translation shaped by lysosomes and lunapark-marked ER junctions.
  20. Cysteine S-acetylation is a widespread post-translational modification on metabolic proteins.
  21. Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging.
  22. TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages.
  23. Functional dominance in the central dogma of tumor mitochondrial genetics.
  24. Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
  25. Open problems in ageing science: a roadmap for biogerontology.
  26. Silencing of mitochondrial gene expression using polymorpholino chimeras.
  27. Human immune aging.
  28. The origin of hepatocellular carcinoma depends on metabolic zonation.
  29. Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.
  30. Lymphoid gene expression supports neuroprotective microglia function.
  31. Size control: Tune the mitochondrial volume to time your cell division!
  32. Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome.
  33. MLH1 Mismatch Repair Deficiency Predicts Exceptional Response to Immune Checkpoint Inhibition in Clear-cell Renal Cell Carcinoma.
  34. Connectogenomics: edges-first spatial biology.
  35. Cell populations in human breast cancers are molecularly and biologically distinct with age.
  36. Cystine import and oxidative catabolism fuel vascular growth and repair via nutrient-responsive histone acetylation.
  37. Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.
  38. Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.
  39. The Aging Microenvironment is a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.
  40. Restoration of cGAS in cancer cells promotes antitumor immunity via transfer of cancer cell-generated cGAMP.
  41. Elevated cellular accumulation of endogenous and exogenous CoQ by altered intracellular trafficking.
  42. Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
  43. Gut-to-brain signaling restricts dietary protein intake during recovery from catabolic states.
  44. An atlas of mitochondrial ATP synthase activity across the lifespan.
  45. Myeloid metabolism and its role in immunotherapy of cancer.
  46. Epistemology of the Origin of Cancer III: Fundamentals of How Metastasis Arises.
  47. Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
  48. Interactome quantitation reveals non-energetic mitochondrial roles in cell type specialization in murine kidney.
  49. Glutamine metabolism drives B cell proliferation under elevated atmospheric pressure.
  50. Cellular senescence in precancer lesions and early-stage cancers.
  51. Regulation of therapeutic protein release in response to circadian biomarkers.
  52. Myeloid cells mediate interferon-driven resistance to immunotherapy in advanced renal cell carcinoma.
  53. Understanding and targeting erythroid cell metabolism.
  54. Predicting metabolic preferences through transcriptomics: a data-driven approach to align metabolic signatures with gene expression profiles.
  55. Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.
  56. Dietary fat disrupts a commensal-host lipid network that promotes metabolic health.
  57. Defining Microbiota-Derived Metabolite Butyrate as a Senomorphic: Therapeutic Potential in the Age-Related T Cell Senescence.
  58. KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC.
  59. A unified framework for systematic curation and evaluation of aging biomarkers.
  60. Cytochrome c Oxidase Subunit 5A (COX5A) Enhances Gastric Cancer Progression by Augmenting ATP Synthesis and Activating the PI3K/Akt Pathway.
  1. Nat Genet. 2025 Nov 03.
    Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
    Sonia Boscenco, Jacqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Tricia Park, Flora McNulty, Sergio Lilla, Sara Zanivan, Alejandro Huerta-Uribe, Benan Nalbant, Mark Zucker, David Sumpton, Geoffray Monteuuis, Christopher B Jackson, Wei Wei, Patrick F Chinnery, Ronan Chaligne, Caleb A Lareau, Ed Reznik, Payam A Gammage.
      The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.
    DOI:  https://doi.org/10.1038/s41588-025-02374-0
  2. Nat Aging. 2025 Nov 04.
    Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression.
    Emily G Shuldiner, Saswati Karmakar, Min K Tsai, Jess D Hebert, Yuning J Tang, Laura Andrejka, Maggie R Robertson, Minwei Wang, Colin R Detrick, Hongchen Cai, Rui Tang, Christian A Kunder, David M Feldser, Dmitri A Petrov, Monte M Winslow.
      Most cancers are diagnosed in people over 60 years of age, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation (widely understood to contribute to cancer risk) it is associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses oncogenic KRAS-driven tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K-AKT pathway, weakened disproportionately. Single-cell transcriptomic analysis revealed that neoplastic cells in aged mice retain age-related transcriptomic changes, showing that the impact of age persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings underscore the interconnectedness of the pathways involved in aging and tumorigenesis and document tumor-suppressive effects of aging that may contribute to the deceleration in cancer incidence with age.
    DOI:  https://doi.org/10.1038/s43587-025-00986-z
  3. Nature. 2025 Nov 05.
    Targeting FSP1 triggers ferroptosis in lung cancer.
    Katherine Wu, Alec J Vaughan, Jozef P Bossowski, Yuan Hao, Aikaterini Ziogou, Seon Min Kim, Tae Ha Kim, Mari N Nakamura, Ray Pillai, Mariana Mancini, Sahith Rajalingam, Mingqi Han, Toshitaka Nakamura, Lidong Wang, Suckwoo Chung, Diane Simeone, David Shackelford, Yun Pyo Kang, Marcus Conrad, Thales Papagiannakopoulos.
      Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation1-3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and can be leveraged therapeutically remains unknown4,5. Here, using genetically engineered mouse models of lung adenocarcinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppressors, GPX46,7 and ferroptosis suppressor protein 1 (FSP1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumours are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout tumours had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary or pharmacological approaches effectively restored the growth of Fsp1-knockout tumours in vivo. Unlike GPX4, expression of FSP1 (also known as AIFM2) was prognostic for disease progression and poorer survival in patients with lung adenocarcinoma, highlighting its potential as a viable therapeutic target. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy for patients with lung cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09710-8
  4. Science. 2025 Nov 06. eadx9717
    NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
    Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Zhifang Lu, Tao Dai, Jui-Chung Chiang, Feng Cai, Imani M Williams, Eliot B Blatt, Zengfu Shang, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Limei Zhang, Ralph J DeBerardinis.
      Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that are incompletely understood. We identified Nudix hydrolase 5 (NUDT5) as a DNPB regulator. During purine salvage, NUDT5 suppresses DNPB independently of its catalytic function but through interaction with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in the DNPB pathway. The NUDT5-PPAT interaction promoted PPAT oligomerization, suppressed PPAT's enzymatic activity, and facilitated disassembly of the purinosome, a metabolon that functions in DNPB. Disrupting the NUDT5-PPAT interaction overcame DNPB suppression during purine salvage, permitting excessive DNPB and inducing thiopurine resistance. Therefore, NUDT5 governs the balance between DNPB and salvage to maintain appropriate cellular purine nucleotide concentrations.
    DOI:  https://doi.org/10.1126/science.adx9717
  5. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]
    Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
    Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.
      Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.
    Keywords:  aging; metabolism; mitochondria; mitoribosome; translation activity
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.012
  6. Nature. 2025 Nov 05.
    Lymph node environment drives FSP1 targetability in metastasizing melanoma.
    Mario Palma, Milena Chaufan, Cort B Breuer, Sebastian Müller, Marie Sabatier, Cameron S Fraser, Krystina J Szylo, Mahsa Yavari, Alanis Carmona, Mayher Kaur, Luiza Martins Nascentes Melo, Feyza Cansiz, June Monge-Lorenzo, Midori Flores, Eikan Mishima, Toshitaka Nakamura, Bettina Proneth, Marcos Labrado, Yanshan Liang, Nicole Cayting, Lan Zheng, Tatiana Cañeque, Ludovic Colombeau, Adam Wahida, José Pedro Friedmann Angeli, Alpaslan Tasdogan, Sheng Hui, Raphaël Rodriguez, Marcus Conrad, Nathan E Reticker-Flynn, Jessalyn M Ubellacker.
      Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers1. However, which ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in cancer remains unclear. In melanoma, glutathione peroxidase 4 (GPX4) impedes ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis2. Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate-cysteine ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts. This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation. In response, lymph node metastatic cells acquire increased reliance on ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes. These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency. Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1. Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression.
    DOI:  https://doi.org/10.1038/s41586-025-09709-1
  7. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00858-5. [Epub ahead of print]85(21): 3893-3894
    An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
    Zachary L Sebo, Navdeep S Chandel.
      Solute carrier (SLC) genes encode the largest membrane transporter superfamily, with many orphan members of unknown function. In recent Cell Metabolism and Molecular Cell articles, Khan et al. and Dias et al. identify SLC25A45 as essential for mitochondrial import of methylated amino acids and subsequent carnitine synthesis.
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.017
  8. Nat Metab. 2025 Nov 04.
    Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
    Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo, Li Gan, Edward T Chouchani, Anna G Orr, Adam L Orr.
      Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s42255-025-01390-y
  9. J Clin Invest. 2025 Nov 03. pii: e181299. [Epub ahead of print]135(21):
    Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release.
