bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–08–02
sixty-two papers selected by
Christian Frezza, Universität zu Köln
  1. The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
  2. Protein thiol alterations drive pathologic liquid-liquid phase separation in the aging brain.
  3. Dietary arginine drives codon-dependent MHC class I translation and improves immunity in colon tumorigenesis and respiratory viral infection.
  4. Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
  5. Transsulfuration links aspartate-asparagine metabolism and redox homeo-stasis to drive tumor growth.
  6. Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
  7. Nutrient stress activates RAB5B-mediated autophagy to remodel the synaptic proteome.
  8. Paired mutation calling and spatial transcriptomics identify cellular neighborhoods associated with the neoplastic outcome of mouse colitis.
  9. Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
  10. NAD Metabolism in Acute Myeloid Leukaemia: Biological Rationale and Therapeutic Opportunities.
  11. Sterol Flux Rewiring: Cholesterol Biosynthesis as a Dynamic Signaling Network.
  12. The glycolytic enzyme PGAM1 functions as a metabolic-autophagy checkpoint to coordinate growth and stress tolerance.
  13. Spatial metabolic heterogeneity shapes CD8+ T cell function in cancer.
  14. Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.
  15. Mitochondrial metabolism and epigenetic crosstalk drive SASP.
  16. Oxidized protein states define metastatic fitness in lung cancer.
  17. The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
  18. Epstein-Barr virus transformation creates a methionine-dependent ferroptosis vulnerability in B cells.
  19. Methionine Regulates Antitumour Function of CD8+ T Cells Through Polyamine Synthesis.
  20. Tracing NAD+ metabolism uncovers adaptive coordination between host and microbiome during colitis.
  21. A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer.
  22. CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.
  23. A spatial multi-omics atlas of immunosenescence reveals germinal-center B cell dysfunction in human lymph nodes.
  24. The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I.
  25. Translational Recoding in Tumors.
  26. Loss of LipT2 disrupts mitochondrial protein lipoylation and metabolic homeostasis in Drosophila melanogaster.
  27. Deciphering the Multiscale Morphology of Somatic Oncogenic Alterations in Hepatocellular Carcinoma.
  28. Futile cycles in metabolic flexibility: The energetic cost of regulatory precision.
  29. NAD+ depletion links metabolic stress to drive innate immune priming and selectively control PANoptosis.
  30. Distributed clonal deletion prevents autoimmune disease progression.
  31. Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ.
  32. Interplay of Epigenetic Reprogramming, Mitochondrial Metabolism, and Dopamine Signalling Pathways Uncovers Metabolic Vulnerabilities in Diffuse Midline Glioma.
  33. OTUD6A promotes de novo pyrimidine synthesis by deubiquitinating and stabilizing CAD in cervical cancer.
  34. Dendritic cell circadian clocks shape memory CD8+ T cell differentiation.
  35. Spatial control of mitochondrial retrograde signaling by nuclear pore-associated contact sites.
  36. Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
  37. Why machines don't speak biology: Toward native biological language models.
  38. Signatures of aging and disease in a single organelle.
  39. Mechanical forces stimulate Golgi export.
  40. Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.
  41. GRP75 sustains CD8+ T cell homeostasis and memory generation through ensuring mitochondrial fitness.
  42. Exchange dynamics and kinetic control of gene regulation complexes.
  43. A brief history of the hyperfunction theory of aging and future directions.
  44. Single-cell spatial mapping of human kidney development implicates the microenvironment in guiding cell fate decisions.
  45. GBP6 maintains mitochondrial bioenergetics to promote immune evasion from NK cells in cervical cancer.
  46. Double-bond geometry determines fatty acid metabolic fate and ferroptosis sensitivity.
  47. Inhibition of mitochondrial protein translation sensitizes tumor cells to death receptor 5 agonistic antibody.
  48. Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the EPAC-RAP1 signaling dependency of primary melanoma.
  49. Pannexin1 promotes cellular senescence by triggering mtDNA release to activate the cGAS-STING pathway.
  50. Decoupling AMPK from fatty acid synthesis allows maintenance of fitness late in life.
  51. Resolving the subcellular redox landscape of Coenzyme Q.
  52. Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples.
  53. Genomic, epigenomic and transcriptomic regulation of cellular senescence.
  54. Who gets told what is impossible?
  55. CXCR4 marks homeostatically activated dendritic cells in the steady state and in cancer.
  56. SpaMTP: integrative statistical analysis and visualization of spatial metabolomics and transcriptomics data.
  57. Sulfur amino acid restriction prevents S-adenosylmethionine-driven liver steatosis, hepatocellular carcinoma, and metabolic remodeling in high-fat-fed GNMT-null mice.
  58. A genome-wide CRISPR screen in human prostate cancer cells reveals drivers of macrophage-mediated cell killing and positions AR as a tumor-intrinsic immunomodulator.
  59. CellTune: an integrative software for accurate cell classification in spatial proteomics.
  60. The phase separation of ZC3H18 transcriptionally activates LDHA and forms lactylation-mediated positive feedback loop to promote tumorigenesis of lung cancer.
  61. The Drosophila CEBPG homolog Irbp18 partners with crc (ATF4) to mediate the integrated stress response in degenerative disease models.
  62. Loss of TAFAZZIN leads to perturbation of amino acid metabolism and reduction of collagen synthesis.
  1. Nat Aging. 2026 Jul 30.
    The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
    Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw, Sierra White, Danyang Li, Callen T Wallace, Frederick Keeney, Felicia Lazure, Esther Elishaev, Lauren Borho, Hope A Townsend, Robin D Dowell, Aaron Clauset, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin Liu, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Benjamin G Bitler, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.
      Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+-SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.
    DOI:  https://doi.org/10.1038/s43587-026-01172-5
  2. Nat Struct Mol Biol. 2026 Jul 30.
    Protein thiol alterations drive pathologic liquid-liquid phase separation in the aging brain.
    Thibaut Vignane, Martín Hugo, Christian Hoffmann, Polina Reichert, Antonia Katsouda, Davide D'Andrea, Han Wang, Johannes V Tromm, Marko Miler, Ferran Comas, Dunja Petrovic, Suyuan Chen, Jan Lj Miljkovic, Danail Stoychev, Erik Lacko, Vladimir M Jovanovic, Suwarna Chakraborty, Sunil J Tripathi, Edwin Vázquez-Rosa, Jordan L Morris, Suvagata Roy Chowdhury, Julien Prudent, Albert Sickmann, Natalija Polovic, Andrew A Pieper, Ilan Davis, Kostas Tokatlidis, Bindu D Paul, Michael P Murphy, Christian Münch, Andreas Papapetropoulos, Dragomir Milovanovic, Milos R Filipovic.
      Cellular homeostasis relies on regulation of processes, including protein post-translational modifications (PTMs) and biomolecular condensation. Aging disrupts the equilibrium of these processes, increasing susceptibility to disease and mortality. Here we used chemoproteomic techniques to generate an atlas of cysteine PTMs in the mouse brain and showed that age-related increases in thiol oxidation promoted the formation of biomolecular condensates. By contrast, protein persulfidation, regulated by hydrogen sulfide production, inhibited biomolecular condensation, preserving protein function. Age-induced alterations in cysteine PTMs influenced the phase separation properties of synapsin 1 and G3BP2, leading to impaired neurotransmitter release and defective stress granule formation and resolution, features associated with aging and neurodegenerative diseases. Mice deficient in cystathionine γ-lyase, the enzyme responsible for hydrogen sulfide production, exhibited reduced lifespans and spontaneously developed protein aggregates with age. Our results highlight the therapeutic potential of protein persulfidation in reversal of dysregulated biomolecular condensation and suggest that sulfide donors could be used to mitigate age-related diseases.
    DOI:  https://doi.org/10.1038/s41594-026-01857-w
  3. Cell. 2026 Jul 30. pii: S0092-8674(26)00818-4. [Epub ahead of print]
    Dietary arginine drives codon-dependent MHC class I translation and improves immunity in colon tumorigenesis and respiratory viral infection.
    Qiushuang Wu, Lara M Seydlitz, Vladislav Iakimov, Dennis J Hsu, Parham Habibzadeh, H Heinrich Hoffmann, Philip B Paty, Charles M Rice, Sohail F Tavazoie.
      Amino acid levels fluctuate across diverse pathological conditions. Whether such amino acid modulations directly shape pathophysiology by regulating host gene expression remains unknown. We found that extracellular arginine restriction, observed in cancer and infection, represses specific arginine tRNAs-directly suppressing translation of major histocompatibility complex I (MHC class I) and antigen presentation. Arginine regulation of MHC class I was codon-usage dependent, as synonymous codon mutations prevented MHC class I modulation. Dietary arginine restriction impaired anti-viral immunity against influenza and SARS-CoV-2 and increased colon tumorigenesis. Conversely, increasing arginine availability via dietary supplementation or myeloid-specific arginase 1 deletion enhanced MHC class I protein levels, suppressed colon tumorigenesis, and improved viral infection outcomes. These disease-modulating effects were abolished in β2-microglobulin (B2m)-deficient mice. Thus, dietary modulation of a single amino acid critically influences codon-biased translation and MHC class I-mediated immunity to respiratory viral infections and cancer, revealing an unexpected mechanism and disease hazard for arginine deficiency and highlighting potential for amino acid-based translation modulation therapy.
    Keywords:  COVID; MHC; MHC-I; arginine; cancer; codon; diet; influenza; tRNA; translation
    DOI:  https://doi.org/10.1016/j.cell.2026.07.020
  4. Res Sq. 2026 Jul 22. pii: rs.3.rs-10117408. [Epub ahead of print]
    Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
    Michel Thiebaut de Schotten, Cynthia Liu, Catherine Kelly, Ke Bo, Tor Wager, Eugene Mosharov, Martin Picard.
      Mitochondria power brain function and cognition, yet no label-free, non-invasive method has existed to explore their relationship to ageing, disease, and cognition in humans. The MitoBrainMap framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here we tested whether it captures meaningful age- and disease-related variation across individuals. MR-predicted mitochondrial density and tissue respiratory capacity declined with age, whereas intrinsic mitochondrial respiratory capacity was relatively preserved. Correlations among predicted features matched known mitochondrial biology, supporting preliminary construct validity. In patients with genetically confirmed mitochondrial diseases, predicted maps revealed region-specific alterations, notably the expected compensatory upregulation of nuclear- encoded complex II. Predicted features were further associated with the energetic stress marker GDF15 and with cognitive performance, linking brain mitochondrial estimates to systemic physiology and behavior. These findings introduce a first-generation, label-free neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.
    DOI:  https://doi.org/10.21203/rs.3.rs-10117408/v1
  5. bioRxiv. 2026 Jul 13. pii: 2026.07.10.737826. [Epub ahead of print]
    Transsulfuration links aspartate-asparagine metabolism and redox homeo-stasis to drive tumor growth.
    Mirko Milosevic, Kristina Dmytruk, Ahmad Alghadi, Pavel Jakoube, Julian Wong Soon, Petra Hyrossova, Muhammad Bin Munim, Sara Isabel Fernandes, Anna Shevzov-Zebrun, Robert Stanko, Isidora Mitric, Zuzana Cockova, Lukas Kucera, Juan Fernández-García, Ales Benda, Bryan Marzullo, Radislav Sedlacek, Jiri Neuzil, Sarah-Maria Fendt, Daniel A Tennant, Matthew G Vander Heiden, Katerina Rohlenova, Jakub Rohlena.
      Cytosolic redox balance is tightly coupled to aspartate synthesis through the malate-aspartate shuttle, and limiting the malate-aspartate shuttle has been proposed to constrain tumor growth by restricting aspartate availability. Here we show that tumors derived from cancer cells lacking GOT1 and GOT2, the cytosolic and mitochondrial aspartate aminotransferases essential for as-partate production and malate-aspartate shuttle function, grow despite impaired canonical as-partate synthesis. This is because cytosolic redox state, not aspartate supply, is the primary metabolic bottleneck in GOT1/GOT2 knockout cells. Using single-cell transcriptomics, metabo-lite tracing, and a loss-of-function CRISPR screen, we find that these tumors engage an adaptive bypass in which availability of asparagine, a product of aspartate, enables serine- and methio-nine-dependent transsulfuration to generate α-ketobutyrate, whose reduction regenerates cy-tosolic NAD⁺ and restores redox homeostasis. Pharmacological inhibition or genetic ablation of transsulfuration abrogates this asparagine-driven rescue. These findings define asparagine as a regulator of cytosolic NAD⁺/NADH balance and reveal a link between amino acid metabolism and redox control that suggests transsulfuration as a targetable vulnerability in tumor redox maintenance.
