bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–07–26
47 papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
  2. Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.
  3. Design Principles and Architecture of Cellular Nutrient Signaling.
  4. Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
  5. Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
  6. Genetic background sets the trajectory of experimental cancer evolution.
  7. Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling.
  8. Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells.
  9. Tertiary lymphoid structures harbour stem-like tumour-specific T cells.
  10. Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.
  11. 3D nanoscale reconstruction of human airway multiciliogenesis reveals cellular architecture remodeling and cilia-mitochondria link via rootlets.
  12. You are when you eat: How food synchronizes liver clocks.
  13. Dynamic dimer-of-dimers architecture defines Mg2+ transport in human CNNM4.
  14. Molecular Pathogenesis and Therapeutic Response of Diffuse Large B Cell Lymphoma Genetic Subtypes.
  15. Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.
  16. Lysosomes and Supersulfides: Emerging Links in Cellular Metabolism and Homeostasis.
  17. PLA2G2F suppresses ferroptosis through phospholipid remodeling.
  18. Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
  19. Mapping mesenchymal diversity in the human small intestine and organoids.
  20. Targeting ATP-citrate lyase across cardiometabolic and oncologic disease.
  21. A genetically encoded sensor of ionic stress links cellular proton dynamics to sleep.
  22. Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice.
  23. Distinct sources and effects of mitochondrial reactive oxygen species.
  24. Ascites-derived lipid barrier at the T cell synapse.
  25. Human genetics across levels of biological organization.
  26. Gene expression adaptation of metastases to their host tissue.
  27. The Legionella pneumophila effector SidL is an adenylyltransferase that modifies the glycolytic intermediate 3-phosphoglycerate.
  28. ELF3 links kidney function GWAS loci to maladaptive epithelial inflammation.
  29. The impact of microbial metabolites on host chromatin and epigenetic regulation.
  30. Hepatocyte HIF2α Downregulates the Urea Cycle Through Suppression of HNF4α.
  31. Efferocytosis activates a DNMT3A-mediated oxidized DNA repair pathway to enable tissue resolution.
  32. Hypoxia as an amplifier of synovial inflammation in rheumatoid arthritis.
  33. Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer.
  34. mTOR signaling contributes to system-driven rhythmic gene expression in mouse liver.
  35. How Big Data and AI are revolutionizing human immunology.
  36. An Insight into the cGAS-STING Pathway Modulation by Metal Complexes to Initiate Immunogenic Cell Death in Cancer.
  37. Positioning TERT at the apex of aging.
  38. Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.
  39. Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.
  40. Mathematical Modelling of the Mitochondrial Dicarboxylate Carrier (SLC25A10).
  41. Expansion of Germline Variants in Primary Hyperparathyroidism: Fumarate Hydratase Deficiency as a Cause of Parathyroid Adenomas.
  42. Mitochondrial tRNA biogenesis, modifications and disease relevance.
  43. Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.
  44. Copper-dependent redox remodeling of the actin cytoskeleton regulates renal epithelial cell mechanics.
  45. Human body single-cell atlas of three-dimensional genome organization and DNA methylation.
  46. Geroprotective insights into the natural metabolite spermidine in aging and age-related diseases.
  47. Understanding and making sense of epigenetic age misalignment across different aging clocks.
  1. Nat Metab. 2026 Jul 23.
    Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
    Deborah Y Moss, Connor N Brown, Andrew M Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J McDaid, Andrew Roe, Aisling Y Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E Ryan, Philip D Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C Greaves, Bryan P Marzullo, Daniel A Tennant, Vicky Coyle, Ian G Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B Longley, Simon S McDade, Melissa J LaBonte, Emma M Kerr.
      Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.
    DOI:  https://doi.org/10.1038/s42255-026-01578-w
  2. Nat Aging. 2026 Jul 24.
    Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.
    Mariah F Calubag, Ismail Ademi, Cara L Green, Dulmalika N H Manchanayake, Hashan S M Jayarathne, Ryan N Marshall, Sandra M Le, Penelope Lialios, Lucia E Breuer, Shoshana Yakar, Reji Babygirija, Michelle M Sonsalla, Isaac Grunow, Chung-Yang Yeh, Yang Liu, Bailey A Knopf, Sarah Yandell, Charles I Opara, William A Ricke, Teresa T Liu, Mark P Keller, Alan D Attie, Marianna Sadagurski, Dudley W Lamming.
      Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s43587-026-01169-0
  3. Annu Rev Genet. 2026 Jul 20.
    Design Principles and Architecture of Cellular Nutrient Signaling.
    Gaurav Singh, Kaveri Vaidya, Sunil Laxman.
      A cell functions as a metabolic economy that parses information on nutrient availability and internal metabolic flux and then converts that to state outcomes that maintain or shift homeostasis. Here, we discuss how the nutrient-signaling machinery in cells follows an hourglass (or bow tie) design architecture, using modular signal integrators. In eukaryotic cells, this architecture is exemplified by two evolutionarily conserved, core complexes: mechanistic target of rapamycin complex 1 (mTORC1)/TORC1 and AMP-activated protein kinase (AMPK). This bow-tie design of core signal integrators enables cells to condense, fan-in, and integrate noisy metabolic information. These integrators then meaningfully transduce this condensed information into durable cell state transitions by fanning-out resource allocations toward distinct outputs that are all within the possibilities of the existing metabolic economy. Through this design, cells can incorporate diverse metabolite- or flux-sensing modules, secondary integrators, and localization or higher-order assemblies to alter response kinetics over time and space. We discuss how these inherent design constraints result in robust yet versatile cellular decision-making that can drive cell-to-cell heterogeneity. Finally, we highlight how genetic mutations in this machinery disrupt information processing through the bow tie, shifting homeostasis toward disease states.
    DOI:  https://doi.org/10.1146/annurev-genet-012026-084152
  4. JCI Insight. 2026 Jul 22. pii: e199182. [Epub ahead of print]11(14):
    Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
    David Alsina, Diana Rubalcava-Gracia, Kristina Bubb, Rodolfo Garcia-Villegas, Akos Vegvari, Roberta Filograna, Florian A Rosenberger, Camilla Koolmeister, Nils-Göran Larsson.