    Chun-Yu Fu, Joshua B Kohl, Filip Liebsch, Davide D'Andrea, Tamás Ditrói, Seiryo Ogata, Franziska Neuser, Max Mai, Anna T Mellis, Emilia Kouroussis, Masanobu Morita, Titus Gehling, José Angel Santamaria-Araujo, Sin Yuin Yeo, Heike Endepols, Michaela Křížková, Viktor Kozich, Marcus Krueger, Julia B Hennermann, Uladzimir Barayeu, Takaaki Akaike, Peter Nagy, Milos Filipovic, Guenter Schwarz.
      Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.
    Keywords:  Amino acid metabolism; Clinical Research; Metabolism; Mitochondria; Neurodegeneration
    DOI:  https://doi.org/10.1172/JCI181299
  10. Cell Rep. 2025 Nov 05. pii: S2211-1247(25)01260-4. [Epub ahead of print]44(11): 116489
    Creatine kinase B regulates glycolysis and de novo lipogenesis pathways to control lipid accumulation during adipogenesis.
    Gianluca Renzi, Romane Higos, Ivan Vlassakev, Abdoul Akim Bello, Muhmmad Omar-Hmeadi, Mattias Hansen, Fatiha Merabtene, Christine Rouault, Ondrej Hodek, Lucas Massier, Bruno Antonny, Geneviève Marcelin, Janane F Rahbani, Simon Lecoutre, Salwan Maqdasy.
      White adipocyte differentiation or adipogenesis requires coordination of metabolic sensing and transcriptional modifications to orchestrate lipid storage. Creatine and its kinases are implicated in adipose energy buffering, but the roles of cytosolic (CKB) and mitochondrial (CKMT2) creatine kinases in adipogenesis are unclear. We find that both CKB and CKMT2 are progressively upregulated during differentiation. Functional studies show that CKB restrains de novo lipogenesis (DNL) by limiting activation of carbohydrate-responsive element-binding protein (ChREBP), a key regulator of lipogenic genes. Mechanistically, CKB interacts with AKT and regulates its activation in response to insulin. Loss of CKB causes persistent AKT-mTORC1 signaling, increases glycolytic flux, and enhances ChREBP activation, thereby promoting glucose-derived lipid synthesis. Thus, CKB acts as a metabolic rheostat linking creatine-kinase activity to insulin signaling and nutrient-responsive transcription. We propose a CKB-AKT-ChREBP regulatory axis that contributes to metabolic remodeling and lipid homeostasis during adipocyte differentiation.
    Keywords:  AKT-mTORC; CKB; CP: metabolism; ChREBP; adipogenesis; creatine kinase; de novo lipogenesis; white adipocyte
    DOI:  https://doi.org/10.1016/j.celrep.2025.116489
  11. Nat Genet. 2025 Nov 05.
    Epigenetically driven and early immune evasion in colorectal cancer evolution.
    Eszter Lakatos, Vinaya Gunasri, Luis Zapata, Jacob Househam, Timon Heide, Nicholas Trahearn, Ottilie Swinyard, Luis Cisneros, Claire Lynn, Maximilian Mossner, Chris Kimberley, Inmaculada Spiteri, George D Cresswell, Gerard Llibre-Palomar, Miriam Mitchison, Carlo C Maley, Marnix Jansen, Manuel Rodriguez-Justo, John Bridgewater, Ann-Marie Baker, Andrea Sottoriva, Trevor A Graham.
      Immune system control is a principal hurdle in cancer evolution. The temporal dynamics of immune evasion remain incompletely characterized, and how immune-mediated selection interrelates with epigenome alteration is unclear. Here we infer the genome- and epigenome-driven evolutionary dynamics of tumor-immune coevolution within primary colorectal cancers (CRCs). We utilize a multiregion multiomic dataset of matched genome, transcriptome and chromatin accessibility profiling from 495 single glands (from 29 CRCs) supplemented with high-resolution spatially resolved neoantigen sequencing data and multiplexed imaging of the tumor microenvironment from 82 microbiopsies within 11 CRCs. Somatic chromatin accessibility alterations contribute to accessibility loss of antigen-presenting genes and silencing of neoantigens. Immune escape and exclusion occur at the outset of CRC formation, and later intratumoral differences in immuno-editing are negligible or exclusive to sites of invasion. Collectively, immune evasion in CRC follows a 'Big Bang' evolutionary pattern, whereby it is acquired close to transformation and defines subsequent cancer-immune evolution.
    DOI:  https://doi.org/10.1038/s41588-025-02349-1
  12. Nat Metab. 2025 Nov 04.
    Mitochondrial ROS sources steer neuroinflammation.
    Huajun Pan, Fei Yin.
      
    DOI:  https://doi.org/10.1038/s42255-025-01391-x
  13. Nat Rev Urol. 2025 Nov 04.
    Mitochondrial metabolic alterations fuel bladder cancer initiation.
    Maria Chiara Masone.
      
    DOI:  https://doi.org/10.1038/s41585-025-01110-x
  14. Nat Commun. 2025 Nov 03. 16(1): 9484
    Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.
    Benjamin J Jenkins, Yasmin R Jenkins, Fernando M Ponce-Garcia, Chloe Moscrop, Iain A Perry, Matthew D Hitchings, Alejandro H Uribe, Federico Bernuzzi, Simon Eastham, James G Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Marta Williams, Morgan Marsden, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ian R Humphreys, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G McDonald, Gareth W Jones, James A Pearson, Emma E Vincent, Nicholas Jones.
      α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T-cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using murine models of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T-cells and delays the onset of diabetes in vivo in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-65417-4
  15. FASEB J. 2025 Nov 15. 39(21): e71215
    Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.
    Adam C Richert, Yuxun Zhang, Sivakama S Bharathi, Abigail Hernandez, Tetyana Dodatko, Joanna Bons, Kayla E Roundtree, Brandon Stauffer, Chunli Yu, Birgit Schilling, Sander M Houten, Eric S Goetzman.
      Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC11) recreate the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC11 is chain-shortened in peroxisomes to glutaryl (DC5)-CoA, which then gives rise to the GA1-like pattern of DC5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC11 chain-shortening can enter mitochondria for reactivation by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT) and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is deficient in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by ω-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.
    Keywords:  dicarboxylic acids; glutaric acidemia I; glutaryl‐coenzyme A; mitochondria; peroxisomes; succinyl‐coenzyme A
    DOI:  https://doi.org/10.1096/fj.202502381R
  16. Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01297-5. [Epub ahead of print]44(11): 116526
    Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis.
    Sumiya Dalangood, Cegui Hu, Chenwei Yuan, Xiang Li, Wen Qiao, Hanjun Li, Rongyu Zhang, Luying Li, Peng Li, Xiang Yu, Wenjin Yin, Jinsong Lu, Jun Gui.
      Cancer-associated adipocytes (CAAs) reprogram the metabolic status of the tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8+T cells in the TME remains unclear. Here, we report that CAAs undergo lipolysis, releasing free fatty acids that promote lipid peroxidation and disturb mitochondrial homeostasis in CD8+T cells, leading to their functional exhaustion. Importantly, we uncover that fibroblast growth factor 21 (FGF21) drives CAA lipolysis in an autocrine manner by upregulating adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling. FGF21 deletion in adipose tissue or ATGL inhibition impedes CAA lipolysis, mitigates lipid peroxidation, normalizes mitochondrial dynamics of CD8+T cells, and restores their effector function, consequently blunting tumor growth. Moreover, FGF21 deficiency or ATGL inhibition enhances the anti-tumor activity of CD8+T cells in response to anti-PD-1 treatment, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipolysis in CD8+T cell dysfunction within the TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.
    Keywords:  ATGL; CD8(+)T; CP: cancer; CP: immunology; FGF21; T cell exhaustion; cancer-associated adipocytes; lipolysis; tumor immunity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116526
  17. Science. 2025 Nov 06. eadv4257
    A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis.
    Tuan-Anh Nguyen, Jung-Ming G Lin, Anne-Sophie M C Marques, Maximilian Fottner, Ludwig G Bauer, Andreas Reicher, Diana Daum, Lorenzo Scrofani, Yusi Liu, Carol Cheng, Luna D'Angelo L D D, Juan Sanchez, Christoph Bueschl, Nara Marella, Pisanu Buphamalai, Florian Traversi, Maša Bereš, Herwig P Moll, Marton Siklos, Jakob-Wendelin Genger, Gerald Hofstaetter, Ludovica Villanti, Monika Malik, Christoph Klimek, Kathrin Runggatscher, Bettina Guertl, Jesper S Hansen, Sarah Dobner, Olga Babosova, Tina Becirovic, Laura P M H de Rooij, Emilio Casanova, Anna Koren, D Sean Froese, David S Rosenblatt, Kristaps Klavins, Andreas Bergthaler, Jörg Menche, J Thomas Hannich, Miriam Abele, Sara Sdelci, Kathrin Lang, Kilian V M Huber, Stefan Kubicek.