    Significance statement: Aspartate synthesis and cytosolic redox balance are both coupled through the malate-aspartate shuttle. We show that the cytosolic NAD⁺/NADH ratio, not aspartate supply, is a critical output of the malate-aspartate shuttle for tumor growth. Availability of asparagine, a product of aspar-tate, enables serine- and methionine-dependent transsulfuration to restore cytosolic NAD⁺/NADH balance, proliferation and tumor growth independently of canonical aspartate pro-duction by the malate-aspartate shuttle. This defines asparagine as a regulator of cytosolic re-dox and identifies transsulfuration as a targetable vulnerability in tumor redox maintenance.
    DOI:  https://doi.org/10.64898/2026.07.10.737826
  6. Science. 2026 Jul 30. 393(6810): eady0832
    Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
    Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.
      Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    DOI:  https://doi.org/10.1126/science.ady0832
  7. Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00844-2. [Epub ahead of print]45(8): 117766
    Nutrient stress activates RAB5B-mediated autophagy to remodel the synaptic proteome.
    Melina Overhoff, Lotte Ickert, Sebastian Marten, Andrew Hill, Frederik Tellkamp, Ali Chitsaz, Saskia L Ludwig, Philipp Antczak, Felix C Koehler, Roman-Ulrich Müller, Marcus Krüger, Natalia L Kononenko.
      Synaptic proteostasis is crucial for neuronal function, yet how synapses adapt to metabolic stress remains unclear. We show that nutrient stress, particularly serum withdrawal, induces autophagy-dependent remodeling of the synaptic proteome, whereas mTORC1 inhibition produces limited effects. Nutrient stress activates synaptic autophagy within 1-2 h and promotes the recruitment of the LC3 lipidation machinery via RAB5B-positive endosomal compartments in a dynein-dependent manner. Live imaging reveals enhanced RAB5B-ATG16L1 co-trafficking and increased ATG5 mobility upon serum withdrawal, indicating spatiotemporally controlled delivery of autophagy precursors to synaptic compartments. Functionally, nutrient deprivation dampens neuronal activity, while a fasting-mimicking diet induces synaptic proteome remodeling overlapping with starvation-associated autophagy cargo. In contrast, restriction of mTORC1-activating amino acids fails to induce comparable remodeling. Together, these findings identify a RAB5B-mediated trafficking pathway that links nutrient sensing to synaptic degradation, revealing how neurons maintain proteostasis under metabolic challenge.
    Keywords:  CP: metabolism; CP: neuroscience; autophagy; endosomes; nutrient stress; proteostasis; synapse; trafficking
    DOI:  https://doi.org/10.1016/j.celrep.2026.117766
  8. Nat Genet. 2026 Jul 28.
    Paired mutation calling and spatial transcriptomics identify cellular neighborhoods associated with the neoplastic outcome of mouse colitis.
    Elisa B Moutin, Linus L H Chang, Giada Giavara, Shenay Mehmed, Mathilde Colombé, Carla Boquetale, Kate Marks, Filipe C Lourenço, Nefeli Skoufou-Papoutsaki, Richard Kemp, Philippe Gascard, Thea D Tlsty, David S Tourigny, Douglas J Winton.
      In the progression from inflammatory bowel disease to associated cancer, the clonal mutational landscape shifts from selection of mutations in inflammatory genes to selection for cancer-driver mutations. How prevalence and expansion of either type of mutant clones could be impacted by the cellular environments in which they arise and how this affects the neoplastic outcome of colitis remains unknown. Here we combine in vivo lineage tracing, in silico modeling, mutational profiling and spatial transcriptomics in a mouse model of colitis-associated tumorigenesis to capture clone fates associated with chronic inflammation. We identify epithelial- and immune-enriched neighborhoods and propose a model in which establishment of a reparative tissue environment facilitates tumor initiation by promoting the selection and expansion of pro-oncogenic clones, reducing the span of inflammation-resistant neighborhoods containing nononcogenic clones.
    DOI:  https://doi.org/10.1038/s41588-026-02673-0
  9. Sci Adv. 2026 Jul 31. 12(31): eaef0140
    Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
    Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.
      Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.aef0140
  10. Nutrients. 2026 Jul 13. pii: 2295. [Epub ahead of print]18(14):
    NAD Metabolism in Acute Myeloid Leukaemia: Biological Rationale and Therapeutic Opportunities.
    Klaartje Somers, Mawar Karsa, Donia M Moujalled.
      Acute myeloid leukaemia (AML) exhibits profound metabolic plasticity that enables leukaemic cells to survive environmental stress, nutrient limitation, and therapeutic pressure, ultimately driving disease persistence and relapse. While genetic and epigenetic alterations have guided risk stratification and therapeutic development, accumulating evidence indicates that nutrient-dependent metabolic rewiring represents a critical and targetable vulnerability in AML. Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor whose intracellular availability is tightly linked to dietary intake of its precursors, including tryptophan, niacin (vitamin B3), nicotinamide, and nicotinamide riboside. NAD supports redox balance, mitochondrial metabolism, DNA repair, and stress adaptation, processes that are particularly critical for leukaemic stem cell survival under therapeutic stress. Recent studies demonstrate that AML cells, including those resistant to venetoclax- and hypomethylating agent-based regimens, exhibit heightened dependence on the NAD salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological inhibition of this pathway induces profound NAD depletion, mitochondrial dysfunction, and selective leukaemic cell death. In this review, we integrate nutritional biology with emerging translational evidence to examine NAD metabolism as a nutrient-regulated metabolic vulnerability in AML. We discuss dietary sources and systemic regulation of NAD, the role of NAD-dependent pathways in leukaemic persistence, the translational exploitation of NAD salvage dependency, and the emerging controversy surrounding NAD supplementation in cancer. Finally, we highlight key knowledge gaps and future directions at the interface of nutrition, metabolism, and therapy response in AML.
    Keywords:  NAD metabolism; NAD supplementation; NAMPT; acute myeloid leukaemia; cancer metabolism; metabolic reprogramming; mitochondrial metabolism; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/nu18142295
  11. J Biol Chem. 2026 Jul 30. pii: S0021-9258(26)02253-2. [Epub ahead of print] 113381
    Sterol Flux Rewiring: Cholesterol Biosynthesis as a Dynamic Signaling Network.
    Marc Poirot, Philippe de Médina, Sandrine Silvente-Poirot.
      Cholesterol biosynthesis is among the best-characterized metabolic pathways in biology, yet a fundamental question remains unresolved: why does this pathway generate more than twenty enzymatic reactions and numerous structurally distinct intermediates if cholesterol is its major biological end product? Over the past several decades, biochemical, genetic, pharmacological, biophysical, and lipidomic studies have progressively revealed that many sterol intermediates are not merely transient precursors. Instead, they possess distinct biophysical, signaling, and oxidative properties that contribute directly to cellular physiology and disease. However, these discoveries have largely been interpreted within separate biological and experimental contexts, including inherited disorders of cholesterol biosynthesis, membrane biology, nuclear receptor signaling, oxysterol metabolism, and pharmacological inhibition of distal sterol enzymes. Here, we propose that sterol flux rewiring provides an integrative framework that connects these independent observations into a unified view of cholesterol metabolism. In this framework, biological responses emerge from dynamic redistribution of metabolic flux, generating distinct sterol states characterized by specific membrane properties, signaling activities, oxidative potentials, and downstream metabolic outputs rather than by the accumulation of individual metabolites alone. This perspective explains how changes in sterol composition reshape membrane organization, oxidative diversification, and interconnected signaling networks, including the epoxycholestanoid pathway. It also provides a coherent framework for understanding how alterations in cholesterol metabolism contribute to development, immunity, neurobiology, ageing, regeneration, and cancer, while highlighting new opportunities for therapeutic strategies aimed at reprogramming sterol-state organization rather than simply inhibiting cholesterol synthesis.
    Keywords:  Cancer metabolism; Cholesterol biosynthesis; EChA; oxysterols; sterol flux rewiring; sterol metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2026.113381
  12. Nat Cell Biol. 2026 Jul 29.
    The glycolytic enzyme PGAM1 functions as a metabolic-autophagy checkpoint to coordinate growth and stress tolerance.
    Yi Zhang, Pengwei Zhao, Hangfei Liang, Zhaojie Liu, Shuling Dong, Yingcong Chen, Weijing Yao, Yuting Chen, Liting Yang, Zhonglan Shi, Lei Zhang, Yibin Pan, Fanghong Zheng, Qi Lin, Shichao Wang, Jinheng Pan, Mingzhu Fan, Shan Feng, Cheng Ma, Lifeng Pan, Ying Xing, Fan Yang, Shuiping Liu, Du Feng, Qiming Sun, Guixin Zhu, Cong Yi.
      Cell survival requires tight coordination between growth-promoting metabolism and cellular quality-control pathways, yet how these processes are integrated remains unclear. Here we identify the conserved glycolytic enzyme PGAM1 as a metabolic-autophagy checkpoint that links glycolysis to autophagy initiation independently of its catalytic activity. Using complementary yeast and mammalian systems we show that PGAM1 functions as a molecular scaffold that recruits phosphatidylinositol 3-kinase complex I to the phagophore assembly site, thereby licensing autophagosome biogenesis. This autophagy-regulatory function is genetically essential, evolutionarily conserved and functionally separable from glycolysis. It is regulated by Atg1/ULK1-mediated phosphorylation that enhances Atg14 binding under starvation. Functionally, PGAM1 coordinates anabolic growth and stress-induced survival to maintain cellular homeostasis. In cancer, PGAM1 upregulation enhances both glycolytic flux and autophagy capacity. Disruption of either function markedly impairs tumour growth, establishing PGAM1 as a homeostatic checkpoint that is hijacked in cancer to drive both proliferation and stress tolerance.
    DOI:  https://doi.org/10.1038/s41556-026-02034-3
  13. Curr Opin Immunol. 2026 Jul 29. pii: S0952-7915(26)00106-8. [Epub ahead of print]102 102829
    Spatial metabolic heterogeneity shapes CD8+ T cell function in cancer.
    Peio Azcoaga, Ilaria Elia.
      Tumors are spatially heterogeneous ecosystems in which malignant, stromal, vascular, and immune cells interact within metabolically distinct niches. These localized microenvironments are shaped by factors such as nutrient availability, hypoxia, acidosis, and immunomodulatory metabolites, all of which strongly influence CD8⁺ T cell infiltration, migration, persistence, and effector function. Growing evidence indicates that spatial metabolic heterogeneity contributes to immune exclusion, T cell dysfunction, and resistance to immunotherapy. This has been accompanied by major advances in spatial metabolomics, particularly mass spectrometry imaging, which now enable the in situ mapping of metabolites within intact tissues. Combined with transcriptomic, proteomic, and imaging-based approaches, these technologies provide unprecedented insight into how metabolism is organized across tumors and how it shapes tumor-immune interactions. In this review, we discuss how metabolic zonation shapes CD8⁺ T cell function across primary tumors and metastatic lesions. We highlight emerging evidence linking localized metabolic programs to T cell exhaustion, impaired motility, and altered immune composition, and discuss therapeutic strategies aimed at improving T cell metabolic fitness, including metabolic modulation and engineering approaches relevant to immune checkpoint blockade and adoptive cell therapies. Finally, we consider the translational potential of spatial metabolomics for biomarker discovery and the development of precision immunometabolic oncology.
    DOI:  https://doi.org/10.1016/j.coi.2026.102829
  14. bioRxiv. 2026 Jul 13. pii: 2026.07.10.737821. [Epub ahead of print]
    Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.
    Matthew T Villaume, Haley E Ramsey, Valeria Impedovo, Michael Davidson, Maria P Arrate, Anand K Singh, Yujin Lee, Anna Skwarska, Yara F Almadani, Natalia Baran, Sovira Chaudhry, Benjamin J Reisman, Eden G TenBarge, Ming Jiang, Sarah Olmstead, Agnieszka E Gorska, Zhiguo Zhao, Andrew J Monteith, Peter M Grace, Brian O Bachmann, Marina Konopleva, Stefano Tiziani, Michael R Savona.
      Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.