      Mitochondrial gene expression is essential for oxidative phosphorylation that generates the bulk of the cellular ATP, and mitochondrial dysfunction is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described in patients presenting with a wide variety of clinical manifestations, including hypotonia, short stature, and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, a finding consistent with a failure to adapt to the metabolic transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for near-genome length transcription but not primase activity. This study highlights genotype-phenotype differences and provides new insights into POLRMT function.
    Keywords:  Cell biology; Metabolism; Mitochondria; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.199182
  5. Nat Struct Mol Biol. 2026 Jul 23.
    Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
    Xiaolong Liu, Hongjun Cai, Hao Wang, Xueyin Zhou, Yutong Zhang, Shuai Liu, Jiajun Zhu, Long Li.
      Metabolite carriers that control essential metabolite transport are imported into mitochondria through the TOM and TIM22 complexes. How TOM and TIM22 coordinate in human mitochondria has remained largely unknown. Here we show that human TOM and TIM22 assemble into a supercomplex that seamlessly couples carrier translocation across the outer and inner membranes, unlike in yeast where the two complexes appear to function separately. Cryo-electron microscopy structures of the human TOM-TIM22 supercomplex reveal unpaired carrier transmembrane segments traversing the TOM channel along a hydrophobic path and exiting through an unexpected lateral groove outside the channel. The membrane-bound small Tim subunits provide the substrate entry site for TIM22, while a membrane-exposed groove of TIM22 serves as the exit for carrier insertion into the inner membrane. These findings provide insights into the human carrier translocation pathway at molecular resolution and establish the TOM-TIM22 supercomplex as a central organizing unit of mitochondrial carrier import.
    DOI:  https://doi.org/10.1038/s41594-026-01849-w
  6. Nature. 2026 Jul 22.
    Genetic background sets the trajectory of experimental cancer evolution.
    Liver Cancer Evolution Consortium
      Human cancers are heterogeneous1. Dissecting how germline genetic variation and environmental factors shape tumour evolution using human datasets is limited by inherent diversity in genetic backgrounds2 and environmental exposures3-5. Here, to overcome these limitations, we re-ran early tumour evolution hundreds of times in diverged inbred mouse strains, generating matched histology and whole-genome and transcriptome sequences. The sex, environment and carcinogenic exposures were all controlled, and the study design allowed us to capture genetic variation comparable with that observed across human populations while exploiting the nested hierarchical structure of strain-litter-animal-tumour relationships. Our analyses reveal that epistatic interactions between genetic background and acquired somatic mutations result in population-specific disease progression, including choice of driver mutations, occurrence of whole-genome duplication and subclonal selection dynamics that mirror both cancer susceptibility and tumour growth rate. Even modest genetic divergence, comparable with that found across human ancestry groups, can strikingly alter selection pressures during cancer development to shape both cancer risk and the trajectory of tumour evolution.
    DOI:  https://doi.org/10.1038/s41586-026-10821-z
  7. Circulation. 2026 Jul 21. 154(3): 223-239
    Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling.
    Shijie Liu, Seth T Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Mahmoud H Elbatreek, Adrian Arrieta, Ian K Williamson, Rebecca L Salazar, Janet Pham, Angela Davidian, Radhika Khanna Neicheril, Benjamin D Gould, Heidi Vitrac, Alia Sadiq, An Q Dinh, Evan C Lien, Francisca N de Luna Vitorino, Joanna M Gongora, Sara A Martinez, Melanie T Odenkirk, Anna K Boatman, Jessie R Chappel, Lawrence S C Czer, Evan P Kransdorf, David J Lefer, Blake M Hanson, Benjamin A Garcia, Erin M Baker, Matthew G Vander Heiden, Philip L Lorenzi, Heinrich Taegtmeyer, David Piwnica-Worms, James F Martin, Anja Karlstaedt.
       BACKGROUND: Metabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase, Acly), which produces acetyl-coenzyme A (CoA) from citrate and CoA and supports de novo lipid synthesis. However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated.
    METHODS: We used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) gene editing to inactivate Acly in cardiomyocytes of Myh6-Cas9 mice. In vivo positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to Acly knockdown. We conducted a multi-omics analysis using RNA sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level.
    RESULTS: We observed reduced ACL abundance and activity in human heart tissue samples from patients with nonischemic cardiomyopathy, which correlated with decreased abundance of Krebs cycle intermediates. Using CRISPR/Cas9 gene editing, we found that cardiac-specific loss of ACL reduces acetyl-CoA synthesis, leading to altered cardiac metabolism characterized by increased glucose uptake and oxidation, impaired energy flux, and elevated AMP to ATP ratios, which collectively promote left ventricular dysfunction. Transcriptomic and mass spectrometry-based metabolomics, as well as proteomic data, reveal compensatory cardiac lipid remodeling and reduced histone 3 acetylation. This metabolic stress promotes activation of AMPK (AMP kinase) and PKA (protein kinase A), which in turn mediates YAP (Yes-associated protein) inhibition through phosphorylation. Stable isotope tracer studies combined with CardioNet simulations demonstrated that increased IDH1 (isocitrate dehydrogenase 1) activity prevents allosteric inhibition of glycolysis from cytosolic citrate accumulation. AAV9-mediated cardiac Idh1 deletion improved cardiac function and energy provision, reducing YAP phosphorylation and restoring downstream YAP signaling.
    CONCLUSIONS: Our findings suggest that ACL plays a pivotal role in cardiac metabolism through regulating lipid synthesis and cardiac function. Exploiting compensatory pathways of citrate metabolism may improve cardiac function during heart failure.
    Keywords:  ATP-dependent citrate lyase; cardio-oncology; metabolism; systems biology
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.076453
  8. Nat Biotechnol. 2026 Jul 22.
    Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells.
    Adi Nagler, Amit Sud, Jack Y Ghannam, Lucas Pomerance, Camila Robles-Oteiza, Alexander B Afeyan, Jackson A Weir, Andrew J C Russell, Wesley S Lu, McKayla Van Orden, Andrea Sonnenholzner, Giovanni J Marrero, Qiyu Gong, Vipin Kumar, Kun Huang, Chloe Tu, Emma Lin, Bohoon Shim, Gabriel R De Oliveira, MacLean C Sellars, Charles H Yoon, David A Reardon, Toni K Choueiri, Lars R Olsen, Sabina Signoretti, Patrick A Ott, David A Braun, Giacomo Oliveira, Shuqiang Li, Kenneth J Livak, Nir Hacohen, Fei Chen, Catherine J Wu.
      Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue. Application of Slide-GoTags to mouse and human tumors revealed colocalization of clonally expanded, neoantigen-specific T cells with tumor cells expressing their cognate neoantigen. We also identified distinct spatial immune landscapes shaped by anti-PD1 or anti-CTLA4 blockade in mouse colorectal tumors. Across human tumor types, Slide-GoTags detected TCR-neoantigen interactions through spatial proximity and identified an enrichment of interferon-driven immunogenicity niches in immunologically 'hot' tumors compared to 'cold' tumors. These niches harbored three T cell clonotypes that colocalized with genotyped neoantigens, highlighting a spatially organized antitumor immune response. Collectively, Slide-GoTags establishes a framework for in situ mapping of T cell-tumor interactions directly from individual tissue.
    DOI:  https://doi.org/10.1038/s41587-026-03194-1
  9. Nature. 2026 Jul 22.
    Tertiary lymphoid structures harbour stem-like tumour-specific T cells.
    Alexander B Afeyan, Adi Nagler, Chloe R Tu, Gabriel Roberti De Oliveira, Berkay Simsek, Maxwell D Seager, Nourhan El Ahmar, Haley E Sax, Emma Lin, Amit Sud, Mehdi Borji, Cleo Forman, Sophia Liu, Patrick A Ott, Toni K Choueiri, Jennifer G Abelin, Richard Burack, Shuqiang Li, Kenneth J Livak, Svitlana Tyekucheva, Derin B Keskin, Fei Chen, Michael B Atkins, Jeremy M Simon, Sabina Signoretti, Giacomo Oliveira, David A Braun, Catherine J Wu.
      Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours1,2, but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8+ T cells and have a reduced terminal exhaustion transcriptional program compared with TLS- tumours. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumours revealed 82 TCRs that were reactive against tumour cells and/or RCC antigens. A subset of tumour-specific T cell clonotypes (12%) was enriched within TLSs, and these expressed an increased program of stem-like progenitor exhaustion, associated with favourable anti-tumour immunity. However, in 60 independent RCC tumours, macrophages within tumour margins of TLS-containing tumours had an inferred immunosuppressive phenotype and were colocalized with exhausted putative tumour-reactive T cells in a subgroup that was further analysed, therefore supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal that TLSs are reservoirs of tumour-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-026-10808-w
  10. Acta Neuropathol. 2026 Jul 23. pii: 10. [Epub ahead of print]152(1):
    Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.
    Matthew Pun, Akash Deogharkar, Siva Kumar Natarajan, Nicholas Nuechterlein, Wentao Tian, Sunjong Ji, Eleanor Young, Fusheng Yang, Debra Hawes, Anthony C Andren, John Henry Owen, Sagar Rau, Fengyun Su, Xuhong Cao, Abhijit Parolia, Mark Prince, Joshua Fry, Paul A Gardner, Rendong Yang, Alexander R Judkins, Carl J Koschmann, Andrew S Venteicher, Costas A Lyssiotis, Arul M Chinnaiyan, Sriram Venneti.
      Chordomas are rare cancers that arise along the axial skeleton. Alterations in metabolism are a hallmark of cancer, and we sought to identify metabolic vulnerabilities in chordoma. We discovered that the tricarboxylic acid (TCA)-related enzyme isocitrate dehydrogenase-1 (IDH1) was expressed highly in bulk and single-cell patient-derived chordomas and was associated with worse survival outcomes. IDH1 catalyzes the conversion of isocitrate and nicotinamide adenine dinucleotide phosphate (NADP+) to alpha-ketoglutarate (⍺-KG) and NADPH. This critical reaction influences TCA cycle metabolism, regulates epigenetic pathways, and affects redox balance. Both IDH1 knockdown and treatment with an inhibitor targeting IDH1 were toxic to chordoma cells. An integrated analysis of the transcriptomic, chromatin, and metabolomic responses on IDH1 inhibition converged on deregulated glutathione metabolism. IDH1 inhibition was associated with increased expression and enrichment of activating H3K27ac at NRF2 (nuclear factor erythroid 2-related factor 2) signature genes including those in the glutathione biosynthetic pathway. This was accompanied by reduction of both NADPH/NADP+ and reduced/oxidized glutathione (GSH/GSSG) ratios. Importantly, IDH1 inhibitor-driven toxicity was rescued via media supplementation with the antioxidant N-acetylcysteine, suggesting that IDH1 inhibition in chordomas creates a redox-dependent metabolic vulnerability. Finally, IDH1 inhibitor treatment reduced tumor growth in two independent chordoma mouse xenograft models. Our findings suggest a potential therapeutic avenue for further exploration in chordoma.
    Keywords:  Chordoma; IDH1; Metabolism; NRF2; Redox
    DOI:  https://doi.org/10.1007/s00401-026-03048-9
  11. Cell Rep. 2026 Jul 22. pii: S2211-1247(26)00792-8. [Epub ahead of print]45(7): 117714
    3D nanoscale reconstruction of human airway multiciliogenesis reveals cellular architecture remodeling and cilia-mitochondria link via rootlets.
    Cell Map Project Team
      A central challenge in single-cell biology is understanding how molecular programs drive changes in cellular architecture that enable specialized function. A striking example of cellular remodeling is the differentiation of airway stem cells into the respiratory multiciliated epithelium, a protective tissue barrier that clears inhaled pathogens and particulate matter. Here, we present its first three-dimensional nanometer-scale reconstruction, revealing coordinated changes in cellular organization, organelle topology, and inter-organelle contacts during multiciliogenesis. We uncover a structural and functional association between motile cilia and mitochondria mediated by rootlets, striated cytoskeletal fibers that remain poorly characterized in human airway multiciliated cells. Rootlets connect to basal bodies through a multiprotein linker containing the uncharacterized rootletin/CROCC homolog CROCC2, oscillate at frequencies comparable to ciliary beating, promote basal body alignment, and when lost, reduce maximal mitochondrial respiratory capacity. Altogether, this work integrates structural, dynamic, and functional analyses to elucidate mechanisms underlying airway mucociliary defense.