      Folate metabolism is intricately linked to purine de novo synthesis through the incorporation of folate-derived one-carbon units into the purine scaffold. By investigating chemical and genetic dependencies caused by mutations in methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1), we discovered a key role for Nudix hydrolase 5 (NUDT5) in regulating purine de novo synthesis. Genetic depletion and selective chemical degradation showed that a scaffolding role, rather than NUDT5 enzymatic activity, was causing this phenotype. NUDT5 interacted with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme of purine de novo synthesis, to repress the pathway in response to increased purine abundance. Through this mechanism, loss of NUDT5 mediates resistance to purine analogs in cancer treatment and prevents adenosine toxicity in MTHFD1 deficiency.
    DOI:  https://doi.org/10.1126/science.adv4257
  18. Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00442-5. [Epub ahead of print]37(11): 2105-2106
    Leveraging genetic and phenotypic variation to discover metabolite-protein interactions.
    Gregory S Ducker, Jared Rutter.
      How metabolites regulate protein function is still poorly understood. Leveraging the power of genetic variation, Xiao et al. built a global protein-metabolite covariation dataset to reveal novel protein-metabolite regulations in mouse that led to the discovery of cysteine catabolism as an unexpected regulator of cholesterol.
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.008
  19. Nature. 2025 Nov 05.
    Secretome translation shaped by lysosomes and lunapark-marked ER junctions.
    Heejun Choi, Ya-Cheng Liao, Young J Yoon, Jonathan Grimm, Nan Wang, Luke D Lavis, Robert H Singer, Jennifer Lippincott-Schwartz.
      The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome density and translation efficiency of secretome mRNAs near lysosomes, an effect that was dependent on eIF2-mediated initiation and was reversed by the integrated stress response inhibitor ISRIB. Lysosome-associated translation was further modulated by nutrient status: amino acid deprivation enhanced lysosome-proximal translation, whereas lysosomal pH neutralization suppressed it. These findings identify a mechanism by which ER junctional proteins and lysosomal activity cooperatively pattern secretome mRNA translation, linking ER architecture and nutrient sensing to the production of secretory and membrane proteins.
    DOI:  https://doi.org/10.1038/s41586-025-09718-0
  20. NPJ Metab Health Dis. 2025 Nov 07. 3(1): 43
    Cysteine S-acetylation is a widespread post-translational modification on metabolic proteins.
    E Keith Keenan, Akshay Bareja, Yannie Lam, Paul A Grimsrud, Matthew D Hirschey.
      Protein acetylation is a fundamental regulatory mechanism occurring primarily on lysine amino acids. Here we report systematic in vivo characterization of cysteine S-acetylation as a widespread post-translational modification in mammalian tissues. By developing specialized sample preparation methods that preserve the labile thioester bond, we identified over 400 sites of cysteine acetylation in mouse liver, mirroring the abundance of lysine acetylation. Proteomic surveys across nine murine tissues revealed tissue-specific acetylation patterns that are enriched on metabolic enzymes in the cytoplasm. Cold exposure in mice triggers coordinated remodeling of the brown adipose tissue cysteine acetylome. Functional studies demonstrate that the acetylation of GAPDH Cys150 abolishes catalytic activity and correlates with nuclear enrichment, paralleling the known effects of S-nitrosylation on this enzyme. These findings establish cysteine acetylation as a widespread modification of metabolic proteins that responds to changes in cellular acetyl-CoA availability, fundamentally expanding the landscape of protein acetylation beyond lysine.
    DOI:  https://doi.org/10.1038/s44324-025-00081-2
  21. Nat Commun. 2025 Nov 03. 16(1): 9667
    Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging.
    Dan Wu, Bo Tan, Zijie Cheng, Haoqi Li, Huimin Li, Yun Yin, Fenfen Ma, Tao Chen, Xin Dong, Wang Wang, Qingxun Hu.
      Reduced nicotinamide adenine dinucleotide phosphate (NADPH) metabolism is independently regulated in different compartments in endothelial cells (EC). The metabolic profile and functional impact of NADPH during EC senescence remain largely unknown. Using a genetically encoded fluorescent indicator, we find that cytosolic, but not mitochondrial, NADPH level increases during EC senescence. Upregulation of glucose-6-phosphate dehydrogenase (G6PD) further elevates cytosolic NADPH level during EC senescence. Suppression of G6PD S-nitrosylation at C385 potentiates G6PD activity. G6PD overexpression alleviates, while its knockdown aggravates, vascular aging. NADPH is indispensable for G6PD to protect against vascular aging through increasing reduced glutathione and inhibiting HDAC3 activity. Among 1419 FDA-approved drugs, folic acid, catalyzed by methylenetetrahydrofolate dehydrogenase to generate NADPH, effectively alleviates vascular aging in angiotensin II-infused mice and naturally aged mice. The connection between NADPH metabolism and EC senescence provides a unique angle for understanding vascular aging and an efficient target for therapy.
    DOI:  https://doi.org/10.1038/s41467-025-64652-z
  22. Nat Genet. 2025 Nov 07.
    TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages.
    Ana Henriques, Maria Salvany-Celades, Paula Nieto, Sergio Palomo-Ponce, Marta Sevillano, Xavier Hernando-Momblona, Emily Middendorp-Guerra, Montserrat Llanses Martinez, Elisabeth Marjolein Haak, Juan Nieto, Ginevra Caratú, Domenica Marchese, Max Ruiz Gil, Sebastien Tosi, Theresa Suckert, Jordi Badia-Ramentol, Adrià Caballé-Mestres, Carolina Sanchez-Zarzalejo, Lidia Mateo, Daniele V F Tauriello, Antoni Riera, Elena Sancho, Camille Stephan-Otto Attolini, Alejandro Prados, Holger Heyn, Eduard Batlle.
      Transforming growth factor β (TGF-β) signaling in the tumor microenvironment predicts resistance to immune checkpoint blockade (ICB). While TGF-β inhibition enhances ICB efficacy in murine cancer models, clinical trials have yet to demonstrate benefit, underscoring the need to better understand its immunoregulatory roles across disease contexts. Using mouse models of advanced colorectal cancer and patient-derived data, we demonstrate that TGF-β impairs antitumor immunity at multiple levels in liver metastases. It acts directly on T cells to block recruitment of peripheral memory CD8+ T cells, thereby limiting the effectiveness of ICB. Concurrently, TGF-β instructs tumor-associated macrophages to suppress clonal expansion of newly arrived T cells by inducing SPP1 expression. This extracellular matrix protein promotes collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, ultimately driving ICB resistance. Our findings reveal how TGF-β coordinates immunosuppressive mechanisms across innate and adaptive immune compartments to promote metastasis, offering new avenues to improve immunotherapy in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41588-025-02380-2
  23. Nat Genet. 2025 Nov 03.
    Functional dominance in the central dogma of tumor mitochondrial genetics.
      
    DOI:  https://doi.org/10.1038/s41588-025-02375-z
  24. Nat Commun. 2025 Nov 04. 16(1): 9664
    Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
    Berwini B Endaya, Lukáš Kučera, Dan-Diem Thi Le, Jessica B Spinelli, Andrea Brožková, Dominika Luptáková, Kryštof Klíma, Gabriela L Oliveira, Petra Brisudová, Klára Boháčová, Štěpána Boukalová, Renata Zobalová, František Kolář, Karel Chalupsky, Klára Dohnalová, Arash Yarmohammadi-Barzegar, Šárka Dvořáková, Evgeniya Biryukova, Marta Kaliaeva, Vladimír Havlíček, Radislav Sedláček, Jan Procházka, Libor Vítek, Sunghyouk Park, Pavel Martásek, Zdeněk Krška, Paulo J Oliveira, Michael V Berridge, Jiří Neužil.
      Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.
    DOI:  https://doi.org/10.1038/s41467-025-65451-2
  25. Geroscience. 2025 Nov 08.
    Open problems in ageing science: a roadmap for biogerontology.
    Angelo Talay, Aleksey V Belikov, Paul Ka Po To, Hamid H Alfatemi, Uri Alon, Joris Deelen, Collin Y Ewald, David Gems, Vera Gorbunova, Jan Gruber, Sara Hägg, John Hemming, Steve Horvath, Alaattin Kaya, Caitlin J Lewis, Andrea B Maier, Maria B Marinova, Graham Pawelec, Shahaf Peleg, Suresh Rattan, Morten Scheibye-Knudsen, Tomas Schmauck-Medina, Vardan Saroyan, Andrei Seluanov, Alexandra Stolzing, Emma Teeling, Robert W Williams, Todd White, Maximilian Unfried, João Pedro de Magalhães.
      The field of ageing science has gone through remarkable progress in recent decades, yet many fundamental questions remain unanswered or unexplored. Here we present a curated list of 100 open problems in ageing and longevity science. These questions were collected through community engagement and further analysed using Natural Language Processing to assess their prevalence in the literature and to identify both well-established and emerging research gaps. The final list is categorised into different topics, including molecular and cellular mechanisms of ageing, comparative biology and the use of model organisms, biomarkers and the development of therapeutic interventions. Both long-standing questions and more recent and specific questions are featured. Our comprehensive compilation is available to the biogerontology community on our website ( www.longevityknowledge.app ). Overall, this work highlights current key research questions in ageing biology and offers a roadmap for fostering future progress in biogerontology.