    DOI:  https://doi.org/10.64898/2026.07.10.737821
  15. Nature. 2026 Jul 29.
    Mitochondrial metabolism and epigenetic crosstalk drive SASP.
    Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.
      Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.
    DOI:  https://doi.org/10.1038/s41586-026-10791-2
  16. bioRxiv. 2026 Jul 19. pii: 2026.06.08.730907. [Epub ahead of print]
    Oxidized protein states define metastatic fitness in lung cancer.
    Maolin Ge, Magdy Gohar, Consuelo Torrini, Yukako Suzuki, Shan Jiang, Yuchen Huang, Benjamin Weinstein, Janice Wong, Naema Nayyar, Md Yousuf Ali, Emily Sullivan, Stefan Harry, Cagri Cakici, Zhuanglin Dai, Nicolò Vivori, Zhi Qiao, Junbing Zhang, Iphia Zhang, Connie Che, Reilly Stevens, Neha Khandelwal, Jinho Jeong, Yue Xu, Sufian Ibrahim, Haoqian Feng, Philipp Haehnel, Christopher W Mount, Maria Martinez-Lage, Lecia Sequist, Chendi Li, Sylvia Azer, Quan Lu, Fan-Yan Wei, Mario L Suvà, Brian B Liau, Aaron N Hata, Edward T Chouchani, A John Iafrate, Michael S Lawrence, Doga Gulhan, Priscilla K Brastianos, Liron Bar-Peled.
      Reactive oxygen species (ROS) are a pervasive feature of human cancers, yet the protein targets through which ROS-regulated cell states shape tumor biology remains poorly understood. Here, using cysteine chemical proteomics, we define signatures of protein states under distinct cellular ROS environments that capture protein oxidation and conformational changes. Quantifying these signatures in primary lung tumors and brain metastases revealed a surprising enrichment of oxidative states in metastasis. To determine how these states support fitness, we performed genome-wide CRISPR screens and identified the mitochondrial Complex I subunit NDUFA10 as a key oxidation-dependent vulnerability. Oxidation of NDUFA10•Cys253 supports Complex I function through a previously unrecognized nucleotide kinase activity that maintains mitochondrial DNA levels. Enforcing a reduced conformation in NDUFA10 disrupts brain metastatic colonization in vivo . These findings establish ROS regulated protein states as a functional layer of tumor fitness, providing a framework for identifying redox-dependent mechanisms that support cancer progression.
    DOI:  https://doi.org/10.64898/2026.06.08.730907
  17. bioRxiv. 2026 Jul 14. pii: 2026.07.13.738221. [Epub ahead of print]
    The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
    Anupriya Singhal, Kate Ryan, Samuel A Rose, Hannah C Styers, Jung Yun Kim, Nikhita Pasnuri, Ashlyn Moore, Jose Meza-Llamosas, Emma Chen, Josephine Adams, Ananya Nandula, Roshan Sharma, Zhuxuan Li, Tal Nawy, Yan Yan, Nuray Tezcan, Olca Basturk, Mara H Sherman, Dana Pe'er, Tuomas Tammela.
      Intra-tumoral heterogeneity is a cardinal feature of solid tumors, yet how distinct cancer cell states functionally contribute to malignant and stromal diversity in situ remains poorly understood. Using mouse models to lineage-trace or genetically ablate the two predominant cancer cell states in autochthonous pancreatic ductal adenocarcinoma (PDAC), we discover that basal cancer cells are highly plastic, whereas classical cancer cells exhibit limited plasticity. Strikingly, ablation of the basal, but not the classical, state induced rapid and durable tumor collapse, driven by loss of immunosuppressive cancer-associated fibroblasts, macrophage repolarization, and reprogramming of the tumor cytokine milieu, culminating in tumor destruction by cytotoxic lymphocytes. Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors. These results reveal the basal cell state controls an immunosuppressive cell circuit critical for PDAC maintenance, motivating therapeutic targeting of the basal cells.
    DOI:  https://doi.org/10.64898/2026.07.13.738221
  18. bioRxiv. 2026 Jul 13. pii: 2026.07.11.737909. [Epub ahead of print]
    Epstein-Barr virus transformation creates a methionine-dependent ferroptosis vulnerability in B cells.
    Shaowen White, Rui Guo, Bidisha Mitra, Hanqi Li, Shunji F Li, Yifei Liao, Rishi Puri, John M Asara, Everett Stone, George Georgiou, Benjamin E Gewurz.
      Epstein-Barr virus (EBV) causes over 200,000 cancers annually, including immunoblastic lymphomas in immunosuppressed hosts. Most transformed cells arrest, yet survive when deprived of the essential amino acid methionine. We instead find that EBV transformed lymphoblastoid cell lines (LCLs), which model the EBV latency III program-driven B-cell lymphoproliferative diseases of immunosuppressed hosts, rapidly die upon methionine restriction. Methionine restriction elevated LCL lipid reactive oxygen species and triggered ferroptosis. Whereas methionine restriction hypomethylates the EBV genome and triggers viral reactivation in latency I Burkitt cells by lowering the cellular methylation potential, the LCL latency III program instead redirected methionine toward redox defense, without altering the SAM/SAH ratio. Stable-isotope tracing revealed that latency III strongly induces transsulfuration, synthesizing cysteine de novo to support glutathione pools. The EBV oncoprotein LMP2A, which mimics B-cell receptor signaling, supported newly infected human B cell cystathionine-β-synthase and cystathionine-γ-lyase expression and methionine dependence, phenocopied by immunoglobulin crosslinking. In vivo , dietary methionine restriction impaired LCL xenograft outgrowth and depleted tumor cystine. Combined methioninase and cyst(e)inase administration blocked both cysteine sources, collapsed tumor glutathione levels, and triggered ferroptosis. Our results define methionine metabolism as a targetable ferroptosis vulnerability of EBV-transformed B cells.
    Highlights: Methionine restriction triggers EBV-transformed lymphoblastoid B cell ferroptosisEBV latency III induces transsulfuration to sustain LCL cysteine and glutathione Methioninase or dietary methionine restriction strongly impair LCL growth in vivo Methioninase plus cyst(e)inase collapses xenograft GSH levels and drives ferroptosis.
    DOI:  https://doi.org/10.64898/2026.07.11.737909
  19. Immunology. 2026 Jul 26.
    Methionine Regulates Antitumour Function of CD8+ T Cells Through Polyamine Synthesis.
    Tian Zhao, Gillian A Carleton, Sam Preshaw, Sarah MacPherson, Madison Shiyuk, Joseph Monaghan, Jun Han, Oro Uchenunu, Robert Rottapel, Ralph J DeBerardinis, Kelly M Stewart, Bo-Hyun Kim, Juan Ausió, David R Goodlett, Helena Pětrošová, Kyle D Duncan, Julian J Lum.
      Methionine is an essential amino acid critical for T cell activation. While methionine restriction (MR) combined with immune checkpoint blockade has been shown to enhance T cell function, the impact of methionine on adoptive T cell therapies remains unknown. Here, we examined the functionality of T cells under MR and pharmaceutical inhibition of the methionine cycle (MAT2Ai), using primary T cells and a murine adoptive T cell therapy model. In vitro, transient MR or MAT2Ai treatment increased interferon gamma (IFNγ) expression in CD8+ T cells, whereas sustained MR led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and supplementation with polyamines reversed MR-induced IFNγ expression. Genetic ablation of S-adenosylmethionine decarboxylase, an enzyme involved in the polyamine synthesis pathway, recapitulated the effect of MR, indicating that transient MR enhances T cell function by inhibiting polyamine synthesis. Despite this, transient MR treatment of ovalbumin (OVA)-specific (OT-I) CD8+ T cells prior to adoptive transfer did not improve antitumour efficacy against EG7-OVA tumours in vivo. In contrast, sustained dietary MR accelerated EG7-OVA tumour growth in mice treated with OT-I T cells, demonstrating that methionine availability is essential for the activity of donor T cells. Importantly, sustained dietary MR promoted terminally exhausted phenotype in tumour-infiltrating donor CD8+ T cells, but not in host T cells. These findings suggest that enhancing methionine availability in the tumour microenvironment may improve the efficacy of adoptive T cell therapies.
    Keywords:  T cell; adoptive cell therapy; cancer immunology; immunometabolism
    DOI:  https://doi.org/10.1111/imm.70177
  20. Cell Rep. 2026 Jul 25. pii: S2211-1247(26)00808-9. [Epub ahead of print]45(8): 117730
    Tracing NAD+ metabolism uncovers adaptive coordination between host and microbiome during colitis.
    Abrar I Alsaadi, Lina Wehkamp, Anant A Pothakamury, Mahmoud S Yahia, Praveena Prasad, Clara Gilloteau, Jaedon Sadler, Jaclyn D Smith, Brenita C Jenkins, Garret S Diven, Johanna Bornhäuser, Taous Mekdoud, Shuchang Tian, Philip Rosenstiel, Stefan Schreiber, Jordan E Bisanz, Konrad Aden, Melanie R McReynolds.
      Host-microbiota metabolic interactions critically regulate nicotinamide adenine dinucleotide (NAD+) homeostasis, and their disruption is increasingly linked to chronic diseases, including inflammatory bowel disease (IBD). However, it remains unclear whether NAD+ dysregulation in IBD arises from impaired production, enhanced consumption, or both. Using multi-omics approaches and stable isotope-labeled NAD+ precursors administered via intravenous infusion in a murine model of dextran sulfate sodium (DSS)-induced colitis, we mapped tissue- and lumen-specific NAD+ metabolism under inflammatory stress. Our results reveal tissue-specific rewiring of NAD+ metabolism, with increased flux through the salvage pathway compensating for reduced de novo NAD+ synthesis from tryptophan. In parallel, microbial de novo NAD+ production was elevated, highlighting a cooperative host-microbiota response to inflammatory stress. These findings demonstrate differential regulation of NAD+ biosynthesis during acute colitis and underscore the dynamic interplay between host and microbial metabolism in maintaining NAD+ homeostasis under inflammatory conditions.
    Keywords:  CP: metabolism; CP: microbiology; DSS colitis; IBD; NAD(+); gut microbiota; host-microbiome interactions; kynurenine pathway; metabolomics; nicotinamide; stable isotope tracing; tryptophan
    DOI:  https://doi.org/10.1016/j.celrep.2026.117730
  21. bioRxiv. 2026 Jun 18. pii: 2026.06.15.732391. [Epub ahead of print]
    A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer.
    Yang Zheng, Caleb Cheng, Yizhi Cao, Gabriel Cruz, Yuping Zhang, Radha Paturu, Somnath Mahapatra, Jing Hu, Rahul Mannan, Hüseyin Karabürk, Rupam Bhattacharyya, Yitong Yin, Yi Zhao, Wenyan Liu, Xuhong Cao, Hui Xue, Chungen Li, Zhen Wang, Stephanie J Miner, Ulka Vaishampayan, Vaibhav Sahai, Lois S Weisman, Ke Ding, Costas A Lyssiotis, Yuzhuo Wang, Yuanyuan Qiao, Arul M Chinnaiyan.
      Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.
    Keywords:  ER stress; PIKfyve; lipid metabolism; lysosome; neuroendocrine prostate cancer
    DOI:  https://doi.org/10.64898/2026.06.15.732391
  22. Cell. 2026 Jul 29. pii: S0092-8674(26)00814-7. [Epub ahead of print]
    CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.
    Alex C Y Chen, Keely Y Ji, Cansu Yerinde, Nelson H Knudsen, Kevin Bi, Shumeng Hao, Vasyl Zhabotynsky, Daniela Martinez, Thomas J Carmona-LaSalle, Kazuhiro Taguchi, Katherine H Xu, Elizabeth M Seider, Marc A Schwartz, Maria Zschummel, Linda T Nieman, Kathleen B Yates, Francesca S Gazzaniga, Brian C Miller, Thorsten R Mempel, Robert T Manguso, Nir Hacohen, Debattama R Sen.