    Keywords:  CP: cell biology; airway respiratory epithelium; cellular organization; cilia; mitochondria; nanoscopy; organelle contacts; rootlets; super-resolution microscopy; volume electron microscopy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117714
  12. Sci Adv. 2026 Jul 24. 12(30): eaej7423
    You are when you eat: How food synchronizes liver clocks.
    Qin Zhou, Mitchell A Lazar.
      Food ingestion synchronizes liver circadian gene expression via hormone and nutrient regulation of the mTOR pathway.
    DOI:  https://doi.org/10.1126/sciadv.aej7423
  13. Cell. 2026 Jul 24. pii: S0092-8674(26)00759-2. [Epub ahead of print]
    Dynamic dimer-of-dimers architecture defines Mg2+ transport in human CNNM4.
    Zhiyong Bai, X Edward Zhou, Wei Lü, Juan Du.
      Mg2+ is essential for all living organisms, yet its transport across mammalian membranes remains poorly understood. Here, we present cryoelectron microscopy (cryo-EM) structures of a full-length mammalian Mg2+ transporter on the plasma membrane, human CNNM4, in outward-facing and occluded states, revealing an unexpected tetrameric assembly organized as a dimer of asymmetric dimers-distinct from the symmetric dimers in prokaryotic homologs and long assumed for eukaryotic CNNMs. We show that Mg2+/ATP binding stabilizes the dynamic intracellular domains and promotes tetramerization, while an acidic patch binds additional Mg2+, potentially acting as a sensor to couple cytoplasmic Mg2+ levels to transport activity. Within the transmembrane domain, a key glutamate flips upon Na+ binding and destabilizes the Mg2+-binding site in the outward-facing state, thereby promoting Mg2+/Na+ exchange. Together, these findings establish a mechanistic framework for CNNM transport and regulation that diverges from prokaryotic models and links CNNM function to human physiology and disease.
    Keywords:  ATP binding; CNNM4; cryo-EM structure; dimer of asymmetric dimers; domain swapping; human; magnesium binding; magnesium homeostasis; magnesium sensing; magnesium transport
    DOI:  https://doi.org/10.1016/j.cell.2026.06.039
  14. Annu Rev Cancer Biol. 2026 Apr;10 439-460
    Molecular Pathogenesis and Therapeutic Response of Diffuse Large B Cell Lymphoma Genetic Subtypes.
    James D Phelan, Julius C Enssle, Sean R Corcoran, George W Wright, Louis M Staudt.
      Diffuse large B cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease. Molecular profiling studies in DLBCL have identified three distinct disease subtypes using gene expression profiling, whereas mutation analysis of tumors has identified at least six separate subtypes. Although each classifier predicts clinical responses to immunochemotherapy and targeted therapies, molecular profiling is not universally performed or uniformly implemented. In this review, we focus on the biology of the LymphGen algorithm defined genetic subtypes revealed by genomic, transcriptomic, and single-cell profiling. We highlight recent advances in understanding the major drivers of disease and discuss how different mutations promote common hallmarks of cancer that are vulnerable to precision medicine agents.
    Keywords:  BTK inhibitor; DLBCL; LymphGen; genetic subtypes
    DOI:  https://doi.org/10.1146/annurev-cancerbio-071124-033604
  15. Cell Metab. 2026 Jul 21. pii: S1550-4131(26)00274-3. [Epub ahead of print]
    Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.
    Daniel R Weilandt, Won Dong Lee, Michael R MacArthur, Lingfan Liang, Corey D Holman, Qingwei Chu, Alexis J Cowan, Joseph A Baur, Ned S Wingreen, Joshua D Rabinowitz.
      Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, lactate, free fatty acids, and ketones. Yet how the simultaneous homeostasis of these nutrients is achieved remains unclear. Here, we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation ("competitive catabolism"). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes insulin resistance: increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose and thus insulin, which acts to restore proper lipid catabolic flux. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.
    Keywords:  competitive catabolism; differential equation modeling; hyperinsulinemia; insulin regulation; insulin resistance; mass action kinetics; metabolic homeostasis; nutrient competition; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.001
  16. J Biochem. 2026 Jul 24. pii: mvag058. [Epub ahead of print]
    Lysosomes and Supersulfides: Emerging Links in Cellular Metabolism and Homeostasis.
    Natsumi Sakata, Takaaki Akaike, Hozumi Motohashi.
      Supersulfides, a class of catenated sulfur-containing biomolecules, are increasingly recognized as key regulators of redox signaling, mitochondrial function, and inflammatory responses. Recent evidence suggests that lysosomes, central organelles for intracellular degradation and nutrient sensing, are closely linked to supersulfide metabolism through lysosomal acidification, cysteine metabolism, and autophagy. Conversely, supersulfides modulate lysosomal activity and inflammatory responses. This review summarizes recent progress in supersulfide biology and lysosomal regulation and discusses evidence supporting functional interactions between these systems. We propose the lysosome-supersulfide axis as a new concept in cellular homeostasis and metabolic regulation.
    Keywords:  Amino acids; autophagy; cysteine; lysosome; supersulfides
    DOI:  https://doi.org/10.1093/jb/mvag058
  17. Nat Struct Mol Biol. 2026 Jul 22.
    PLA2G2F suppresses ferroptosis through phospholipid remodeling.
    Yingying Hu, Joleen Csuka, Presha Rajbhandari, Penghsuan Huang, Nicholas Carbone, Deguang Liang, Wei Gu, Alban Ordureau, Brent R Stockwell, Xuejun Jiang.
      Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation, and it has emerged as a potential therapeutic vulnerability of cancer. Here we identify the secretory phospholipase PLA2G2F (phospholipase A2 group IIF) as a ferroptosis suppressor in bladder cancer and elucidate its regulation and mechanism of action. PLA2G2F functions through an intracellular mechanism by localizing to the endoplasmic reticulum to inhibit ferroptosis. Our genetic and pharmacological analyses reveal that peroxisome proliferator-activated receptor γ (PPARG), a nuclear hormone receptor and transcription factor previously implicated in ferroptosis regulation, upregulates PLA2G2F and that PPARG-mediated ferroptosis resistance is largely dependent on PLA2G2F in bladder cancer. Further, lipidomic profiling suggests that PLA2G2F preferentially acts on ether-linked phospholipids containing polyunsaturated fatty acids, thereby reducing the pool of peroxidation-prone polyunsaturated fatty acid-containing phospholipids. Together, our findings establish PLA2G2F as an endoplasmic reticulum-resident ferroptosis suppressor regulated by PPARG and show that inhibiting PPARG signaling or PLA2G2F activity can sensitize bladder cancer cells to ferroptosis induction.