    Keywords:  Ageing and longevity science; Biogerontology; Biology of ageing; Database; Natural language processing
    DOI:  https://doi.org/10.1007/s11357-025-01964-4
  26. Nat Rev Mol Cell Biol. 2025 Nov 03.
    Silencing of mitochondrial gene expression using polymorpholino chimeras.
    Drishan Dahal.
      
    DOI:  https://doi.org/10.1038/s41580-025-00923-3
  27. Immunity. 2025 Oct 31. pii: S1074-7613(25)00464-9. [Epub ahead of print]
    Human immune aging.
    Marina Terekhova, Pavla Bohacova, Maxim N Artyomov.
      Aging is an essential aspect of human life, and studying its mechanisms is crucial for extending lifespan and improving quality of life. The immune system plays a central role in the onset of age-related diseases. Understanding the differences between healthy and dysfunctional aging provides key insights into the fundamental immune alternations that occur prior to the point where the system begins to fail. In this review, we explore current perspectives on human immune aging. We focus on changes in the composition of, and consequential functional effects within, the major immune compartments in both circulation and tissues. We discuss earlier findings obtained through flow cytometry, alongside more recent studies utilizing single-cell and advanced cytometry techniques. We highlight here how these methods complement each other and explore potential sources of discrepancies. Finally, we address the challenges that persist in the field of human immune aging.
    Keywords:  adaptive immunity; flow cytometry; human aging; immune repertoire; innate immune cells; single cell
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.009
  28. Science. 2025 Nov 06. eadv7129
    The origin of hepatocellular carcinoma depends on metabolic zonation.
    Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Eric Chen, Lin Li, Jingjing Wang, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J Siegwart, Stephen S Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu.
      The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. While the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown if cancers arise from some zones but not others, and if there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 and Arid2 mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The zone 3 genes Gstm2 and Gstm3 were required for efficient HCC initiation, in part through inhibition of ferroptosis. In the liver, the zonal determinants of HCC development can reveal metabolic vulnerabilities of cancer.
    DOI:  https://doi.org/10.1126/science.adv7129
  29. J Biol Chem. 2025 Nov 04. pii: S0021-9258(25)02735-8. [Epub ahead of print] 110883
    Cyclophilin D is a new non-canonical substrate of the mitochondrial intermembrane space assembly pathway.
    Mara Equisoain Redin, Veronica Bazzani, Eve Harding, Joshua McHale, Carlo Vascotto.
      Mitochondrial protein import is essential for organelle function and cellular homeostasis. While Cyclophilin D (CypD) is a well-characterized regulator of the mitochondrial permeability transition pore (MPTP) and resides in the matrix, the mechanisms underlying its import remain poorly defined. In this study, we identify CypD as a novel non-canonical substrate of the mitochondrial intermembrane space assembly (MIA) pathway mediated by the oxidoreductase Mia40. Structural analysis revealed conserved cysteine pairs in CypD that are compatible with disulfide bond formation. Using in vitro pull-down assays, we demonstrate a redox-sensitive interaction between CypD and Mia40, which was further confirmed by co-immunoprecipitation and proximity ligation assays. Expression of CypD cysteine mutants in cells revealed that residues Cys82 and Cys203 are critical for Mia40-dependent interaction and protein stability. Notably, expression of the Cys203Ala mutant significantly reduced cell viability, suggesting a key functional role for this residue. Functional experiments showed that depletion of Mia40 leads to a significant reduction in mitochondrial CypD levels, a result that was confirmed in a series of leukemia cell lines with variable Mia40 expression. Our results shed light on a previously unrecognized import mechanism for CypD and expand the known substrate repertoire of Mia40, demonstrating that the MIA pathway also contributes to the import of mitochondrial matrix proteins. This work highlights the functional versatility of the MIA pathway beyond the intermembrane space and reveals an additional regulatory level in mitochondrial proteostasis with implications for cell death signalling and mitochondrial pathophysiology.
    Keywords:  Cyclophilin D; Mia40; mitochondria; protein import; redox
    DOI:  https://doi.org/10.1016/j.jbc.2025.110883
  30. Nature. 2025 Nov 05.
    Lymphoid gene expression supports neuroprotective microglia function.
    Pinar Ayata, Jessica M Crowley, Matthew F Challman, Vinaya Sahasrabuddhe, Maud Gratuze, Sebastian Werneburg, Diogo Ribeiro, Emma C Hays, Violeta Durán-Laforet, Travis E Faust, Philip Hwang, Francisco Mendes Lopes, Chrysa Nikopoulou, Sarah Buchholz, Robert E Murphy, Taoyu Mei, Anna A Pimenova, Carmen Romero-Molina, Francesca Garretti, Tulsi A Patel, Claudia De Sanctis, Angie V Ramirez Jimenez, Megan Crow, Felix D Weiss, Jason D Ulrich, Edoardo Marcora, John W Murray, Felix Meissner, Andreas Beyer, Dan Hasson, John F Crary, Dorothy P Schafer, David M Holtzman, Alison M Goate, Alexander Tarakhovsky, Anne Schaefer.
      Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.
    DOI:  https://doi.org/10.1038/s41586-025-09662-z
  31. Curr Biol. 2025 Nov 03. pii: S0960-9822(25)01254-0. [Epub ahead of print]35(21): R1053-R1055
    Size control: Tune the mitochondrial volume to time your cell division!
    Mikael Björklund.
      A new study links mitochondrial volume control with growth and cell division, suggesting that cells not only sense their mitochondrial content but also use this information to decide when to divide.
    DOI:  https://doi.org/10.1016/j.cub.2025.09.054
  32. Nature. 2025 Nov 03.
    Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome.
    Varun K Narendra, Tandrila Das, Linsey J Wierciszewski, Rebecca J Londoner, Joshua K Morrison, Pia Martindale, Tessa Devine, Kevin Chen, Michael Trombetta, Yuzuka Kanno, Alejandro E Casiano, Elisa de Stanchina, Caleb A Lareau, Scott W Lowe, Alexander D Gitlin.
      Somatically acquired mutations in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) were recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic)1. UBA1 mutations in VEXAS lead to clonal expansion within the HSPC and myeloid, but not lymphoid, compartments. Despite its severity and prevalence, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and hematologic disease are unknown. Here, we employ somatic gene editing approaches to model VEXAS-associated UBA1 mutations in primary macrophages and HSPCs. Uba1-mutant macrophages exposed to inflammatory stimuli underwent aberrant apoptotic and necroptotic cell death mediated by Caspase-8 and RIPK3-MLKL, respectively. Accordingly, in mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation in a RIPK3-Caspase-8-dependent manner. In contrast, Uba1 mutation in HSPCs induced an unfolded protein response and myeloid bias independently of RIPK3-Caspase-8. Mechanistically, aberrant cell death of Uba1-mutant macrophages coincided with a kinetic defect in Lys63/Met1 (i.e., linear) polyubiquitylation of inflammatory signaling complexes. Collectively, our results link VEXAS pathogenesis with that of rarer monogenic autoinflammatory syndromes; highlight specific ubiquitin-associated defects stemming from an apical mutation in the ubiquitylation cascade; and support therapeutic targeting of the inflammatory cell death axis in VEXAS.
    DOI:  https://doi.org/10.1038/s41586-025-09815-0
  33. Eur Urol. 2025 Nov 04. pii: S0302-2838(25)04721-9. [Epub ahead of print]
    MLH1 Mismatch Repair Deficiency Predicts Exceptional Response to Immune Checkpoint Inhibition in Clear-cell Renal Cell Carcinoma.
    Mark T Dawidek, Lina Posada Calderon, Parantu K Shah, Rohan Mittal, Burcin Agridag Ucpinar, Ziad Bakouny, Kevin Meli, Eddy Saad, Renée-Maria Saliby, H Jun Woo, Yash S Khandwala, Marc Eid, Chris Labaki, Marc Machaalani, Jonathan Coleman, Paul Russo, Ritesh R Kotecha, Maria I Carlo, Oguz Akin, David A Braun, Toni K Choueiri, Ed Reznik, Ying-Bei Chen, Robert J Motzer, Martin H Voss, A Ari Hakimi.
      Immune checkpoint inhibition can result in deep and durable responses in clear-cell renal cell carcinoma (ccRCC), yet no biomarkers currently guide management. While mismatch repair (MMR) deficiency is an established predictive biomarker for immunotherapy response in other malignancies, this has not been evaluated in ccRCC, despite the proximity of MMR gene MLH1 to VHL on chromosome 3p. Through genomic and immunohistochemical analyses across multiple cohorts, we identify somatic MLH1 deficiency as a relatively rare but robust predictor of exceptional immunotherapy response in ccRCC.
    Keywords:  Biomarkers; Immunotherapy; Renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.eururo.2025.09.4162
  34. Trends Biotechnol. 2025 Nov 06. pii: S0167-7799(25)00419-6. [Epub ahead of print]
    Connectogenomics: edges-first spatial biology.