      Immune aging impairs T cell-mediated tumor control as well as cancer immunotherapy outcomes. The most important drivers of T cell dysfunction in aged tumors remain unknown. We performed single-cell CRISPR screens to identify Dusp5 and Zfp219 as key regulators of CD8+ T cell persistence and effector differentiation within aged tumors. Loss of Dusp5 increased extracellular signal-regulated kinase (ERK) phosphorylation and globally enhanced T cell proliferation. Conversely, Zfp219 deletion induced epigenetic reprogramming and increased expression of cytotoxic molecules, enhancing antitumor immunity specifically in aging. Levels of the human ortholog ZNF219 were higher within intratumoral CD8+ T cells from older cancer patients, which correlates with worse survival following immunotherapy. Zfp219 ablation synergized with immune checkpoint inhibitors to expand effector-like CD8+ T cells, leading to tumor clearance in aged mice. Our findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction that can be targeted to rejuvenate antitumor immunity in older cancer patients.
    Keywords:  T cells; antitumor immunity; cancer immunology and immunotherapy; immune aging; in vivo single-cell CRISPR screen
    DOI:  https://doi.org/10.1016/j.cell.2026.07.016
  23. Cell Press Blue. 2026 Jul 20. pii: 100053. [Epub ahead of print]1(4):
    A spatial multi-omics atlas of immunosenescence reveals germinal-center B cell dysfunction in human lymph nodes.
    Negin Farzad, Archibald Enninful, Yao Lu, Fabio Parisi, Anthony Fung, Yumi Kwon, Yajuan Li, Margaux Labrosse, Mingyu Yang, Francesco Strino, Liang Chen, Junchen Yang, Mei Zhong, Fu Gao, Bo Tao, Joseph Cunningham, Zhiliang Bai, Haikuo Li, Fang Wang, Michael Stankewich, Dongjoo Kim, Mingze Dong, Lisa M Bramer, Keyi Li, Meera R Bhat, Evan Loe, Joseph Craft, Ljiljana Pasa-Tolic, Stephanie Halene, Lingyan Shi, Yuval Kluger, Mina L Xu, Rong Fan.
      Immunosenescence is a hallmark of human aging and contributes to age-related immune decline, yet the development of senescence-associated phenotypes in the human lymphoid organs remains poorly understood. Here, we integrate single-cell and spatial multi-omics to systematically characterize age-related senescence in human lymph nodes (LNs) across the lifespan. Spatial proteomic profiling of 99 LN sections from 51 donors (18-86 years) using high-plex immunofluorescence (~20 million cells) mapped senescence markers (p16, p21, HMGB1, and γ-H2AX) at single-cell resolution, revealing diverse senescent-like cell types ("senotypes") and a stepwise shift from extrafollicular to germinal-center localization with age. In aged LNs, germinal-center B cells exhibit focal accumulation of senescence-associated programs, accompanied by impaired functional signatures, metabolic remodeling, and altered regulatory networks. These findings define a spatially organized landscape of immunosenescence in human lymphoid tissue and highlight germinal-center B cells as a key locus of age-associated immune dysfunction.
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100053
  24. bioRxiv. 2026 Jul 17. pii: 2026.07.16.738975. [Epub ahead of print]
    The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I.
    Brandon R Desousa, Yohei Abe, Martin Kampmann, Isha H Jain.
      Complex I (CI) is the largest and most disease-associated component of the mitochondrial electron transport chain. While many diseases are linked to defects in specific CI subunits, the extent to which non-mitochondrial proteins contribute to CI function or disease is less clear. Here, we perform genome-wide CRISPR screens to identify regulators of CI abundance across its N, Q, and P modules, which mediate NADH oxidation, quinone reduction, and proton pumping, respectively. These screens identify THAP12 as a previously unrecognized transcriptional regulator of CI biogenesis. THAP12 loss selectively destabilizes CI and impairs oxidative ATP production. Mechanistically, THAP12 functions in the nucleus as a DNA-binding factor that directly activates genes required for CI assembly and iron-sulfur cluster maintenance, including NDUFAF3, NDUFAF4 and BOLA3. Patient-derived fibroblasts carrying THAP12 mutations exhibit conserved transcriptional defects and profound CI deficiency, establishing THAP12-associated neurodevelopmental disorder as a secondary mitochondrial CI disease. Finally, hypoxia rescues growth defects in THAP12-deficient cells, nominating low-oxygen therapy as a potential treatment strategy. Together, these findings identify THAP12 as a dedicated regulator of CI assembly and expand the genetic landscape of CI disease.
    DOI:  https://doi.org/10.64898/2026.07.16.738975
  25. Cold Spring Harb Perspect Biol. 2026 Jul 29. pii: a041869. [Epub ahead of print]
    Translational Recoding in Tumors.
    Chen Weller, Osnat Bartok, Panagiotis Poulis, Yardena Samuels.
      Protein synthesis is tightly regulated in cells; however, in cancer, ribosomes deviate from canonical translation, generating altered protein products. These deviations arise from cell-intrinsic alterations, as well as extrinsic pressures within the tumor microenvironment, collectively reshaping the translational landscape and reducing translation fidelity. Translational recoding in cancer expands proteome diversity and promotes tumor fitness by enhancing stress adaptation, metabolic, and phenotypic plasticity. At the same time, recoding events generate peptides that are often presented as tumor-specific antigens, thereby eliciting immune responses against cancer. Accordingly, therapeutic strategies that modulate translational fidelity and induce recoding are emerging to enhance tumor immunogenicity and improve immunotherapy responses. Here, we examine the drivers and consequences of translational recoding in cancer, its dual role in promoting tumor adaptation while shaping immune surveillance, and its potential as a targetable vulnerability in cancer therapy.
    DOI:  https://doi.org/10.1101/cshperspect.a041869
  26. FEBS Lett. 2026 Jul 29.
    Loss of LipT2 disrupts mitochondrial protein lipoylation and metabolic homeostasis in Drosophila melanogaster.
    Yoshihito Kishita, Manabu Tsuda, Yukiko Sato-Miyata, Satomi Takeo, Toshiro Aigaki.
      Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes involved in central metabolism. In humans, mutations in the lipoyl transferase LIPT2 impair mitochondrial protein lipoylation and cause severe metabolic disease. Here, we investigated the Drosophila homolog, lipT2, in vivo. lipT2 mutants exhibited locomotor defects and shortened lifespan, accompanied by markedly reduced lipoylation of pyruvate dehydrogenase (PDH) and 2-oxoglutarate dehydrogenase (OGDH). Loss of lipT2 impaired glucose oxidation and disrupted tricarboxylic acid (TCA) cycle activity, leading to reduced mitochondrial energy production. Metabolomic analysis revealed altered amino acid homeostasis, including a marked reduction in aspartate, a key TCA cycle-derived metabolite. These findings demonstrate that defective lipoylation disrupts central metabolic processes and energy homeostasis.
    Keywords:  Drosophila melanogaster; LipT2; carbon flux; energy metabolism; metabolic homeostasis; mitochondrial protein lipoylation
    DOI:  https://doi.org/10.1002/1873-3468.70422
  27. bioRxiv. 2026 Jul 16. pii: 2026.07.15.738764. [Epub ahead of print]
    Deciphering the Multiscale Morphology of Somatic Oncogenic Alterations in Hepatocellular Carcinoma.
    Qionghua Shen, Tai Ngo, Hanieh Mazloom-Farsibaf, Kelly Wong, Lin Li, Kushal Bhatt, Felix Y Zhou, Bo-Jui Chang, Xiaoding Wang, Zhiguo Shang, John Haug, Hazel M Borges, Reto Fiolka, Hao Zhu, Kevin M Dean.
      Somatic oncogenic mutations are typically defined by their molecular alterations, yet how they reorganize cellular architecture within intact tissues remain largely unknown. Here, we demonstrate that distinct oncogenic drivers produce unique multiscale architectural phenotypes that can be quantitatively resolved in intact liver tissue. Using iterative expansion microscopy, multiscale light-sheet imaging, and three-dimensional morphometric analysis, we systematically mapped structural remodeling from single-cell morphology to mitochondrial architecture in mosaic mouse models of hepatocellular oncogene activation. NRAS and CTNNB1 induced fundamentally different morphological programs. NRAS activation drove extensive remodeling of cell morphology, membrane curvature, and surface irregularity, whereas CTNNB1 activation largely preserved global cell morphology while selectively altering mitochondrial organization and shape. We first established a zonation-aware reference state for interpreting oncogene-associated organelle remodeling by resolving mitochondrial differences between periportal and pericentral hepatocytes. Within this framework, CTNNB1 activation shifted mitochondrial features toward a pericentral-like state, consistent with the role of Wnt/β-catenin signaling in hepatic zonation and metabolic identity. Furthermore, integrating cellular morphology, membrane geometry, and mitochondrial architecture improved discrimination of oncogenic states beyond any individual structural feature, demonstrating that mutation-specific phenotypes arise through coordinated remodeling across multiple biological scales. Together, these findings establish multiscale structural phenotyping as a framework for linking oncogenic genotype to three-dimensional cellular organization and reveal that distinct oncogenic drivers remodel different architectural compartments during liver oncogene activation.
    DOI:  https://doi.org/10.64898/2026.07.15.738764
  28. Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Jul 27. pii: S1388-1981(26)00048-X. [Epub ahead of print] 159762
    Futile cycles in metabolic flexibility: The energetic cost of regulatory precision.
    Radhika Khandelwal, Lianggong Ding, Anand Kumar Sharma.
      Futile cycles (FCs), also known as substrate cycles, are a pair of opposing biochemical reactions that continually convert a substrate into a product and back. In doing so, FCs waste ATP without producing a tangible metabolic output (thus termed 'futile'). Because ATP hydrolysis is exothermic, recent studies have extensively focused on the thermogenic function of various FCs, particularly in adipose tissue. However, the function of FCs on other target organs and their primary biological functions remain poorly defined. In this forward-looking minireview/perspective, we discuss a few underexplored functions of FCs that underpin metabolic flexibility and systemic metabolic health. We propose an integrative model in which discrete FCs across metabolic organs act in concert to regulate cellular energetics and organismal metabolic physiology. We postulate that FCs sense and integrate metabolic status, redox balance, and metabolite signaling, with mitochondria serving as the central hub where energetic and signaling cues converge to generate a calibrated cellular response. Given the broad regulatory role of FCs, including in metabolic flexibility, future studies should aim to define the wider functions vis-à-vis metabolic homeostasis in health and disease.
    Keywords:  Futile cycles; Lipid metabolism; Metabolic flexibility; Metabolic flux; Mitochondria; Thermogenesis
    DOI:  https://doi.org/10.1016/j.bbalip.2026.159762
  29. J Immunol. 2026 Jul 10. pii: vkag203. [Epub ahead of print]215(7):
    NAD+ depletion links metabolic stress to drive innate immune priming and selectively control PANoptosis.
    Roman Sarkar, Nagakannan Pandian, Balamurugan Sundaram, Bhesh Raj Sharma, Peter A Gorsuch, Rebecca E Tweedell, Thirumala-Devi Kanneganti.
      The innate immune system can detect infection, tissue damage, and other homeostatic disruptions to initiate an immune response, drive inflammation, and promote programmed cell death. While these responses can be beneficial in host defense, aberrant activation of inflammatory, lytic cell death pathways can be pathogenic. Emerging evidence suggests that cellular metabolic disruption can promote inflammatory cell death, but the mechanistic connections between these processes are not well understood, limiting our ability to identify regulatory nodes that can be therapeutically targeted. Here, we found that intracellular levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+) were depleted in response to cell death triggers that drive pyroptosis, necroptosis, PANoptosis, and ferroptosis. However, restoring NAD+ inhibited PANoptosis but not the other forms of cell death. Mechanistically, NAD+ restoration reduced the expression of PANoptotic sensors or regulators, including the transcription factor IRF1, a critical factor for innate immune sensor priming in PANoptosis. Our findings thereby suggest that NAD+ depletion is an early cell death signaling event and that restoring NAD+ levels specifically blocks PANoptosis by suppressing priming. Hence, targeting NAD+ metabolism represents a potential therapeutic strategy for infectious and inflammatory diseases associated with dysregulated PANoptosis.
    Keywords:  AIM2; NLRC5; NLRP12; NLRP3; ZBP1
    DOI:  https://doi.org/10.1093/jimmun/vkag203
  30. Cell Rep. 2026 Jul 25. pii: S2211-1247(26)00801-6. [Epub ahead of print]45(8): 117723
    Distributed clonal deletion prevents autoimmune disease progression.