    DOI:  https://doi.org/10.1038/s41594-026-01830-7
  18. Biochim Biophys Acta Mol Cell Res. 2026 Jul 20. pii: S0167-4889(26)00093-5. [Epub ahead of print]1873(7): 120194
    Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
    Andreas Carlström, Carmela Vazquez-Calvo, Martin Ott.
      Mitochondrial gene expression is a remnant of the endosymbiotic origin of the organelle, which contains a complete gene expression system that contributes only a handful of subunits to the complexes driving oxidative phosphorylation (OXPHOS). During evolution, many processes of gene expression in mitochondria have diverged from the bacterial ancestor. A central problem to assemble oxidative phosphorylation complexes is that they contain subunits from two genetic sources. Hence, mechanisms have evolved to synchronize expression of nuclear and mitochondrial genes to avoid problems with stoichiometry, which could hamper their assembly. Here, we will summarize recent insights into how gene expression operates with a focus on the mechanisms related to the control of mitochondrial translation in yeast and human cells.
    Keywords:  Evolution; Gene expression; Mitochondria; Mitoribosomes; Translation initiation; Translational activators; Translational regulation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120194
  19. Nat Cell Biol. 2026 Jul 22.
    Mapping mesenchymal diversity in the human small intestine and organoids.
    Kelli F Johnson, Xiangning Dong, Yu-Hwai Tsai, Angeline Wu, Sydney G Clark, Abigail Vallie, Sha Huang, Charlie J Childs, Rachel K Zwick, Ian Glass, Katherine D Walton, Ophir D Klein, Jason R Spence.
      The organization of diverse mesenchymal populations during human small intestinal development is critical for tissue architecture and function yet remains poorly defined. Here, to construct a comprehensive, tissue-scale map of the developing human small intestine at single cell resolution, we leveraged single-cell RNA-sequencing data to build a Xenium spatial transcriptomics gene panel covering the cell diversity of the human small intestine. We defined five subpopulations occupying discrete anatomical locations within the lamina propria and submucosa-the subepithelial cells, lamina propria fibroblasts, submucosal fibroblasts, smooth muscle cells and CXCL13+ fibroblasts. Our data establish molecular markers to distinguish these populations in both sequencing and imaging data. We leverage this high-resolution atlas to interrogate cell-cell signalling, benchmark pluripotent stem cell-derived human intestinal organoids and to demonstrate how this resource can incorporate relative spatial organization into tissue analysis, with broad implications for modelling development, regeneration and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02027-2
  20. Pharmacol Res. 2026 Jul 20. pii: S1043-6618(26)00263-X. [Epub ahead of print]231 108348
    Targeting ATP-citrate lyase across cardiometabolic and oncologic disease.
    Chiara Macchi, Silvia Pedretti, Serena Ghisletti, Alberto Corsini, Nico Mitro, Cesare R Sirtori, Massimiliano Ruscica.
      ATP-citrate lyase (ACLY) is a key metabolic enzyme that links mitochondrial citrate export to the generation of cytosolic acetyl-CoA, thereby supporting de novo lipogenesis, cholesterol biosynthesis, protein acetylation, chromatin remodelling, and transcriptional control. Interest in ACLY inhibition initially arose from its lipid-lowering properties and led to the clinical development of bempedoic acid, whose ability to reduce low-density lipoprotein cholesterol and improve cardiovascular outcomes now provides the strongest clinical proof of concept for targeting this pathway. Beyond dyslipidaemia, preclinical evidence suggests that targeting the ACLY pathway and related bempedoic acid-responsive metabolic programs may ameliorate metabolic dysfunction-associated steatotic liver disease (MASLD). ACLY inhibition is expected to reduce de novo fatty-acid and cholesterol synthesis by limiting cytosolic acetyl-CoA availability, whereas parent bempedoic acid can directly activate PPARα, and thereby enhance fatty-acid oxidation. However, unlike the cardiovascular setting, robust clinical data supporting ACLY inhibition in MASLD are still lacking. More recently, the identification of nuclear ACLY functions has substantially expanded its biological significance, establishing ACLY as a metabolic-epigenetic integrator that couples nutrient availability to chromatin remodelling, transcriptional programs and immune responses. In cancer, dysregulated ACLY activity contributes to tumour growth, metabolic plasticity, therapy resistance and immune evasion, and its inhibition has shown promising antitumour effects in preclinical models. This review summarizes ACLY biology and pharmacology, emphasizing established cardiovascular applications, emerging MASLD opportunities and exploratory oncologic indications, while highlighting unresolved translational questions.
    Keywords:  ATP-citrate lyase; Bempedoic acid; Cancer; Epigenetic regulation; Lipid lowering drugs; Metabolic dysfunction-associated steatotic liver disease
    DOI:  https://doi.org/10.1016/j.phrs.2026.108348
  21. Sci Adv. 2026 Jul 24. 12(30): eaef3219
    A genetically encoded sensor of ionic stress links cellular proton dynamics to sleep.
    Zhijian Ji, Bingying Wang, Zhimin Ma, Lina Verbakel, Junqiang Liu, Yanchang Bian, Wenjie Zeng, Chan-I Chung, Shuaian Wei, Jianxiu Zhang, Supeng Yang, Morgane Bourgeois, Laurent Mouchiroud, Xiaokun Shu, Dengke K Ma.