    Reem Yasser, Mingrui Yu, Nianchao Qian, Han Chang, Joshua A Weinstein.
      Spatial omics maps cell types and spatial context together. Current methods fall into two streams: mapping coordinates (where things are) and measuring connections between cells that are in contact or close proximity. We introduce the term connectogenomics as a practical umbrella for sequencing assays that directly record such contacts as a network. Combining coordinates with measured contacts lets us verify whether apparent neighbors truly interact and turn network features - such as contact density or hub centrality - into quantitative readouts. We propose a framework with four complementary tiers and a feedback loop: directly measured molecular contacts can validate coordinate-based analyses, while coordinate maps guide where to prioritize contact measurements. We illustrate this approach in cancer immunotherapy, development, and pooled genetic screens.
    Keywords:  connectogenomics; graph theory; spatial omics; systems biology; tissue microenvironment
    DOI:  https://doi.org/10.1016/j.tibtech.2025.10.012
  35. Nat Aging. 2025 Nov 04.
    Cell populations in human breast cancers are molecularly and biologically distinct with age.
    Adrienne Parsons, Esther Sauras Colón, Meghana Manjunath, Hanyun Zhang, Julia Chen, Milos Spasic, Beyza Koca, Busem Binboga Kurt, Rachel A Freedman, Elizabeth A Mittendorf, Alexander Swarbrick, Peter van Galen, Sandra S McAllister.
      Aging is associated with increased breast cancer risk, and the oldest and youngest patients have worse outcomes, irrespective of subtype. It is unknown how age affects cells in the breast tumor microenvironment or how they contribute to age-related pathology. Here we discover age-associated differences in cell states in human estrogen receptor-positive and triple-negative breast cancers using analyses of existing bulk and single-cell transcriptomic data. We generate and apply an Age-Specific Program ENrichment (ASPEN) analysis pipeline, revealing age-related changes, including increased tumor cell epithelial-mesenchymal transition and cancer-associated fibroblast inflammatory responses in triple-negative breast cancer. Estrogen receptor-positive breast cancer displays increased ESR1 expression and reduced vascular and immune cell metabolism with age. Cell interactome analysis reveals candidate signaling pathways that drive age-related cell states. Spatial analyses across independent clinical cohorts support the computational findings. This work identifies potential targets for age-adapted therapeutic interventions for breast cancer.
    DOI:  https://doi.org/10.1038/s43587-025-00984-1
  36. Cell Metab. 2025 Oct 31. pii: S1550-4131(25)00437-1. [Epub ahead of print]
    Cystine import and oxidative catabolism fuel vascular growth and repair via nutrient-responsive histone acetylation.
    Maria-Kyriaki Drekolia, Janina Mettner, Daiyu Wang, Fredy Delgado Lagos, Christian Koch, Dennis Hecker, Jeanette Eresch, Yifang Mao, Marion Bähr, Dieter Weichenhan, Julio Cordero, Janina Wittig, Boran Zhang, Hanyu Cui, Xiaoming Li, James A Oo, Andreas Weigert, Mauro Siragusa, Stephan Klatt, Ingrid Fleming, Stefan Günther, Mario Looso, Ralf P Brandes, Harald F Langer, Andreas Papapetropoulos, Mahak Singhal, Marcel H Schulz, Christoph Plass, Joerg Heineke, Gergana Dobreva, Jiong Hu, Sofia-Iris Bibli.
      Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.
    Keywords:  CSE; SLC7A11; aging; cystine; epigenetics; vascular growth
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.003
  37. Nat Immunol. 2025 Nov 07.
    Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.
    Jie Ting Low, Youngjun Kim, Mai Matsushita, Ping-Chih Ho.
      Oxygen availability and fluctuation are common changes in tissues and organs undergoing infection and damage. While acute hypoxia can rapidly alter immune cell metabolism and activity, chronic hypoxia can induce long-lasting changes in immune responses via oxygen-guided adaptation in signaling cascades and epitranscriptomic programs. These adaptations are orchestrated mainly by oxygen-sensing hydroxylases and oxygen-sensing epigenetic modifiers that regulate downstream hypoxia-inducible factor pathways and epigenetic reprogramming. In this Review, we summarize how acute and chronic hypoxia influence innate immune cell function and metabolism, thereby tailoring immune cell behavior within the tissue microenvironment. We further highlight the dual roles of hypoxia in regulating innate immune cell function in different (patho)physiological contexts and evaluate therapeutic strategies that target oxygen-sensing pathways to restore immune competence and tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41590-025-02317-1
  38. FASEB Bioadv. 2025 Nov;7(11): e70071
    Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.
    Ethan Pei, Junfeng Ma.
      De novo proline synthesis is a highly conserved and essential biochemical pathway in mammals. Beyond serving as a fundamental building block for proteins, proline also plays key roles in diverse cellular functions and maintaining tissue homeostasis. Over the past decade, accumulating evidence has underscored the significance of this pathway in regulating critical cellular processes, including redox balance, cell growth, signal transduction, and the synthesis of nucleotides and proteins, as well as overall cellular metabolism. The biosynthesis of proline is tightly controlled by multiple evolutionarily conserved mechanisms to ensure proper cellular function. Importantly, disruptions in proline metabolism-particularly changes in the activity or expression of enzymes involved in its synthesis and degradation-have been implicated in the onset and progression of several diseases, notably cancer and fibrosis. In this review, we highlight recent advances in understanding the regulation of de novo proline synthesis. We also examine how dysregulation of this pathway contributes to disease development and influences therapeutic outcomes. Finally, we explore the therapeutic potential of targeting proline metabolism in disease treatment.
    Keywords:  biochemistry; de novo synthesis; metabolism; proline
    DOI:  https://doi.org/10.1096/fba.2025-00147
  39. Cancer Res. 2025 Nov 07.
    The Aging Microenvironment is a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.
    Priyanka Gupta, Rabi Murad, Li Ling, Yijuan Zhang, Karen Duong-Polk, Weiliang Huang, Marzia Scortegagna, Swetha Maganti, Cheska Marie Galapate, Cosimo Commisso.
      Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC) risk and outcomes. Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrated that organismal aging accelerates PDAC progression and metastasis. Transcriptomic and secretome profiling identified a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. Direct testing of the functional impact of stromal aging in heterochronic co-implantation models revealed that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, failed to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, this work establishes a conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, these findings raise compelling questions about the underlying molecular mechanisms and lay the foundation for future efforts to therapeutically target stromal aging in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1904
  40. Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2409556122
    Restoration of cGAS in cancer cells promotes antitumor immunity via transfer of cancer cell-generated cGAMP.
    Alexander M Cryer, Pere Dosta, Michelle Z Dion, Leonardo de la Parra Soto, Eliz Amar-Lewis, Gabriela Garcia de Leon Carmona, Alejandro Abraham Espinosa Pérez, Diego Fernando Ruiz Aguilar, Triana Huerta, Beatriz Nicolás Ruiz, Nathalie Nicole Casteele Hernandez, Yael Soria, Natalie Artzi.
      Cancer cells comprise a significant proportion of the tumor microenvironment (TME) and often have compromised expression or repression of cyclic GMP-AMP (cGAMP) synthase (cGAS), which prevents effective stimulation of interferon genes (STING) signaling. Here, we leverage the cancer cells and hijack their cellular machinery for increased production of cGAMP, differing from conventional strategies whereby synthetic STING agonists are delivered to immune cells in the TME as a bolus dose, are rapidly cleared and can cause systemic toxicity. Increasing evidence suggests that cGAMP derived from cancer cells can act on proximal immune cells, activating STING, contributing to an antitumor immune response. We used lipid nanoparticles (LNPs) to deliver mRNA coding for cGAS which catalyzes the production of cGAMP. We observed dramatic increases in extracellular and intracellular cGAMP when cancer cells were transfected with cGAS mRNA and genomic DNA, the substrate for cGAS. We confirmed that cGAS and cGAMP are functional due to activation of immune cells, through a combination of extracellular transfer and cell-cell contact mechanisms. Treatment of syngeneic murine melanoma with cGAS LNPs reduced tumor growth significantly and further benefit was observed upon combination with immune checkpoint blockade (anti-PD-1). Moreover, we found increased activation in CD8+ T cells, NK cells, macrophages, and dendritic cells in the TME post treatment with cGAS LNPs. These findings highlight how cancer cells can be used to actively contribute to their own elimination and may be a broadly applicable strategy for delivery of other reprogramming molecules to cancer cells and wider therapeutic combinations.
    Keywords:  cGAS–STING; cancer; cell–cell communication; delivery; mRNA
    DOI:  https://doi.org/10.1073/pnas.2409556122
  41. J Biol Chem. 2025 Nov 04. pii: S0021-9258(25)02730-9. [Epub ahead of print] 110878
    Elevated cellular accumulation of endogenous and exogenous CoQ by altered intracellular trafficking.
    Ying Wang, Siegfried Hekimi.