    Anna M Newen, Uzair A Ansari, Mikala J Simpson, Fiona Flynn, Sukriti Sharma, Michael Ivanov, Ishaan Antani, Dylan Pfannenstiel, Baktiar Karim, Laura Bassel, Brian Capaldo, Qingrong Chen, Daoud Meerzaman, Indu Raman, Chengsong Zhu, Cornelius Y Taabazuing, Hamid Kashkar, Christian T Mayer.
      Self-reactive B cells arise during development and can increase pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that self-tolerance is enforced through temporally distinct mitochondrial outer membrane permeabilization (MOMP) checkpoints. Using conditional Bcl-2 expression to inhibit MOMP either from B cell development or activation, we find that early inhibition permits survival of autoreactive B cells after peripheral egress, expanding the pool available for activation and AID-dependent diversification. This results in broadened class-switched IgG autoreactivity, complement activation, kidney pathology, and drives lethal autoimmune disease. In contrast, post-activation MOMP inhibition promotes autoreactive cell accumulation and autoantibody production but causes limited tissue damage and normal survival. Together, these findings support a Distributed Clonal Deletion Model in which temporally distinct checkpoints cooperate to constrain autoimmune disease progression.
    Keywords:  AID; B cell tolerance; CP: immunology; MOMP; SLE; activation-induced cytidine deaminase; autoimmunity; clonal deletion; germinal center; mitochondrial outer membrane permeabilization; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.celrep.2026.117723
  31. Nat Cell Biol. 2026 Jul 27.
    Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ.
    Binwu Tang, Jacob Minin, Victoria M Gonzalez, Zoya Z Khan, Andrew R Gaines, Yuval Raviv, Yu-An Yang, Christine P Carney, Zachary G Millman, Daniel Grun, Cristiana M Pineda, Alina Sharma, Dominic Esposito, Hualong Yan, Jing Huang, Andy D Tran, Michael Kruhlak, Howard H Yang, Maxwell P Lee, Lalage M Wakefield.
      Cancer stem cells (CSCs) drive metastasis and therapy resistance, yet their behaviour within the complex tumour microenvironment remains poorly understood. Here we use a fluorescent reporter that marks CSCs to show that CSCs and their more differentiated progeny display strikingly different population dynamics during metastatic lung colonization in breast cancer models. CSC expansion is rapidly curtailed early in colonization, suggesting a strong negative feedback mechanism acting selectively on this subpopulation. We showed that CSCs are exceptionally sensitive to local microenvironmental cues such as cell crowding and nutrient availability. They respond earlier and more extensively than their differentiated progeny, thereby coupling tumour growth to resource and space availability. Microenvironmental signals converge on the transcriptional regulatory complex YAP/TAZ/TEAD, with CSC sensitivity arising from elevated signal reception and greater chromatin accessibility at TEAD-regulated enhancers. Targeting upstream inputs to this pathway reversed chemotherapy-induced CSC enrichment in lung metastases, suggesting a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41556-026-02013-8
  32. Cancers (Basel). 2026 Jul 08. pii: 2186. [Epub ahead of print]18(14):
    Interplay of Epigenetic Reprogramming, Mitochondrial Metabolism, and Dopamine Signalling Pathways Uncovers Metabolic Vulnerabilities in Diffuse Midline Glioma.
    Han Shen, Yizhou Huang, Kristina M Cook, Eric Hau.
      Diffuse midline glioma (DMG) is one of the most aggressive paediatric brain tumours and remains almost universally fatal despite decades of research. The defining molecular feature of approximately 80% of DMG tumours is H3K27M, which disrupts PRC2 activity and profoundly remodels chromatin architecture. Increasing evidence suggests that this epigenetic alteration not only rewires transcriptional programs but also influences tumour metabolism. Several studies indicate that H3K27M-mutant tumours exhibit altered mitochondrial metabolism, oxidative phosphorylation activity, redox regulation, and cellular stress responses, although the extent of oxidative phosphorylation dependence varies between models, tumour subtypes, and cellular states. In parallel, dopaminergic signalling has been implicated in cancer stem cell maintenance, metabolic regulation, and tumour survival across multiple malignancies, including glioma. The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses. In this review, we examine emerging connections between epigenetic dysregulation, mitochondrial metabolism, and dopamine signalling in DMG. We propose that H3K27M-driven epigenetic reprogramming may impose metabolic constraints that increase tumour reliance on mitochondrial bioenergetics and stress-buffering pathways. Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease.
    Keywords:  DMG; dopamine; epigenetics; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cancers18142186
  33. Oncogene. 2026 Jul 30.
    OTUD6A promotes de novo pyrimidine synthesis by deubiquitinating and stabilizing CAD in cervical cancer.
    Liming Liao, Lizhou Zeng, Yiliang Zhao, Zihao Guo, Tong Zeng, Ronghui Yang, Yu Xu, Xuesong Wu, Hongkun Wu, Mengyao Chen, Tao Zhu, Yapeng Ji, Binghui Li, Chuanzhen Yang.
      Carbamoyl-phosphate synthetase II, aspartate transcarbamylase and dihydroorotase (CAD) is a multifunctional, rate-limiting enzyme involved in de novo pyrimidine synthesis. Its activity is tightly regulated, primarily through phosphorylation and allosteric mechanisms. However, the contribution of other post-translational modifications to CAD regulation remains largely unexplored. Here we identify ubiquitination as a novel regulatory mechanism controlling CAD stability. We show that CAD undergoes K29-linked ubiquitination and proteasomal degradation following ubiquitination at lysine residues K1325 and K1411 within its carbamoyl-phosphate synthetase II (CPS II) domain. Inhibiting CAD ubiquitination by mutating these lysine sites promotes its stability, de novo pyrimidine synthesis and tumor growth. Notably, CAD protein expression is elevated in cervical cancer and is associated with poor prognosis. Furthermore, we identify OTU domain-containing protein 6 A (OTUD6A) as a deubiquitylase that directly interacts with the CPS II domain of CAD, leading to its deubiquitylation and stabilization. OTUD6A overexpression enhances de novo pyrimidine synthesis and tumor growth in a CAD-dependent manner. OTUD6A is also upregulated in cervical cancer, positively correlating with CAD protein levels and poor prognosis of cervical cancer patients. Collectively, our results reveal the OTUD6A-CAD axis as a critical regulator of pyrimidine metabolism in cervical cancer, highlighting a potential vulnerability for therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41388-026-03909-3
  34. Sci Adv. 2026 Jul 31. 12(31): eaeh3719
    Dendritic cell circadian clocks shape memory CD8+ T cell differentiation.
    Ward Vleeshouwers, Suzanne van Duikeren, J Fréderique de Graaf, Dominique M B Veerkamp, Marissa E Linger, Sytze H T Jorritsma, Sebenzile K Myeni, Laura Kervezee, Ramon Arens.
      Circadian rhythms regulate diverse immune processes, yet how they influence memory CD8+ T cell differentiation remains unclear. Here, we show that the time of day of antigen encounter shapes CD8+ T cell fate and antiviral immunity. Immunization during the active phase promotes the generation of progenitor-like memory CD8+ T cells and enhances T cell-mediated protection upon viral challenge. Mechanistically, dendritic cell-intrinsic circadian clocks regulate expression of the costimulatory ligand CD70, thereby directing T cell differentiation. These findings uncover a dendritic cell-mediated circadian mechanism that governs memory T cell fate decisions and suggest that aligning immune priming with circadian time may be leveraged to optimize T cell immunity.
    DOI:  https://doi.org/10.1126/sciadv.aeh3719
  35. bioRxiv. 2026 Jul 24. pii: 2026.07.23.740218. [Epub ahead of print]
    Spatial control of mitochondrial retrograde signaling by nuclear pore-associated contact sites.
    Sahana Mitra, Giulia Burrone, Surya Rubarajan, Christophe Klein, Tyler Kwok, Suchit Gutta, Keyu Chloe Li, Elizaveta Berson, Joseph Orofino, Maria Dafne Cardamone, Michael Blower, Valentina Perissi.
      Mitochondria relay their functional state to the nucleus via retrograde signaling, yet whether the spatial organization of the mitochondrial network plays a role in this process remains unclear. Here, we show that stress-induced clustering of mitochondria around the nucleus is a crucial part of the retrograde response. Perinuclear clustering facilitates the formation of mitochondria- nucleus contact sites (MNCS) and the nuclear entry of GPS2, a key mediator of mitochondrial retrograde signaling essential for activating nuclear-encoded mitochondrial and stress-response genes in response to various mitochondrial stressors. Unexpectedly, TSPO-driven MNCS are dispensable for GPS2-based retrograde signaling. Instead, we identify the mitochondrial import receptor TOMM70 and the nucleoporin RanBP2/NUP358 as components of a stress-induced nuclear pore-associated tethering complex required for promoting GPS2 nuclear translocation and activation of downstream programs. These findings establish MNCS as a functional gateway for mitochondrial retrograde signaling, highlighting that organelle positioning and tethering at the nuclear pore provide an unexpected layer of stress regulation.
    DOI:  https://doi.org/10.64898/2026.07.23.740218
  36. Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2602775123
    Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
    Wasi Iqbal, Ben Zucker, Xiaoying Liu, Ruiru Wang, Hongfei Zhu, Sijie Chen, Renjie Zhou, Xingguo Liu, Michael M Kozlov, Liting Duan.
      Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.
    Keywords:  membrane elasticity; membrane pearling; membrane tension; mitochondria; mitochondrial fission
    DOI:  https://doi.org/10.1073/pnas.2602775123
  37. Cell. 2026 Jul 28. pii: S0092-8674(26)00801-9. [Epub ahead of print]
    Why machines don't speak biology: Toward native biological language models.
    Yonatan Stelzer, Amos Tanay.
      Recent advances in AI inspire visions of universal models of biology. Yet living systems are evolved, emergent processes whose behaviors cannot be inferred from their parts alone. We propose grounding AI in canonical biological processes, constructing data-driven world models with explicit mechanistic links across molecules, cells, and their dynamics in space and time.
    Keywords:  artificial intelligence; biological computation; canonical biological processes; developmental biology; embryogenesis; emergence; evolutionary contingency; explanatory reductionism; large language models; multi-scale modeling; systems biology; world models
    DOI:  https://doi.org/10.1016/j.cell.2026.07.003
  38. Science. 2026 Jul 30. 393(6810): 461
    Signatures of aging and disease in a single organelle.
    Jeeyoon Na, Anne Brunet.
      Changes in lysosomal metabolites are associated with both aging organs and lysosomal storage diseases.
    DOI:  https://doi.org/10.1126/science.aej5901
  39. J Cell Biol. 2026 Oct 05. pii: e202510026. [Epub ahead of print]225(10):
    Mechanical forces stimulate Golgi export.
    Chandini Bhaskar Naidu, Javier Vera Lillo, Eugenia Almacellas, Anabel-Lise Le Roux, Sabine Bardin, Nicolas Mateos, Jessica Angulo-Capel, Adam Wolowczyk, Yugo Terashima, Yuichi Wakana, Pere Roca-Cusachs, Maria F Garcia-Parajo, Franck Perez, Bruno Goud, Jean-Baptiste Manneville, Stéphanie Miserey, Felix Campelo.
      Cells face diverse mechanical stimuli that vary with cell type, state, and pathological conditions. Mechanobiology investigates how cells sense and respond to these forces. While most work has focused on the cell surface and nucleus as primary mechanosensors, how intracellular organelles adapt to extracellular mechanical forces remains largely unknown. Here, we show that extracellular mechanical signals influence the secretory function of the Golgi apparatus. By subjecting adherent cells to mechanical challenges-cell spreading on different ligands, altered substrate stiffness, or equibiaxial strain-we reveal that extracellular forces modulate Golgi-to-cell surface carrier biogenesis, thereby regulating exocytosis. Together with changes in Golgi membrane tension, we identify molecular determinants of the mechanotransduction pathway, including microtubule acetylation, diacylglycerol production, and protein kinase D activity. In turn, inhibition of Golgi export suppresses this mechanoresponse and causes impaired cell spreading. These findings uncover a bidirectional mechanotransduction axis in which extracellular mechanics tune Golgi secretory output, providing a framework for investigating organelle-based mechanoadaptation in physiology and disease.
    DOI:  https://doi.org/10.1083/jcb.202510026
  40. J Immunother Cancer. 2026 Jul 27. pii: e015462. [Epub ahead of print]14(7):
    Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.
    Zhiwei Zhang, Yu-An Xie, Chenglin Mu, Shiying Sheng, Jinyuan Zhang, Jie Han, Jiwen Li, Zhengfu He, Xia Liu.