      Although biosensors for specific cellular ions are widely available, real-time monitoring of overall ionic strength in living organisms remains challenging. Here, we present a genetically encoded nuclear translocation ionic sensor (GENTIS) that enables direct visualization of ionic stress in vivo. Using this sensor alongside longitudinal tracking via an automated microfluidic platform, we find that Caenorhabditis elegans larvae experience highly synchronized, rhythmic elevations in intestinal ionic strength during the molt, a stage during which developmentally timed sleep occurs. Cytosolic proton accumulation through inhibition of vacuolar-type adenosine triphosphatases (V-ATPases) triggers GENTIS nuclear translocation and evokes behavioral quiescence, characterized by reduced feeding, locomotion, and activation of sleep-active neurons. Apical membrane V-ATPases naturally undergo disassembly during molting and stress, conditions that cause proton accumulation and sleep. Notably, this proton-linked sleep is suppressed by proton buffering with ammonium. Together, these findings establish GENTIS as a powerful tool for tracking ionic strength dynamics in vivo and reveal that proton ionic rhythms contribute to the regulation of sleep.
    DOI:  https://doi.org/10.1126/sciadv.aef3219
  22. EMBO J. 2026 Jul 21.
    Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice.
    Noëlle Sieg, Johanna Stachelscheid, Besarta Thaqi, Tanja Schwab, Fabian Schorn, Daniela Hahn, Adrian Georg Simon, Yuri Tolkach, Nima Abedpour, Simon E Tröder, Ingo Voigt, Felix Gaedke, Katja Wiegmann, Susanne Brodesser, Astrid Schauss, Branko Zevnik, Martin Krönke, Reinhard Büttner, Alexander Quaas, Michael Hallek, Melanie Fritsch, Hamid Kashkar.
      Caspase-3 (CASP3) and caspase-7 (CASP7) are the two major executioner caspases that are proteolytically activated by upstream initiator caspases. They possess almost indistinguishable activity, which has led to the overall view that these caspases have functionally redundant roles. Here, we generate knock-in mice expressing cleavage-resistant CASP3(D175A) or CASP7(D198A). Our results show that proteolytic activation of CASP3 and CASP7 is decisive for their activity in vivo and controls redundant processes during embryonic development as combined expression of both CASP3(D175A) and CASP7(D198A) causes embryonic lethality. In adult mice, however, activation of CASP3 and CASP7 controls different processes in different tissues, without the involvement of apoptosis. While CASP7 activation is required for male fertility by controlling spermatogenesis, CASP3 activation appears crucial for lymphoid tissue development by regulating interferon signalling. Our findings shed light on emerging roles of caspases in non-apoptotic processes and provide impetus for reconsidering their involvement in physiological and pathological conditions.
    DOI:  https://doi.org/10.1038/s44318-026-00871-4
  23. Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00473-9. [Epub ahead of print]
    Distinct sources and effects of mitochondrial reactive oxygen species.
    Daniel Barnett, Caroline Booraem, Anna G Orr, Adam L Orr.
      Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondrial ROS (ISOMRs) and revealed that ISOMRs have distinct, dynamic, and often reversible roles in diverse physiological and pathological processes, including neurodegenerative diseases, immune and metabolic dysregulation, and ischemia-reperfusion injury. This review describes the upstream molecular events that control ISOMR activity, recently developed tools for studying mtROS in general and ISOMRs more specifically, and the evolving perspectives on ISOMR roles in context-specific cell signaling. Future studies to define predictive principles of ISOMR regulation are necessary to open frontiers of redox biology and identify therapeutic strategies for selective modulation of ISOMR-dependent mechanisms in aging and disease.
    Keywords:  cell metabolism; cell signaling pathways; complex I; complex III; disease mechanisms; electron leak; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.009
  24. Nat Metab. 2026 Jul;8(7): 1455-1456
    Ascites-derived lipid barrier at the T cell synapse.
    Teresa Manzo.
      
    DOI:  https://doi.org/10.1038/s42255-026-01564-2
  25. Nat Rev Genet. 2026 Jul 23.
    Human genetics across levels of biological organization.
    Diederik S Laman Trip, Pedro Beltrao.
      Genetic variation influences human physiology across biological scales from molecules to cells, tissues, organs and the whole organism. Unravelling how variants and their genetic effects propagate across these levels, through molecular interactions, cellular programmes and tissue architectures, to shape phenotypes remains a central challenge in human genetics. Resolving this challenge requires deciphering the genetic architecture of each biological layer and developing systems-level analyses that aim to integrate across scales. Network-based and computational approaches, including artificial intelligence, offer opportunities to move beyond statistical associations towards a context-aware, mechanistic understanding of the genetics underlying human traits and disease, although integration across layers remains limited. Here we review recent advances in mapping genetic effects across biological scales, from intracellular networks that capture molecular interactions, through single-cell and spatial omics approaches that define cellular and tissue contexts, to population-scale imaging genomics that links genetic variation to organ-level and organismal phenotypes. We discuss emerging strategies and remaining challenges for integrating these layers into mechanistic models of genotype-phenotype relationships.
    DOI:  https://doi.org/10.1038/s41576-026-00991-x
  26. iScience. 2026 Aug 21. 29(8): 116744
    Gene expression adaptation of metastases to their host tissue.
    Luise Nagel, Marten Wenzel, Sascha Hoppe, Mohammad Karimpour, Patrick S Plum, Abdossamad Hamoudi, Israt Jahan, Sarah Schmitt, Marek Franitza, Roger Wahba, Marc Bludau, Christiane J Bruns, Alexander Quaas, Andreas Beyer, Axel M Hillmer.
      Adaptation of metastatic cells to their host tissue determines the pathogenicity of cancer. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. We present a new concept to identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We generated quadruple-paired single-cell RNA-sequencing data from malignant and benign tissues from untreated donors with colorectal adenocarcinoma and liver metastasis. Utilizing a computational approach, we deduce tissue-adaptive expression patterns by identifying genes that consistently adapt to the host tissue. Expression changes in metastases are reminiscent of benign liver epithelial cells, including basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by peroxisome proliferator-activated receptor alpha (PPAR-α). This approach identifies the molecular adaptation of cancers to the host environment, which potentially increases the pathogenicity of metastatic cells, proposing a new therapeutic strategy to target adaptive processes.
    Keywords:  adaptation; colorectal cancer; liver metastasis; single cell sequencing
    DOI:  https://doi.org/10.1016/j.isci.2026.116744
  27. Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00471-5. [Epub ahead of print]
    The Legionella pneumophila effector SidL is an adenylyltransferase that modifies the glycolytic intermediate 3-phosphoglycerate.