      Coenzyme Q (CoQ) is produced in the inner membrane of mitochondria, from where it is transported to other cellular membranes. Cellular CoQ levels drop when its synthesis is interrupted, indicating that it can be degraded or eliminated in some way by currently still uncharacterized mechanisms. Low cellular iron availability has been found to lower CoQ levels, at least in part by inhibiting the action of the CoQ biosynthetic enzyme COQ7. These findings prompted us to test the effect of elevated intracellular iron content on CoQ levels. In the mouse macrophage cell line RAW264.7, we found that supplementation with ferrous ions (Fe2+) boosts CoQ levels rapidly and reversibly. Iron loading also increases the cellular accumulation of exogenous CoQ10 provided in the media. N-acetyl cysteine significantly attenuates the elevation of CoQ levels by iron, suggesting that the effect of iron is mediated by a redox mechanism, although overall cellular reactive oxygen species (ROS) levels were not affected. Treating RAW264.7 cells with the ROS-generator paraquat also dramatically increases CoQ, further pointing to a redox mechanism. No effect on the abundance of several COQ proteins was observed after iron or paraquat treatment, indicating that their effect on CoQ levels is unlikely to arise from altered mitochondrial CoQ synthesis. In contrast, we observed that targeting lysosome function also affects CoQ levels, suggesting that the effects we observe relate to degradation and/or recycling. Our study suggests that targeting these mechanisms could allow for new therapeutic options to boost cellular CoQ levels in patients.
    Keywords:  CoQ; CoQ turnover; Coenzyme Q; Coenzyme Q deficiency; UQ; iron; lysosome; paraquat; ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2025.110878
  42. J Cell Sci. 2025 Nov 03. pii: jcs.263920. [Epub ahead of print]
    Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
    Sebabrata Maity, Anwesha Dutta Gupta, Izaz Monir Kamal, Rajdeep Das, Rupsha Mondal, Arpit Tyagi, Deepak Sharma, Joy Chakraborty, Saikat Chakrabarti, Oishee Chakrabarti.
      The endoplasmic reticulum (ER) and mitochondria are known to affect myriad cellular mechanisms. More recently, dynamic association between them has been identified in different eukaryotes; these interactions vary in their composition and involvement in regulation of intracellular machineries. FAM134B or RETREG1, originally identified as an oncogene, regulates ER membrane shape and curvature. It is a key ER-phagy or reticulophagy receptor, which promotes autophagy of not only the ER but also simultaneous dual autophagy of ER and mitochondria. While it is known that FAM134B can potentiate contact with mitochondria, its direct involvement in affecting mitochondrial dynamics remains unexplored. Here we show that FAM134B can interact with the canonical fission-promoting protein, DRP1. Functional depletion of FAM134B leads to local Actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in hyperfusion. A decrease in FAM134B levels is observed with aging in rat brains, cell and mouse models of Parkinson's disease and patient-derived samples. Our study establishes FAM134B as the ER partner that helps in maintaining mitochondrial morphology and dynamics.
    Keywords:  DRP1; FAM134B; Fission; Mitochondrial hyperfusion
    DOI:  https://doi.org/10.1242/jcs.263920
  43. Cell. 2025 Nov 04. pii: S0092-8674(25)01134-1. [Epub ahead of print]
    Gut-to-brain signaling restricts dietary protein intake during recovery from catabolic states.
    Nikolai P Jaschke, Joseph R Luchsinger, Zuojia Chen, Vera C Wulfmeyer, Xavier de la Rosa, Oliver Hahn, Cuiling Zhang, Nathaniel D Bachtel, Jaime L Cullen, Tilman D Rachner, Ruslan Medzhitov, Markus M Rinschen, Chuan Wu, Andrew Wang.
      Dietary needs are dynamic, with optimal ranges for nutrients varying over time and across physiological states. How optimal nutrient set points are established and why they are adjusted remains largely unknown. In our efforts to understand the physiology of recovery, we made the surprising observation that mice restrict protein intake at the expense of caloric supply. We identified three amino acids-glutamine (Q), lysine (K), and threonine (T)-within dietary protein, which are necessary and sufficient for protein aversion during recovery from catabolic states. The anorexigenic effects of QKT are driven by ammoniagenesis in the gut, sensed by enterochromaffin cells in a TRPA1-dependent fashion and transduced to brainstem neurons via serotonin signaling, inducing anorexia. We propose that this mechanism serves as a first-line defense against ammonia toxicity. In summary, we identified a set of adaptive food preferences during recovery ("recovery behavior"), with implications for understanding diseases of pathologic recovery and the development of therapeutic interventions deployed to enhance recovery.
    Keywords:  TRPA1; amino acids; ammonia; dietary protein; gut-brain axis; high protein diet; protein leverage; recovery; urea cycle
    DOI:  https://doi.org/10.1016/j.cell.2025.10.005
  44. Mol Metab. 2025 Oct 31. pii: S2212-8778(25)00185-1. [Epub ahead of print] 102278
    An atlas of mitochondrial ATP synthase activity across the lifespan.
    Muzna Saqib, Dylan C Sarver, Christy M Nguyen, Fangluo Chen, Marcus M Seldin, G William Wong.
      Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102278
  45. J Immunother Cancer. 2025 Nov 04. pii: e012127. [Epub ahead of print]13(11):
    Myeloid metabolism and its role in immunotherapy of cancer.
    Valentina Garlatti, Francesca Maria Consonni, Giulia Ballerini, Martina Incerti, Andrea Balboni, Marco Cassatella, Antonio Sica.
      The proper functioning of the immune system requires an adequate balance between myeloid and lymphoid populations. Tumor growth alters this balance, also through the dramatic expansion of immunosuppressive myeloid populations, which block specific immunity, fueling tumor growth and dissemination and limiting the effectiveness of antitumor therapies, including immunotherapy. Tumors alter the expansion and functions of myeloid cells by acting locally in the tumor microenvironment, as well as on myeloid progenitors, through the manipulation of metabolic traits that govern their functions. The understanding of these metabolic alterations and their clinical translation is expected to offer new valid therapeutic options.
    Keywords:  Immunosuppression; Immunotherapy; Macrophage; Myeloid-derived suppressor cell - MDSC; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2025-012127
  46. Cell Physiol Biochem. 2025 Nov 02. 59(6): 753-799
    Epistemology of the Origin of Cancer III: Fundamentals of How Metastasis Arises.
    Björn L D M Brücher, Ijaz S Jamall.
      Metastasis, like carcinogenesis, involves the disruption of homeostasis such that cancer cells travel from the primary tumor to distant parts of the body. Almost all cancer deaths are due to metastatic spread. The prevailing theory of metastasis is an incomplete doctrine and far from sufficient as only 0.2% of free cancer cells result in the spread of cancer. To develop reasonable and effective cancer therapies and to prevent (or reverse) carcinogenesis and metastasis, a comprehensive understanding of how both carcinogenesis and metastasis arise is necessary. Fundamental questions in cancer biology have been asked and answered over decades of research: How do most cancers develop (Epistemology of the Origin of Cancer I, 2014-2022)? Which is the first cancer cell (II, 2023)? The third basic question in cancer biology remaining to be addressed is: What are the fundamentals of how metastasis develops? The pre-cancerous niche (PCN) that forms during carcinogenesis is altered by ongoing complex signaling into a premetastatic niche 1 (PMN-1): p130(cas)/crk/DOCK180 formation is necessary for lamellipodia formation, thereby enabling cell mobility. Cancer-associated fibroblasts (CAFs) begin to release fibronectin CXCL12 and Keratin 19. PMN-1 is transformed into PMN-2 during ongoing crosstalk and transformation of anti- into pro-tumorigenic platelets, macrophages, and neutrophils. Finally, persistent signaling and immune evasion result in the conversion of PMN-2 to PMN-3 with heterogeneous cancer satellites - the term "satellite" is used herein in accordance with its original meaning (a cell or particle escorting another). PMN-3 serves as a prerequisite for intravasation, traveling, and dissemination of cancer cells away from the primary tumor. Eight heterogeneous cancer satellites, including Trojan horses (immune evasion), travel alone or in combination: (1) cancer cells and (2) CAFs migrate along the CXCL12 and fibronectin gradient; (3) cancer cells surrounded by CAFs are shielded from the immune system and travel away from the primary cancer; (4) CXCL12 and Keratin 19 coat cancer cells; (5) platelets surround cancer cells and (6) CAFs, thereby facilitating cancer spread; and (7) neutrophil extracellular traps shield cancer cells and (8) CAFs. Metastasis in epithelial cancer occurs in parallel with carcinogenesis after the pre-cancerous niche is transformed into pre-metastatic niches (PMNs), which are indispensable to the origin of metastasis. Eight heterogeneous cancer satellites, including Trojan horses responsible for immune evasion, alongside reciprocally affecting sequences, wander alone or in conjunction with other cancer cells. This elucidates why the current practice of multimodal anti-cancer cell therapy should now be seen in a new light in which the benefits depend not on direct cancer cell effects, but on indirect cytopenic effects, which have previously been regarded merely as adverse effects.