       BACKGROUND: Mitophagy is a mitochondrial quality control process that maintains cellular homeostasis in cancer, yet whether its dysregulation can be exploited to induce tumor immunogenicity remains unclear.
    METHODS: We integrated pancancer single-cell transcriptomic analyses with genetic perturbation strategies in hepatocellular carcinoma models, including CRISPR/Cas9-mediated gene depletion, in vivo syngeneic tumor systems, and RNA-based lipid nanoparticle delivery. Mechanistic investigations combined mitochondrial functional assays, imaging-based mitophagy analysis, flow cytometry, and transcriptional profiling, together with evaluation of immune checkpoint blockade responses in preclinical and clinical cohorts.
    RESULTS: We identify translocase of the outer mitochondrial membrane 40 (TOMM40) as a mitochondrial import gatekeeper that restrains PINK1-Parkin-dependent mitophagy. Loss of TOMM40 induces catastrophic mitochondrial dysfunction and triggers a lethal form of hyperactivated mitophagy. This process is immunogenic and converts immune-cold tumors into immune-inflamed states characterized by enhanced CD8+ T-cell infiltration and activation. Mechanistically, TOMM40 deficiency leads to intracellular reactive oxygen species accumulation, which activates NF-κB signaling and drives upregulation of major histocompatibility complex class I antigen presentation machinery, thereby increasing tumor visibility to cytotoxic T cells. In parallel, TOMM40 loss induces programmed death-ligand 1 upregulation, establishing an adaptive immune resistance program. Functionally, TOMM40-deficient tumors exhibit markedly increased responsiveness to immune checkpoint blockade and generate systemic antitumor immune protection. Clinically, a TOMM40-loss transcriptional signature is associated with improved immunotherapy outcomes across multiple independent patient cohorts.
    CONCLUSIONS: TOMM40 functions as a mitochondrial immune checkpoint that controls the threshold of immunogenic mitophagy. Its loss reprograms mitochondrial stress into antigen presentation and immune activation, providing a strategy to convert immune-cold tumors into immune-responsive states.
    Keywords:  Antigen Presentation; Immunotherapy; Mitochondria
    DOI:  https://doi.org/10.1136/jitc-2026-015462
  41. Cell Death Differ. 2026 Jul 31.
    GRP75 sustains CD8+ T cell homeostasis and memory generation through ensuring mitochondrial fitness.
    Fan Zhao, Pengfei Wang, Zejin Cui, Zhishan Zhao, Lize Wu, Rui Zhang, Dale Gao, Jiayan Wu, Yuwen Shao, Xuexiao Jin, Yadan Bai, Kaixiang Zhu, Linrong Lu.
      The development and functional maintenance of CD8+ T cells are metabolically regulated processes in which mitochondria serve as the central hub. Here, we identify glucose-regulated protein 75 (GRP75) as a critical mitochondrial regulator controlling these processes. Using T cell-specific Hspa9 (encodes GRP75) knockout mice, we demonstrate that GRP75 deficiency disrupts CD8+ T cell fate, leading to defective T cell homeostasis and impaired memory differentiation. Mechanistically, impaired mitochondrial function in GRP75-deficient CD8+ T cells leads to perturbation of IL-7R signaling and aberrant expression of effector-associated molecules. Further studies reveal that GRP75 deficiency leads to upregulation of interferon regulatory factor 4 (IRF4), a critical transcription factor for effector versus memory fate, which in turn suppresses memory CD8+ T cell differentiation. Our findings establish GRP75 as a pivotal mitochondrial checkpoint that coordinates metabolic state and functional fate in CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41418-026-01830-6
  42. Nat Rev Mol Cell Biol. 2026 Jul 30.
    Exchange dynamics and kinetic control of gene regulation complexes.
    Alexander Johnson-Buck, Adrien Chauvier, Abrar A Abidi, Djem U Kissiov, Xavier Darzacq, Robert Tjian, Sarah A Woodson, Nils G Walter.
      The classical view of gene regulation complexes as stable, modular machines needs amending based on emerging insights into their dynamic nature. Whereas recent advances in structural biology have provided high-resolution snapshots of these complex machines, single-molecule and live-cell imaging techniques reveal a more fluid picture: biological function emerges not from static architectures but from transient, dynamic assemblies that continually exchange their components and whose activity is tuned through kinetic control. In this Perspective, we propose dynamic, reversible assembly as a framework for understanding the mechanisms of RNA processing and gene regulation. Drawing on specific case studies from ribosome biogenesis, spliceosomes, small RNAs and transcription factors, we explore how ribonucleoprotein complexes and transcriptional ensembles form and dissolve in time, how protein intrinsically disordered regions collectively enable transcription factors to achieve specificity, and the kinetic principles underlying the fidelity, adaptability and robustness of cellular processes and their related pathologies. In doing so, we show how molecular interactions are governed by rates rather than by equilibrium affinities, providing a foundation for time-integrated structure-function studies.
    DOI:  https://doi.org/10.1038/s41580-026-00991-z
  43. Aging (Albany NY). 2026 Jul 24. 18(1): 908-915
    A brief history of the hyperfunction theory of aging and future directions.
    João Pedro de Magalhães.
      Aging remains a mystery of biology, and debate regarding why we age has been ongoing for centuries. Many theories of aging have been proposed, most of which focus on errors and the gradual accumulation of molecular damage. By contrast, aging may be primarily a programmatic process, arising from developmental programs that continue to run later in life and, as a form of antagonistic pleiotropy, become detrimental. Here, I review the history of programmatic theories of aging, from early caloric restriction experiments to more recent conceptual frameworks to which Mikhail Blagosklonny made key contributions, particularly the hyperfunction theory. The discovery that single-gene manipulations can modulate aging in animal models, together with evidence that rapamycin extends lifespan, provides empirical support for the hyperfunction theory. Finally, I discuss the prospects of the hyperfunction theory and its implications for the future of aging biology.
    Keywords:  antagonistic pleiotropy; longevity; programmatic aging; quasi-program
    DOI:  https://doi.org/10.18632/aging.206403
  44. Nat Genet. 2026 Jul 30.
    Single-cell spatial mapping of human kidney development implicates the microenvironment in guiding cell fate decisions.
    Jonathan Levinsohn, Samuel Grindel, Bernhard Dumoulin, Amin Abedini, Carolina Conte, Aria Zheyuan Huang, Rena Levin-Klein, Boaz Weisz, Grace Rabinowitz, Andi M Bergeson, Eunji Ha, Konstantin A Klötzer, Nancy Zhang, Paul Titchenell, Mingyao Li, Joo-Seop Park, Juan Pablo Arroyo, Laura S Finn, Kotaro Sasaki, Pazit Beckerman, Oren Pleniceanu, Paola Romagnani, Alex J Hughes, Katalin Susztak.
      Evolution has used cell-cell communication as a strategy to coordinate organ development, enabling the reproducible generation of intricate structures. Classically, these interactions have been studied one at a time in model organisms, limiting our understanding of how cellular interplay coordinates human development. We investigated human kidney development using single-cell RNA sequencing and spatial transcriptomics, analyzing over 700,000 cells. By mapping gene expression and differentiation trajectories in space, we define the spatial organization of kidney development. Our analysis revealed unrecognized plasticity, showing that cell fate established during early patterning can be later revised. This plasticity provides a potential mechanism for how cell fate is robustly established in complex patterned tissues. Additionally, through a genome-wide, spatially aware cell-cell interaction analysis, we link localized ligand signals to cell fate decisions. We also define biologically meaningful cellular neighborhoods based on aggregated extracellular cues, providing a blueprint to understand the coordination of human development at scale.
    DOI:  https://doi.org/10.1038/s41588-026-02665-0
  45. Cell Rep. 2026 Jul 27. pii: S2211-1247(26)00782-5. [Epub ahead of print]45(8): 117704
    GBP6 maintains mitochondrial bioenergetics to promote immune evasion from NK cells in cervical cancer.
    Lili Qian, Yuebo Li, Jiani Zheng, Tingting Liang, Rui Zhao, Xiaolin Wang, Xu Liu, Xinru Liu, Xian Song, Mingming Zhu, Shuangfeng Chen, Weiqi Yin, Chuan Chen, Ying Zhou, Fang Ni.
      Metabolic reprogramming and immune evasion are central hallmarks of cancer progression; yet, how mitochondrial metabolism shapes immune escape remains unclear. Here, we identify GBP6 as a tumor-intrinsic mitochondrial factor associated with aggressive cervical cancer. GBP6 is enriched in high-risk tumors and correlates with poor clinical outcomes. GBP6 knockdown suppresses tumor cell proliferation and promotes cell death. Mechanistically, GBP6 localizes to mitochondria, interacts with TACO1, and supports respiratory complex IV integrity and activity. GBP6 depletion disrupts mitochondrial bioenergetics, reduces membrane potential and NADPH availability, increases ROS production, and compromises the GSH-GPX4 antioxidant axis, thereby promoting lipid peroxidation and ferroptosis-associated cell death. This mitochondrial redox stress induces ICAM-1 expression through ROS-NF-κB signaling, enhancing NK-cell adhesion, immune synapse formation, and tumor-cell killing. In xenograft models, GBP6 depletion sensitizes tumors to adoptively transferred NK cells. These findings identify GBP6 as a mitochondrial regulator linking metabolic fitness to innate immune evasion in cervical cancer.
    Keywords:  CP: cancer; CP: immunology; GBP6; ICAM-1; cervical cancer; ferroptosis; immunotherapy; mitochondrial metabolism; natural killer cell
    DOI:  https://doi.org/10.1016/j.celrep.2026.117704
  46. bioRxiv. 2026 Jul 20. pii: 2026.07.17.739092. [Epub ahead of print]
    Double-bond geometry determines fatty acid metabolic fate and ferroptosis sensitivity.
    Cynthia A Harris, Shunji Kato, Yurika Otoki, Elisa Martin Perez, Dylan Boone, Juan Lorenzo B Pablo, Anna Greka, James A Olzmann.
      Ferroptosis is driven by the accumulation of oxidatively damaged membrane phospholipids, making membrane lipid composition a central determinant of cell death sensitivity. While fatty acid chain length and degree of unsaturation are well-established regulators of ferroptosis, whether fatty acid stereochemistry contributes to ferroptosis susceptibility is mostly unexplored. Here, we systematically screened structurally diverse fatty acids for their ability to modulate ferroptosis and unexpectedly identified trans-unsaturated fatty acids as potent sensitizers. Compared with its cis counterpart linoleic acid, the trans polyunsaturated fatty acid (PUFA) linoelaidic acid more strongly enhanced lipid peroxidation and promoted the accumulation of ferroptosis-susceptible phospholipid species. Unexpectedly, the trans monounsaturated fatty acid petroselaidic acid also sensitized cells to ferroptosis, whereas its cis stereoisomer petroselinic acid suppressed ferroptosis. Mechanistically, petroselaidic acid required stearoyl-CoA desaturase-dependent conversion to a PUFA, directly demonstrating that double-bond geometry can redirect fatty acid metabolic fate through altered recognition by lipid metabolic enzymes. Although linoelaidic acid and petroselaidic acid followed distinct metabolic pathways, both converged on phospholipid remodeling that expanded pools of ferroptosis-susceptible membrane lipids. Together, our findings demonstrate that fatty acid double-bond geometry determines their metabolic fate and the membrane phospholipid composition, establishing lipid stereochemistry as a previously unrecognized structural determinant of ferroptosis sensitivity.
    DOI:  https://doi.org/10.64898/2026.07.17.739092
  47. FEBS J. 2026 Jul 29.
    Inhibition of mitochondrial protein translation sensitizes tumor cells to death receptor 5 agonistic antibody.
    Gabriele Casagrande Raffi, Jian Chen, Elsemieke Passchier, Cor Lieftink, Chrysa Papagianni, Jeanette H W Leusen, Roderick L Beijersbergen, Liqin Wang, Rene Bernards.