    Joshua J Black, A Maxwell Burroughs, Edrees H Rashan, Charles R Nosal, Katerina A Romanov, Marco A Catipovic, Catherine Valadez, L Aravind, Kevin G Hicks, Caren L Freel Meyers, Tamara J O'Connor, Matthew G Vander Heiden, Rachel Green.
      The large effector arsenal of the bacterial pathogen Legionella pneumophila has been a rich source of biochemistry, highlighting the immense diversity of strategies deployed in host-pathogen conflict. Here, we redefine the purported translation inhibitor SidL as an adenylyltransferase that targets a glycolytic metabolite, discovering that it modifies 3-phosphoglycerate with adenosine monophosphate (AMP) to produce the previously unknown molecule 2-AMP-3-phosphoglycerate. When expressed alone in mammalian cells, SidL adenylates 3-phosphoglycerate, disrupts glycolysis, and blocks the nutrient-responsive translation regulator mTORC1, which we propose indirectly causes translation inhibition. Moreover, we observe SidL-dependent production of 2-AMP-3-phosphoglycerate in macrophages during L. pneumophila infection, the timing of which is consistent with a role for SidL in the early stages of the infection cycle. Thus, our study uncovers a mechanism by which an intracellular pathogen uses the chemical modification of a glycolytic intermediate to target central carbon metabolism in the host.
    Keywords:  3-phosphoglycerate; AMP; AMPylase; Adenylyltransferase; Ceg14; Legionella pneumophila; Lpg0437; MCF1-SHE; PAP2; SidL; SidL/Ceg14/Lpg0437; bacterial pathogenesis; glycolysis; mTOR
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.007
  28. Sci Adv. 2026 Jul 24. 12(30): eaec6741
    ELF3 links kidney function GWAS loci to maladaptive epithelial inflammation.
    Yanjuan Hou, Konstantin Kloetzer, Bernhard Dumoulin, Eunji Ha, Hongbo Liu, Dhanunjay Mukhi, Magaiver Andrade-Silva, Xuemei Hu, Siyu Pan, Katalin Susztak.
      Genome-wide association studies (GWAS) have uncovered over a thousand loci associated with kidney function, but the effector genes and mechanisms remain largely unknown. Here, we demonstrate that ELF3 is the effector gene at a kidney function GWAS locus and acts as an epithelial proinflammatory amplifier of the reprogramming of injured proximal tubules (iPTs). E74-like factor 3 (ELF3) expression is induced in iPTs in both mouse models and human chronic kidney disease (CKD), where it defines transitional epithelial states enriched for inflammatory gene programs and surrounded by leukocyte infiltrates. Conditional deletion of Elf3 in mice after injury reduced iPT accumulation, cytokine production, and immune cell recruitment. Mechanistically, ELF3 directly bound and activated components of the noncanonical nuclear factor κB (NF-κB) pathway (Nfκb2, Map3k14, and Il6r) and was required for NFκB2 nuclear translocation and cytokine induction. Spatial transcriptomics and immunofluorescence of human CKD kidneys confirmed that ELF3 expression correlates with epithelial inflammation, disease progression, and loss of kidney function. Together, these findings establish ELF3 as a genetically validated effector gene that drives inflammatory reprogramming in iPTs, nominating it as a therapeutic target to blunt maladaptive inflammation in CKD.
    DOI:  https://doi.org/10.1126/sciadv.aec6741
  29. Nat Metab. 2026 Jul 21.
    The impact of microbial metabolites on host chromatin and epigenetic regulation.
    Tohfa Kabir, Zoe K Lawler, Leah A Gates.
      The chemical diversity of histone post-translational modifications (PTMs), or histone marks, has been greatly expanded with the discovery of understudied and emerging modifications. The microbiome and microbial metabolites have been identified as crucial regulators of these novel PTMs, many of which have key roles in gene regulation. Thus, select histone marks represent a mechanism of host-microbe interaction via chromatin. This Perspective details the emerging roles of histone marks in gene regulation and host physiology. We discuss how these PTMs are regulated by microbial metabolism and the molecular mechanisms of how these microbiota-dependent histone PTMs affect host gene expression. We also highlight examples of the functional roles of these histone marks in physiology and disease, with a focus on the intestine and associated tissues. Understanding the mechanistic link between the microbiota and the host epigenome, particularly emerging histone marks, provides new avenues of how microbial metabolites influence host physiology.
    DOI:  https://doi.org/10.1038/s42255-026-01577-x
  30. Gastro Hep Adv. 2026 ;5(9): 101039
    Hepatocyte HIF2α Downregulates the Urea Cycle Through Suppression of HNF4α.
    Marc T Cantwell, Marwa O El-Derany, Raja Gopal Reddy Mooli, Sadeesh K Ramakrishnan, Yatrik M Shah.
       Background and Aims: Hypoxia contributes to chronic liver diseases such as metabolic dysfunction-associated steatotic liver disease through the activation of hypoxia-inducible factors (HIFs). Hif2α has been shown to drive a severe steatohepatitis and fibrosis phenotype in mice. How Hif2α drives this injury is not fully known. We identified a core regulatory pathway that was disrupted in hepatocytes in a Hif2α-dependent fashion to identify a possible common signaling pathway that may predispose to progression of inflammation and fibrosis.
    Methods: We utilized mouse primary hepatocytes and mouse liver tissue from genetic models of chronic hypoxia along with standard molecular methods and ammonia assays to identify abnormal nitrogen metabolism.
    Results: The urea cycle is significantly depressed in a HIF2α-dependent fashion, which leads to elevation of ammonia. The urea cycle is controlled by a master regulator of hepatocyte function called hepatocyte nuclear factor 4 alpha (HNF4α), which is suppressed by Hif2α.
    Conclusion: Hif2α suppresses expression of a master regulator of hepatocyte biology, HNF4α, leading to significant disruption in hepatocyte-specific pathways such as the urea cycle. How Hif2α regulates HNF4α remains a point of active investigation, but inhibition of Hif2α may represent a therapeutic target to maintain the full function of a mature hepatocyte.
    Keywords:  HNF4α; Hif2α; Urea Cycle
    DOI:  https://doi.org/10.1016/j.gastha.2026.101039
  31. J Clin Invest. 2026 Jul 21. pii: e203265. [Epub ahead of print]
    Efferocytosis activates a DNMT3A-mediated oxidized DNA repair pathway to enable tissue resolution.