    Keywords:  Biochemistry ; Biology ; Carcinogenesis ; Metastasis ; Physiology
    DOI:  https://doi.org/10.33594/000000826
  47. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00448-9. [Epub ahead of print]
    Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
    Eleanor Minogue, Pilar Baldominos, Lauren Hsu, Marcia C Haigis, Judith Agudo.
      The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.007
  48. Mol Cell Proteomics. 2025 Nov 03. pii: S1535-9476(25)00540-7. [Epub ahead of print] 101441
    Interactome quantitation reveals non-energetic mitochondrial roles in cell type specialization in murine kidney.
    A A Bakhtina, M D Campbell, B D Sibley, M Sanchez-Contreras, A Keller, M T Sweetwyne, J E Bruce.
      Evolution of multicellular life forms has involved adaptation of organs that consist of multiple cell types, each with unique functional properties that as a collection, achieve complex organ function. Since each cell type is adapted to deliver specific functionality within the context of an organ, knowledge on functional landscapes occupied by individual cell types could improve comprehension of organ function at the molecular level. In kidney, podocytes and tubules are two cell types of the nephron, each with vastly different functional roles. Podocytes envelop the blood vessels in the glomerulus and act as filters while tubules, located downstream of the glomerulus, are responsible for reabsorption of important nutrients. Mitochondria hold a critical and well-studied role in tubules due to the high energetic requirements required to fulfill their function. In podocytes however, questions remain regarding the relevance of mitochondrial function in both normal physiology and pathology. Quantitative cross-linking mass spectrometry and proteomics together with a transgenic mitochondrial tagging strategy were used to investigate kidney cell-type specificity of mitochondria. These efforts revealed that despite similarities of podocyte and tubule mitochondrial proteomes, each contain unique features corresponding to known distinct functional roles. These include increased demand for energy production through the TCA cycle in tubules and increased detoxification demand in podocytes. Moreover, tubule and podocyte mitochondrial interactome differences revealed additional cell-type specific functional insights with alterations in betaine metabolism, lysine degradation, and other pathways not regulated through proteome abundance levels. Most importantly, these efforts illustrate that cell specific mitochondrial interactome differences within an organ can now be visualized. Therefore, this approach can generally be used to map cell-specific mitochondrial changes in disease, aging or even with therapy to better understand the roles and contributions of each cell type in normal physiology and pathology within an organ in ways not previously possible.
    DOI:  https://doi.org/10.1016/j.mcpro.2025.101441
  49. Biochem Biophys Res Commun. 2025 Oct 30. pii: S0006-291X(25)01608-0. [Epub ahead of print]790 152892
    Glutamine metabolism drives B cell proliferation under elevated atmospheric pressure.
    Ayato Maeda, Akihiro Nita, Toshiro Moroishi.
      Mechanical forces are increasingly recognized as critical regulators of immune cell function; however, the effects of static pressure on B cell biology remain poorly understood. In this study, we investigated how elevated atmospheric pressure influences B cell proliferation and metabolism. Using murine and human B cell lines cultured under normal or elevated static pressure, we found that increased pressure significantly enhances and sustains long-term B cell proliferation. Transcriptomic analysis revealed a downregulation of glycolytic pathways, corroborated by decreased glucose consumption. In contrast, glutamine consumption was elevated, indicating a metabolic shift toward glutaminolysis. Functional assays confirmed that both glutamine availability and glutaminase activity are essential for the pressure-induced proliferative response. These findings identify glutamine metabolism as a key mediator of B cell adaptation to mechanical pressure and suggest that static pressure is a previously underappreciated regulator of B cell function and immune metabolism.
    Keywords:  B cells; Glutaminase; Glutamine metabolism; Immunometabolism; Mechanical pressure; Mechanotransduction; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152892
  50. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00447-7. [Epub ahead of print]
    Cellular senescence in precancer lesions and early-stage cancers.
    TBEL Consortium
      Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.006
  51. Nat Commun. 2025 Nov 06. 16(1): 9812
    Regulation of therapeutic protein release in response to circadian biomarkers.
    Nik Franko, Shichao Li, Silvia Galvan, Zsoka Csorba, Ana Palma Teixeira, Mingqi Xie, Martin Fussenegger.
      The human circadian clock integrates external environmental changes and internal physiological signals to generate natural oscillations of secreted endocrine signals to regulate diverse biological processes. Here, we explore human receptors responsive to molecules displaying in vivo oscillatory patterns and identify melatonin receptor 1A (MTNR1A) as a promising molecular sensor to trigger transgene expression. We engineer a melatonin-inducible gene switch consisting of ectopically expressed MTNR1A linked to an amplifier module utilizing the native Gαs protein-mediated cell signaling cascade, which involves adenylyl cyclase, cAMP, protein kinase A and the cAMP-responsive transcription factor CREB, to drive transgene expression from a synthetic promoter. This system operates within the physiological melatonin concentration range, selectively responding to night-phase levels of the diurnal rhythm, while remaining unresponsive to day-phase levels. Such temporal control suggests its potential for personalized cell- and gene-based therapies requiring once-per-day dosing regimen. As proof-of-concept, we show that alginate-encapsulated engineered cells implanted in C3H/HeJ male mice can translate circadian inputs or clinically licensed MTNR1A agonists into regulated GLP-1 expression as a therapeutic output exclusively secreted during nighttime, highlighting potential as an experimental cell therapy for obesity-dependent type-2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-025-64761-9
  52. Immunity. 2025 Oct 31. pii: S1074-7613(25)00468-6. [Epub ahead of print]
    Myeloid cells mediate interferon-driven resistance to immunotherapy in advanced renal cell carcinoma.
    Kevin Bi, Soki Kashima, Sabrina Y Camp, Kevin Meli, Eddy Saad, Breanna M Titchen, Chris Labaki, Ziad Bakouny, Erica M Pimenta, Jihye Park, Erin Shannon, Jingxin Fu, Sherin Xirenayi, Jack Horst, Lotus Lum, Jeffrey J Ishizuka, Toni K Choueiri, David A Braun, Eliezer M Van Allen.
      Sustained type-I and type-II interferon (IFN) signaling can drive multiple mechanisms of resistance to immune checkpoint blockade (ICB). Here, we used single-cell RNA sequencing data to characterize the effects of IFNs in the tumor-immune microenvironment (TME) of renal cell carcinoma (RCC) and then examined how IFN-driven cellular phenotypes modulate ICB efficacy. Using mixed-effects models, we inferred the IFN inducibility of putative IFN-stimulated genes (ISGs) within cell types. Genes encoding inhibitory ligands and immune checkpoints were strongly expressed and IFN inducible in macrophages but less so in RCC tumor cells. In orthogonal clinical trial cohorts, a signature of myeloid IFNγ signaling, but not tumor IFNγ signaling, predicted primary resistance to first-line ICB plus anti-VEGF therapy. Functionally, IFNγ-conditioned macrophages inhibited T cell killing of RCC tumor cells in vitro. Our inferential modeling approach offers a framework for biomarker discovery through deconvolution of cytokine signaling effects in the TME and points to myeloid cells as mediators of tumor-extrinsic, IFN-driven resistance to immunotherapy in RCC.
    Keywords:  IFNs; cancer immunology; immunotherapy; immunotherapy resistance; interferon signaling; myeloid cells; renal cell carcinoma; tumor immunology; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.013
  53. Trends Cell Biol. 2025 Nov 03. pii: S0962-8924(25)00224-7. [Epub ahead of print]
    Understanding and targeting erythroid cell metabolism.
    Min Ni, Natalia Scaramellini, Irene Motta, Jian Xu.
      Red blood cell (RBC) production, or erythropoiesis, serves as a paradigm for studying cellular differentiation in both physiological and pathological contexts. While the transcriptional and epigenetic programs controlling erythropoiesis are well characterized, the metabolic regulation of this complex process remains underexplored. Recent discoveries that pyruvate kinase activators improve outcomes in sickle cell disease and thalassemia underscore the therapeutic potential of targeting metabolism in RBC disorders. However, further progress is limited by an incomplete understanding of the metabolic networks supporting erythropoiesis and RBC function. This review highlights emerging insights into erythroid metabolic reprogramming involving bioenergetic and biosynthetic processes, newly discovered pathways shaping the erythroid metabolome, and the promise and challenges of exploiting metabolic vulnerabilities in inherited and acquired red cell disorders.
    Keywords:  erythropoiesis; metabolism; metabolism-directed therapy; sickle cell disease; thalassemia
    DOI:  https://doi.org/10.1016/j.tcb.2025.10.001
  54. Biochem Biophys Rep. 2025 Dec;44 102302
    Predicting metabolic preferences through transcriptomics: a data-driven approach to align metabolic signatures with gene expression profiles.
    Lente J S Lerink, Marleen J de Winter, Jaap A Bakker, Ian P J Alwayn, Rutger J Ploeg, John F Mulvey, Jan H N Lindeman.