      While many antagonistic antibodies are in routine clinical use, only a single agonistic antibody has received regulatory approval to date. While antibodies that activate Death Receptor 5 (DR5) were thought to have utility in the treatment of cancer by enhancing extrinsic apoptosis signaling, to date all clinical studies with these DR5 agonists have failed to deliver significant clinical benefit. A notable example of this is the DR5 agonistic antibody conatumumab. Here, we provide two potential avenues to improve the activity of DR5 agonists. First, we show that a dimeric IgA version (dIgA2) of the conatumumab antibody has a higher toxicity to cancer cells and a shorter half-life in vivo compared to the original IgG version of the antibody. Moreover, we conducted a genome-wide CRISPR screen to identify genes for which inactivation enhances the sensitivity of cancer cells to the dIgA2 DR5 antibody. We found that inhibition of mitochondrial protein translation synergizes with DR5 agonists. Consequently, antibiotics that inhibit mitochondrial protein translation also synergize with DR5 agonists. Finally, we show that these antibiotics activate the Integrated Stress Response (ISR) and upregulate DR5 through the EIF2a-ATF4 axis, which sensitizes cancer cells to DR5 activation. These data suggest a potential combination strategy for the effective use of DR5 agonistic antibodies.
    Keywords:  CRISPR screening; apoptosis; dimeric IgA; integrated stress response; mitochondria
    DOI:  https://doi.org/10.1111/febs.70669
  48. Oncogene. 2026 Jul 25.
    Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the EPAC-RAP1 signaling dependency of primary melanoma.
    Sireesh Kumar Teertam, Mithalesh K Singh, Sarah Altameemi, Sonia Gude, Sushmita Roy, Ryan N Rossman, Michael A Newton, Daniel D Bennett, Nihal Ahmad, Xiaodong Cheng, Vijayasaradhi Setaluri.
      Progression of cutaneous primary melanoma that arises from melanocytes leads to lethal metastatic disease. Molecular mechanisms that control the growth of primary melanoma in the skin and promote progression are not fully understood. Previously we showed that RAP guanine exchange factors EPAC1/2 (Exchange Proteins Activated by cyclic AMP) promote the growth of primary melanoma and loss of dependency on EPACs is associated with metastatic progression. In this study, we show that EPACs are activated during malignant transformation of melanocytes, and chemical inhibition or genetic deletion of EPAC inhibits melanomagenesis in Braf/Pten mice. Low expression of EPAC mRNA and its effector RAP1-GTP protein in primary melanoma correlate with better recurrence-free survival. RNAseq analysis of matched primary and metastatic melanoma cells treated with an EPAC inhibitor showed that TXNIP, an important regulator of redox homeostasis, is a downstream effector of EPAC signaling. We also show that EPACs promote melanoma growth by regulating redox homeostasis and mitochondrial ROS through activation of mechanistic target of rapamycin complex 1 (mTORC1) that stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), a transcriptional activator of redox regulator TXNIP and glycolytic enzymes. Our data suggest that targeting mechanisms that melanoma cells employ to bypass EPAC dependency is a potential therapeutic approach.
    DOI:  https://doi.org/10.1038/s41388-026-03895-6
  49. Biochim Biophys Acta Mol Basis Dis. 2026 Jul 28. pii: S0925-4439(26)00251-6. [Epub ahead of print] 168388
    Pannexin1 promotes cellular senescence by triggering mtDNA release to activate the cGAS-STING pathway.
    Jiaqi Li, Xin Zhao, Yanting Shen, Liuwei Huang, Jie Guo, Jun Wang.
      Cellular senescence is a pivotal driver of the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). We previously identified Pannexin 1 (Panx1) as an endoplasmic reticulum (ER)-resident calcium (Ca2+) leak channel that promotes renal tubular senescence; however, the precise downstream effectors remain elusive. Here, we establish a novel mechanistic link between Panx1 and the cGAS-STING pathway. We show that Panx1 triggers cGAS-STING activation by facilitating the cytosolic release of mitochondrial DNA (mtDNA). Mechanistically, we establish a strict hierarchical relationship in this process: the opening of the mitochondrial permeability transition pore (mPTP) serves as a mandatory prerequisite for BAX translocation to mitochondria, which together orchestrate the efflux of immunogenic mtDNA. Cytosolic mtDNA accumulation engages the cGAS-STING pathway, driving the senescence-associated secretory phenotype (SASP) through NF-κB signaling while concurrently activating IRF3-mediated interferon responses. Genetic or pharmacological blockade of the Panx1-mPTP-BAX-cGAS signaling cascade effectively attenuates the senescent phenotype in human tubular epithelial cells. In mouse models of renal ischemia/reperfusion injury, pharmacological inhibition of Panx1 or STING alleviates renal tubular senescence, fibrosis, and the pathological progression from AKI to CKD. Our findings define the Panx1/mPTP/BAX/cGAS-STING axis as a fundamental driver of cellular senescence, offering refined therapeutic targets for mitigating senescence-associated kidney pathologies.
    Keywords:  BAX; Cellular senescence; Pannexin1; cGAS-STING; mPTP; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168388
  50. Elife. 2026 Jul 31. pii: RP111611. [Epub ahead of print]15
    Decoupling AMPK from fatty acid synthesis allows maintenance of fitness late in life.
    Hanane Hadj-Moussa, Megan Ulusan, Dorottya Horkai, Mohammed Kamran Afzal Mirza, Jonathan Houseley.
      Although lifespan has long been the focus of ageing research, preventing functional decline late in life is a more pressing societal need. Here, we investigate the basis of senescence and declining fitness during replicative ageing in budding yeast, and describe a metabolic perturbation that preserves late-life fitness even on an unrestricted glucose diet. We show that senescence can be prevented by constitutive activation of AMPK, though only for approximately half the ageing population, and use genetic and functional assays to link this heterogeneous response with differences in cytosolic acetyl coenzyme A (Acetyl-CoA) metabolism. In one class of ageing cell, AMPK activity maintains fitness late in life through pathways that transport cytosolic Acetyl-CoA into mitochondria, but AMPK also inhibits fatty acid synthesis which leads to lipid starvation in the other class of ageing cell. Therefore, AMPK activity has both positive and negative effects, but we show that constitutive AMPK activity uncoupled from fatty acid synthesis inhibition (the A2A mutant) suppresses senescence and maintains fitness in both classes of ageing cell. Our findings support a model in which lipid starvation and excess Acetyl-CoA availability are major drivers of senescence in replicatively aged wild-type yeast. This work shows that ageing is not intrinsically associated with declining fitness, at least in yeast, and that re-engineering highly conserved metabolic pathways allows fitness to be preserved very late in life.
    Keywords:  AMPK; S. cerevisiae; acetyl coenzyme A; ageing; cell biology; healthspan; lipid synthesis; metabolism
    DOI:  https://doi.org/10.7554/eLife.111611
  51. Cell Chem Biol. 2026 Jul 30. pii: S2451-9456(26)00243-6. [Epub ahead of print]
    Resolving the subcellular redox landscape of Coenzyme Q.
    Tae Ha Kim, Chi Thi Ngoc Nguyen, Dahee Jang, Sae Bom Lee, Yun Jae Cha, Seon Min Kim, Yun Ji Lim, Tae Hwan Choi, Taeryeong Kim, Jae-Young Lee, Eun-Woo Lee, Sung Eun Kim, Tong-Shin Chang, You Jeong Lee, Maria Fedorova, Derek A Pratt, Marcus Conrad, Sung Won Kwon, Yun Pyo Kang.
      Coenzyme Q (CoQ) is an essential electron carrier and lipophilic antioxidant whose biological functions depend on its redox state. However, accurate measurement of reduced and oxidized CoQ is hindered by rapid ex vivo oxidation during sample preparation and analysis. Here, we develop a dual-isotope-based oxidation-correction LC-MS/MS platform that enables accurate quantification of CoQ redox status across diverse biological matrices. Coupled with rapid subcellular fractionation, this approach resolves cytosolic and mitochondrial CoQ pools and reveals that the CoQ10H2/CoQ10 ratio is substantially higher in the cytosol than in mitochondria. During ferroptosis, compartment-specific remodeling of CoQ redox status is observed, consistent with distinct roles for CoQ in plasma membrane and mitochondrial biology. The platform also enables robust analysis of plasma CoQ redox status in mouse and human samples. These advances provide a broadly applicable approach for studying redox biology, ferroptosis, mitochondrial metabolism, and biomarker discovery.
    Keywords:  CoQ; clinical biomarker; dual-isotope-based oxidation correction; ferroptosis; mass spectrometry; redox biochemistry; subcellular fractionation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.001
  52. Nat Genet. 2026 Jul 31.
    Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples.
    Nicola Calonaci, Eriseld Krasniqi, Daniel Colic, Stefano Scalera, Giorgia Gandolfi, Salvatore Milite, Konstantin Bräutigam, Andrea Sottoriva, Trevor A Graham, Leonardo Egidi, Biagio Ricciuti, Marcello Maugeri-Saccà, Giulio Caravagna.
      The interplay between somatic mutations and copy number alterations influences tumor evolution and prognosis. These alterations are often treated independently, overlooking gene mutant dosage (GMD)-a key property of their interaction. Here we develop a computational framework that infers mutation copy number and multiplicity from targeted sequencing panels without requiring matched normal samples. We derive GMD for over 500,000 mutations across 60,000 pan-cancer samples. By stratifying more than 20,000 patients according to GMD across multiple genes, we identify 46 tumor-type-specific biomarkers predictive of survival, 13 of which were undetectable using binary mutant/wild-type models, 26 were associated with metastatic spread and 20 predicted metastatic tropism. Our method reveals GMD patterns as independent predictors of disease prognosis, metastatic potential and site-specific dissemination across diverse tumor types. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis and holds the potential to substantially enhance biomarker discovery.
    DOI:  https://doi.org/10.1038/s41588-026-02666-z
  53. Nat Rev Genet. 2026 Jul 29.
    Genomic, epigenomic and transcriptomic regulation of cellular senescence.
    Rahagir Salekeen, Tra L Kieu, Paul D Robbins, Laura J Niedernhofer, Linshan Laux.
      Cellular senescence is a complex, highly regulated cell state induced by cellular damage and stress. Senescence is central to many areas of biology, with roles in tumour suppression, tissue regeneration, antiviral defence and diverse age-related pathologies. Senescence is characterized by stable cell cycle arrest, metabolic alterations, chromatin remodelling and the secretion of pro-inflammatory and tissue-modifying factors that are collectively termed the senescence-associated secretory phenotype. Recent technological advances, including new genetic models, single-cell and spatial multi-omics platforms and machine-learning approaches, promise to enable the phenotyping, tracing and manipulation of senescent cells with unprecedented precision and resolution. This Review defines our current understanding of the genetic pathways that regulate senescence induction, maintenance, propagation and heterogeneity, including the DNA damage response, non-genotoxic stress pathways, epigenetic changes and cell-cell communication. We also emphasize key challenges in distinguishing senescence from other cell fates and the need for next-generation biomarkers to capture the varied phenotypes and functions of senescent cells.
    DOI:  https://doi.org/10.1038/s41576-026-00982-y
  54. Nat Rev Cancer. 2026 Jul 27.
    Who gets told what is impossible?
    Johanna A Joyce.
      
    DOI:  https://doi.org/10.1038/s41568-026-00961-9
  55. Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00847-8. [Epub ahead of print]45(8): 117769
    CXCR4 marks homeostatically activated dendritic cells in the steady state and in cancer.
    Mariana Pereira da Costa, Cécile Piot, Margarida Bonifacio, Victor Bosteels, Adi Biram, Estelle Wu, Lies van Baarle, Michael D Buck, Caetano Reis E Sousa.
      Conventional dendritic cells (cDCs) can be activated by pathogen signals and inflammation to drive T cell immunity to infection, but they can also undergo "homeostatic activation" at steady state. However, homeostatically activated cDCs closely resemble those activated by microbial or viral stimuli, hindering their study. Here, we identify the chemokine receptor CXCR4 as a specific marker of homeostatically activated cDCs across mouse tissues. CXCR4 is induced in cDCs in the steady state but not following stimulation with Toll-like receptor agonists or type I interferons. In tumors, CXCR4 expression or a gene signature derived from mouse spleen CXCR4hi cDCs marks the so-called "mregDCs" that have acquired tumor-derived material. Notably, the gene signature derived from mouse spleen CXCR4hi cDCs further identifies mregDCs in human cancers. Thus, CXCR4 distinguishes homeostatic from inflammatory cDC activation programs, providing a means to identify and study this cDC state in both physiological and pathological contexts.
    Keywords:  CP: Immunology; activation; cancer; conventional dendritic cells; homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117769
  56. Nat Methods. 2026 Jul 31.
    SpaMTP: integrative statistical analysis and visualization of spatial metabolomics and transcriptomics data.