      Complex organisms such as mammals have a sophisticated metabolic network to meet energy demand under varying conditions. This network, which includes the exchange of metabolites between organs, is absent in ex vivo model systems like cell culture or isolated organ perfusion. These systems therefore require external management of metabolic substrates; since failure to meet the specific metabolic requirements will lead to cellular stress, non-physiological behaviour and in turn limited translatability, it should be ensured that model systems exhibit ex vivo metabolism that recapitulates in vivo processes. To better support but also assess tissue and cell metabolism under ex vivo conditions, it is thus crucial to be knowledgeable of their specific in vivo metabolic preferences. As in vivo organ- and cell-specific metabolic preferences are only partially characterised, a surrogate marker of metabolism is required that can easily be measured in both in vivo and ex vivo isolated organ or cell culture systems. In an attempt to identify surrogate predictive markers of metabolism that could be easily measured in ex vivo model systems, we investigated the extent to which organ-specific metabolite consumption and production patterns (referred to as "metabolic signatures") from available arteriovenous flux data align with organ-specific metabolic gene expression patterns. Whilst different tissues displayed distinctive patterns in the consumption and production of metabolites, these did not directly correspond to expression of known metabolic genes. These findings are indicative of the complexity of mammalian metabolism.
    Keywords:  Arteriovenous measurements; Metabolic flux; Metabolism; Substrate preference; Transcriptome profiles; Transcriptomics
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102302
  55. Blood. 2025 Nov 05. pii: blood.2025030209. [Epub ahead of print]
    Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.
    Gentaro Kawano, Riichiro Ikeda, Daisuke Ishihara, Takahiro Shima, Teppei Sakoda, Shunsuke Yamamoto, Yu Kochi, Yuichiro Semba, Sanae Ashitani, Yasuo Mori, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Tomoyoshi Soga, Koichi Akashi, Yoshikane Kikushige.
      Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly due to the persistence of leukemia stem cells (LSCs) capable of metabolic adaptation. While venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSCs undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. Inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSCs.
    DOI:  https://doi.org/10.1182/blood.2025030209
  56. Cell Metab. 2025 Nov 05. pii: S1550-4131(25)00441-3. [Epub ahead of print]
    Dietary fat disrupts a commensal-host lipid network that promotes metabolic health.
    Kendra Klag, Darci Ott, Trevor S Tippetts, Rebekah J Nicolson, Sean M Tatum, Kaylyn M Bauer, Emmanuel Stephen-Victor, Allison M Weis, Rickesha Bell, James Weagley, J Alan Maschek, Dai Long Vu, Stacey Heaver, Ruth Ley, Ryan O'Connell, William L Holland, Scott A Summers, W Zac Stephens, June L Round.
      The microbiota influences metabolic health; however, few specific microbial molecules and mechanisms have been identified. We isolated a Turicibacter strain from a community of spore-forming bacteria that promotes leanness in mice. Human metagenomic analysis demonstrates reduced Turicibacter abundance in individuals with obesity. Similarly, a high-fat diet reduces Turicibacter colonization, preventing its weight-suppressive effects, which can be overcome with continuous Turicibacter supplementation. Ceramides accumulate during a high-fat diet and promote weight gain. Transcriptomics and lipidomics reveal that the spore-forming community and Turicibacter suppress host ceramides. Turicibacter produces unique lipids, which are reduced during a high-fat diet. These lipids can be transferred to host epithelial cells, reduce ceramide production, and decrease fat uptake. Treatment of animals with purified Turicibacter lipids prevents obesity, demonstrating that bacterial lipids can promote host metabolic health. These data identify a lipid metabolic circuit between bacteria and host that is disrupted by diet and can be targeted therapeutically.
    Keywords:  SPT; Turicibacter; bacterial lipids; ceramides; high-fat diet; lipids; metabolism; microbiota; obesity; sphingolipids; spore-forming bacteria
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.007
  57. Aging Cell. 2025 Nov 07. e70257
    Defining Microbiota-Derived Metabolite Butyrate as a Senomorphic: Therapeutic Potential in the Age-Related T Cell Senescence.
    Nia Paddison Rees, Jessica Conway, Ben Dugan, Sayeda S Amir, Aimee Parker, Simon R Carding, Niharika A Duggal.
      Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs). Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial ROS accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB. Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.
    Keywords:  T cell; ageing; cellular senescence; inflammation
    DOI:  https://doi.org/10.1111/acel.70257
  58. Cell Death Dis. 2025 Nov 03. 16(1): 777
    KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC.
    Jun Chen, Yikang Ji, Xin Chen, Mi Zhang, Mei Zhang, Xin Hu, Xing Xu, Yu Zhang, Zhen Zhang, Xinhua Pan, Ming Yan, Jianjun Zhang, Qin Xu, Xi Yang, Wantao Chen, Xu Wang.
       ABSTACT: As a key tumor suppressor, KDM6A plays critical roles in maintaining epigenetic homeostasis and suppressing tumorigenesis. However, the regulatory mechanisms controlling KDM6A activity in head and neck squamous cell carcinoma (HNSCC) are not well defined. In this study, we employed tissue microarray analysis of clinical specimens to identify Ser829 as a predominant phosphorylation site of KDM6A in HNSCC and other solid tumors. Using mass spectrometry and biochemical assays, we demonstrate that CDK1-mediated phosphorylation at Ser829 enhances KDM6A binding to SFN, leading to its nuclear export and functional inactivation. Integrated chromatin profiling and metabolic analyses revealed that phosphorylated KDM6A-pSer829 drives glycolytic reprogramming through H3K27Me3-dependent transcriptional silencing of PER2, ultimately promoting tumor growth in vitro and in vivo. These findings establish KDM6A post-translational modification as a pivotal regulator of metabolic adaptation in HNSCC progression, providing a potential therapeutic target for combating cancer through this epigenetic-metabolic axis.
    DOI:  https://doi.org/10.1038/s41419-025-08130-w
  59. Nat Aging. 2025 Nov 04.
    A unified framework for systematic curation and evaluation of aging biomarkers.
    Kejun Ying, Seth Paulson, Alec Eames, Alexander Tyshkovskiy, Siyuan Li, Nir Eynon, Macsue Jacques, Robin Grolaux, Kirsten Seale, Erik Jacques, Ludger J E Goeminne, Andrea Cipriano, Martin Perez-Guevara, Mehrnoosh Emamifar, Maximiliano Casas Martínez, Dayoon Kwon, Anna Kosheleva, Michael Snyder, Dane Gobel, Chiara Herzog, Daniel L McCartney, Riccardo E Marioni, Jessica Lasky-Su, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev.
      Aging biomarkers are essential tools for quantifying biological aging, but systematic validation has been hindered by methodological inconsistencies and fragmented datasets. Here we show that the ability of traditional aging clocks to predict chronological age does not correlate with mortality prediction capacity (R = 0.12, P = 0.67), suggesting that these metrics capture distinct biological processes. We developed Biolearn, an open-source framework enabling standardized evaluation of 39 biomarkers across over 20,000 individuals from diverse cohorts. The Horvath skin and blood clock achieved the highest chronological age accuracy (R2 = 0.88), while GrimAge2 demonstrated the strongest mortality association (hazard ratio = 2.57) and healthspan prediction (hazard ratio = 2.00). Our systematic evaluation reveals considerable heterogeneity in biomarker performance across different clinical outcomes, with optimal biomarkers varying according to specific application. Biolearn provides unified data processing pipelines with quality control and cell-type deconvolution capabilities, establishing a foundation for reproducible aging research and facilitating development of robust aging biomarkers.
    DOI:  https://doi.org/10.1038/s43587-025-00987-y
  60. J Cell Mol Med. 2025 Nov;29(21): e70922
    Cytochrome c Oxidase Subunit 5A (COX5A) Enhances Gastric Cancer Progression by Augmenting ATP Synthesis and Activating the PI3K/Akt Pathway.
    Dongyan Li, Limin Zhou.
      Gastric cancer (GC) is a lethal malignancy characterised by poor prognosis. In this study, we identify cytochrome c oxidase subunit 5A (COX5A) as a key metabolic driver and prognostic biomarker in GC. COX5A was upregulated in tumours and correlated with poor survival. Mechanistically, COX5A enhanced mitochondrial oxidative phosphorylation to elevate ATP production, activating PI3K/Akt signalling to drive proliferation, migration, and invasion. These effects were reversed by PI3K/Akt inhibitors. JC-1 assays revealed COX5A-mediated mitochondrial membrane potential elevation, indicating amplified bioenergetic output. In vivo, COX5A silencing suppressed xenograft tumour growth. Our results demonstrate COX5A orchestrates metabolic reprogramming and PI3K/Akt-mediated progression in GC, positioning it as both a prognostic indicator and therapeutic target.
    Keywords:  ATP synthesis; COX5A; PI3K/Akt pathway; gastric cancer; mitochondrial function
    DOI:  https://doi.org/10.1111/jcmm.70922
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