    Andrew Causer, Tianyao Lu, Jurgen Kriel, Joel J D Moffet, Christopher C J Fitzgerald, Andrew Newman, Hani Vu, Xiao Tan, Tuan Vo, Cedric Cui, Vinod K Narayana, James R Whittle, Sarah A Best, Saskia Freytag, Quan Nguyen.
      Spatially resolved multimodal data enable the exploration of transcriptional, proteomic and metabolic regulation, yet analytical tools to integrate these spatial omics modalities, particularly spatial metabolomics, remain limited. We developed SpaMTP, an end-to-end framework that implements functions within a common Seurat architecture. It introduces analyses for metabolite annotation, joint clustering, enrichment tests, spatial alignment, multimodal integration, visualization and seamless software interoperability. Its utility is demonstrated across different biological systems.
    DOI:  https://doi.org/10.1038/s41592-026-03140-8
  57. bioRxiv. 2026 Jul 22. pii: 2026.07.17.738958. [Epub ahead of print]
    Sulfur amino acid restriction prevents S-adenosylmethionine-driven liver steatosis, hepatocellular carcinoma, and metabolic remodeling in high-fat-fed GNMT-null mice.
    Griffin S Hampton, Andres F Ortega, Cha Mee Vang, Ferrol I Rome, Mickael Goelzer, Louise Lantier, Curtis C Hughey.
      The expression of glycine N-methyltransferase (GNMT), a critical regulator of S-adenosylmethionine (SAM) levels, is down-regulated in humans with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). In low-fat-fed mice, GNMT knockout (KO) induces liver steatosis that progresses to HCC. This is accompanied by increased SAM and a shunting of tricarboxylic acid (TCA) cycle intermediates away from gluconeogenesis to other biosynthetic pathways that support lipid accretion and tumorigenesis. The objective of this study was to test whether this metabolic remodeling persists in GNMT KO mice with diet-induced obesity and to determine if the liver pathophysiology and metabolic dysregulation are dependent on elevated SAM. To accomplish this, GNMT KO mice and wild-type (WT) littermates were fed a high-fat control or high-fat sulfur amino acid restricted (SAAR) diet to mitigate SAM accumulation. 2 H/ 13 C isotope infusions in mice quantified in vivo liver glucose and TCA cycle fluxes. Metabolomics, respirometry, and pyruvate tolerance tests were completed to more fully interpret the 2 H/ 13 C metabolic flux analyses. KO mice had impaired gluconeogenesis sourced from TCA cycle intermediates. A concurrent elevation in metabolites of pathways that use both SAM and TCA cycle intermediates indicated increased liver polyamine turnover, transsulfuration, and de novo lipogenesis. Importantly, SAAR prevented the increase in SAM, the associated metabolic dysregulation, and the appearance of liver steatosis and HCC. In conclusion, the results of these experiments suggest that the loss of GNMT in mice with diet-induced obesity rewires metabolism in a SAM-dependent manner that precipitates liver steatosis and the transition to HCC.
    DOI:  https://doi.org/10.64898/2026.07.17.738958
  58. Oncogene. 2026 Jul 28.
    A genome-wide CRISPR screen in human prostate cancer cells reveals drivers of macrophage-mediated cell killing and positions AR as a tumor-intrinsic immunomodulator.
    Anniek Zaalberg, Audrey Lacoste, Emma Minnee, Isabel Mayayo-Peralta, Karianne Schuurman, Sebastian Gregoricchio, Thijs A van Schaik, Liesbeth Hoekman, Dapei Li, Eva Corey, Hans Janssen, Cor Lieftink, Stefan Prekovic, Natalie Proost, Marieke van de Ven, Serge Zander, Maarten Altelaar, Peter S Nelson, Roderick L Beijersbergen, Wilbert Zwart, Andries M Bergman.
      Macrophages are the most abundant immune cells in the prostate tumor microenvironment and capable of killing tumor cells, but tumor intrinsic modulators of resistance to the innate immune system are unknown. To identify genes essential for macrophage-mediated killing, we performed a genome-wide co-culture CRISPR screen and identified Androgen Receptor (AR), PRKCD, and multiple components of the NF-κB pathway (IKBKB/IKBKG/CHUK) as tumor-intrinsic essential factors to allow for macrophage-mediated killing. Mechanistically, both AR and NF-κB directly drive expression of PRKCD within cancer cells, functionally implicating all hits within one molecular pathway. Importantly, androgen deprivation and AR-inhibition both rendered tumor cells resistant to macrophage-mediated killing, which positions tumor-intrinsic AR signaling as a bona fide immunomodulatory pathway. Proteomic analyses showed a selective downregulation of the oxidative phosphorylation pathway in PRKCD- and IKBKG-KO cells, suggesting impaired mitochondrial function, which was confirmed by electron microscopy analyses. Finally, phosphoproteomic analyses revealed that all hits perturbing macrophage-mediated tumor cell eradication, impaired ferroptosis signaling in the tumor cells, which was confirmed transcriptionally using samples from a neoadjuvant phase II clinical trial with the AR-inhibitor enzalutamide. These data reveal immune protection from macrophages as an adverse consequence of hormonal therapy in prostate cancer patients.
    DOI:  https://doi.org/10.1038/s41388-026-03912-8
  59. Nat Methods. 2026 Jul 31.
    CellTune: an integrative software for accurate cell classification in spatial proteomics.
    Yuval Bussi, Dana Shainshein, Eli Ovits, Sarah Posner, Nofar Azulay, Noa Maimon, Tal Keidar Haran, Raz Ben-Uri, Caitlin Brown, Noam Schuldiner, Eylon Yaniv, David Van Valen, Idan Milo, Ofer Elhanani, Robert Schiemann, Leeat Keren.
      Spatial proteomics measures multiple proteins in situ, capturing tissue complexity. However, cell classification in densely packed tissues remains challenging because of the lack of efficient classification algorithms, annotation tools and high-quality labeled datasets to benchmark computational methods. We introduce CellTune, an integrated software for analysis of large spatial proteomics datasets, which streamlines precise cell classification through an optimized human-in-the-loop active learning workflow. It advances core capabilities for analysis of large datasets with an intuitive and code-free interface. To evaluate CellTune, we created CellTuneDepot, a resource of 40,000 manually annotated cells and 3.5 million high-quality labeled cells across 60 cell types. CellTune outperforms alternative methods, achieving accuracy comparable to human performance while enabling increased classification resolution and discovery of novel cell types. Together, CellTune and CellTuneDepot provide researchers with a tool for state-of-the-art classification accuracy and resolution at scale to drive biological insights.
    DOI:  https://doi.org/10.1038/s41592-026-03162-2
  60. Oncogene. 2026 Jul 26.
    The phase separation of ZC3H18 transcriptionally activates LDHA and forms lactylation-mediated positive feedback loop to promote tumorigenesis of lung cancer.
    Dandan Yin, Chang Zhang, Yuancheng Li, Jiali Dai, Tianyu Qu, Jun Su, Xiyi Lu, Pingping Wu, Liang Han, Erbao Zhang.
      RNA-binding proteins (RBPs) play crucial roles in tumorigenesis and cancer treatment. As metabolic reprogramming is known to participate in tumorigenesis, elucidation of the mechanisms of crosstalk between RBPs and metabolism could provide new insights into cancer biology. Here, we found that the RBP ZC3H18 is overexpressed in lung cancer through copy number gain, which exerts oncogenic functions. Mechanistically, ZC3H18 undergoes phase separation to transcriptionally activate a key metabolic enzyme, lactate dehydrogenase A (LDHA), by binding to the LDHA promoter, thus promoting glycolysis and the production of lactate. The accumulation of lactate, in turn, activates the transcription of ZC3H18 through histone H3K18 lactylation (H3K18la) and directly induces the lactylation of ZC3H18 at the Lys186 residue (K186) in post-translational, thus forming a positive ZC3H18/LDHA/lactate/ZC3H18 feedback loop. Moreover, the combination of ZC3H18 inhibition and an LDHA small-molecule inhibitor (GSK2837808A) exhibited better antitumor efficacy in lung cancer patient-derived xenograft (PDX) model, suggesting the therapeutic potential of targeting the ZC3H18/LDHA axis. Taken together, our findings clarify the dialogue between RBP phase separation and lactate metabolism from a novel perspective and suggest that the ZC3H18/LDHA axis may serve as a potential therapeutic target for lung cancer.
    DOI:  https://doi.org/10.1038/s41388-026-03817-6
  61. Cell Rep. 2026 Jul 27. pii: S2211-1247(26)00804-1. [Epub ahead of print]45(8): 117726
    The Drosophila CEBPG homolog Irbp18 partners with crc (ATF4) to mediate the integrated stress response in degenerative disease models.
    Sahana Mitra, Huai-Wei Huang, Rhihab Faruk, Arissa Low, Adam I Yeo, Hyung Don Ryoo.
      The integrated stress response (ISR) coordinates cellular adaptation to diverse stress conditions. In Drosophila, two bZIP transcription factors, Xrp1 and crc (ATF4 homolog), are induced during ISR. Crc protein can dimerize with two CEBP factors in vitro, but the in vivo relevance of those interactions remained unknown. Here, we report that the CEBPG homolog, Irbp18, is an essential partner of crc during ISR. Specifically, Irbp18 is broadly required for the transcriptional induction of ISR target genes in the photoreceptors of ninaEG69D, a Drosophila model of retinitis pigmentosa. Moreover, CUT&RUN analysis indicates that Irbp18 loss reduces or abolishes crc binding to target DNAs in photoreceptors and impairs crc's ability to induce target transcripts upon overexpression. Functionally, Irbp18 loss causes retinal degeneration and suppresses ISR signaling in parkin mutants, a model of Parkinson's disease. Together, these findings identify Irbp18 as a cofactor for crc, impacting pathological outcomes in Drosophila models of degeneration.
    Keywords:  ATF4; CEBP; CP: molecular biology; CP: neuroscience; ISR; Irbp18; bZIP; dimerization; integrated stress response; parkin; retinal degeneration; transcription factor
    DOI:  https://doi.org/10.1016/j.celrep.2026.117726
  62. bioRxiv. 2026 Jul 20. pii: 2026.07.19.739395. [Epub ahead of print]
    Loss of TAFAZZIN leads to perturbation of amino acid metabolism and reduction of collagen synthesis.
    Abu Ramim, Tyler Ralph-Epps, Linh Vo, Hyejeong Jang, Janaka S S Liyanage, Kaitlin Lowran, Miriam L Greenberg.
      Barth syndrome is a life-threatening genetic disorder caused by mutations in the TAFAZZIN (TAZ) gene, which disrupt remodeling of cardiolipin in mitochondria. The disease is associated with cardiac and skeletal myopathy, neutropenia, fatigue, and metabolic dysfunction. Previous studies showed that loss of TAZ decreases pyruvate dehydrogenase activity, reduces glucose flux into the TCA cycle, and impairs fatty acid metabolism. To test the hypothesis that amino acid (AA) metabolism may be altered to compensate for these deficiencies, we characterized AA metabolism in TAZ-deficient mouse myoblasts (TAZ-KO). Levels of branched-chain amino acids (BCAAs) were reduced, while proline levels were increased in TAZ-KO cells. Levels of proline dehydrogenase and glutamate dehydrogenase, which convert proline to TCA cycle intermediates, were increased. 13 C 5 -proline isotope tracing demonstrated elevated conversion of proline into glutamate and TCA cycle intermediates. SILAC analysis using [U- 13 C 6 , 15 N 2 ]-Lys and [U- 13 C 6 ]-Arg revealed decreased synthesis of collagen and proteins associated with extracellular matrix (ECM). Gene expression and protein analyses revealed reduced collagen expression, lower total collagen content, decreased collagen crosslinking enzymes, decreased proline hydroxylation and reduced synthesis of new collagen and cell-adhesion proteins. SILAC analysis using [U- 13 C 6 , 15 N 2 ]-proline also showed diminished incorporation of proline into newly synthesized ECM proteins. Together, our findings reveal that loss of TAZ leads to increased proline catabolism to the TCA cycle, decreased incorporation of proline into collagen, and impaired collagen synthesis and ECM remodeling.
    DOI:  https://doi.org/10.64898/2026.07.19.739395
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒02 at 4:56.