    Kleopatra Avrampou, Santosh R Sukka, David Ngai, Patrick Ampomah, Xiaobo Wang, George Kuriakose, Jacob Glass, Bernhard Dorweiler, Hanna Winter, Lars Maegdefessel, Hanrui Zhang, Aaron Viny, Ira Tabas.
      Efferocytosis, the clearance of apoptotic cells by macrophages, promotes tissue resolution. Efficient resolution requires efferocytosis-induced macrophage proliferation (EIMP) to expand pro-resolving macrophages. Here, we show that efferocytosis activates base excision repair (BER) to remove 8-OHdG from DNA, enabling EIMP. Mechanistically, efferocytosis promotes poly(ADP-ribose) polymerase-1 (PARP1) chromatin binding and PARylation to facilitate DNA repair complex assembly, and increases nuclear MTH1/NUDT1, which hydrolyzes 8-OHdG. Both processes require DNA-methyltransferase-3A (DNMT3A), which is activated during efferocytosis. Using a model where dexamethasone-induced thymocyte apoptosis triggers efferocytosis-mediated thymic repair, we showed that DNMT3A is required for increases in nuclear PARP1/MTH1, oxidized DNA suppression, EIMP in thymic macrophages, and thymic repair. We next studied a human-relevant model of atherosclerosis regression, where efferocytosis drives protective lesional fibrous cap thickening. We compared WT mice with a model of DNMT3A-clonal hematopoiesis (CH), in which loss-of-function DNMT3A mutations promote atherosclerotic disease. Atherosclerosis regression in WT mice led to decreased nuclear 8-OHdG and increases in nuclear PARP1/MTH1 and EIMP in lesional macrophages and fibrous cap thickening, all of which were impaired in DNMT3A-CH regression. These findings reveal that efferocytosis initiates a BER pathway to allow macrophage proliferation for tissue resolution, with possible therapeutic relevance to atherosclerosis regression and DNMT3A-CH.
    Keywords:  Atherosclerosis; Cell biology; Macrophages; Vascular biology
    DOI:  https://doi.org/10.1172/JCI203265
  32. Nat Rev Rheumatol. 2026 Jul 22.
    Hypoxia as an amplifier of synovial inflammation in rheumatoid arthritis.
    Mary Canavan, Orla Tynan, Jean Fletcher, Ursula Fearon.
      Inflammatory arthritis is characterized by neovascularization, leukocyte extravasation and synovial hyperplasia, leading to joint destruction and functional disability. Although increased synovial angiogenesis is a hallmark of synovial inflammation, efficiency of the oxygen supply to the synovium is poor, leading to a hypoxic gradient that impacts differential cellular responses. This hypoxic gradient occurs as infiltrating cells and cells that reside within the joint increase their metabolic demand beyond what the highly dysregulated vasculature can supply. This hypoxic environment favours an increase in reactive oxygen species, leading to oxidative damage that further promotes inflammation. In this adverse microenvironment, synovial cells adapt to generate energy and switch their cellular metabolism from a resting regulatory state to a highly metabolically active state, enabling them to produce essential building blocks to support their proliferation. This metabolic shift results in the accumulation of metabolic intermediates that function as signalling molecules, which further dictate the inflammatory response. However, the synovium is a complex multicellular tissue, and the specific cellular reliance on oxygen and metabolites differs across the synovium. Cellular demands depend on anatomical location, cell-cell interactions and competition for nutrients. Understanding the complex interplay between hypoxia-induced signalling pathways, oxidative stress and inflammatory responses will provide a better insight into the underlying mechanisms of disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41584-026-01397-z
  33. Sci Immunol. 2026 Jul 24. 11(121): eaeb7315
    Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer.
    Weiwei Yu, Ruya Sun, Xiaoyang Lu, Qiqi Deng, Heng Zhang, Sheng Chen, Siqi Dai, Tianyi Hu, Xiangyuan Li, Yidong Yang, Lihao Chen, Zhexu Chi, Jian Zhang, Siwen Zhang, Yiyi Zhu, Dehang Yang, Qianzhou Yu, Zhen Wang, Quanquan Wang, Fan Yang, Qian Xiao, Kefeng Ding, Di Wang.
      Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment. It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism. We identified that up-regulation of solute carrier family 7 member 1 (SLC7A1) increased arginine utilization and promoted tumor growth, whereas down-regulation of SLC7A2 decreased lysine catabolism to support immune evasion. Repression of lysine catabolism in tumor cells reduced glutaconic acid (GC), a medium-chain acyl-CoA dehydrogenase-dependent lysine catabolite that has immunostimulatory effects on antitumor CD8 T cells. GC modified pyruvate kinase M2 (PKM2) through posttranslational glutaconylation at key lysine residues Lys336 (K336) and K337. This modification reinforced PKM2 dimers, transcriptionally driving metabolic reprogramming and reinvigorating antitumor CD8 T cells. Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb7315
  34. Sci Adv. 2026 Jul 24. 12(30): eaec0131
    mTOR signaling contributes to system-driven rhythmic gene expression in mouse liver.
    Aishwarya Sahasrabudhe, Chanté R Guy, Audrey Jacq, Chieh-Wen Ho, Ben J Greenwell, Jerome S Menet.
      Rhythmic gene expression is essential to the daily organization of biological processes. While cycling transcriptomes are regulated by circadian clocks present in nearly every cell, accumulating evidence indicates that they can also be initiated by rhythmic food-driven systemic signals independently of circadian clocks. The underlying mechanisms remain however largely unknown. Here, we show that signaling through the nutrient-sensing kinase mechanistic target of rapamycin (mTOR) is both necessary and sufficient to mediate food-driven hepatic rhythmic gene expression, rhythmic regulation of the liver metabolome, and endoplasmic reticulum stress response. Acute inhibition of mTOR before the active phase desynchronizes the phase of mTOR-driven rhythmic genes without affecting clock-controlled rhythmic genes, indicating that alignment of rhythmic mTOR activity to the circadian cycle is critical for overt cycling transcriptomes. These findings may explain how misalignment between clock and systemic signals contributes to disease and underscore the use of mTOR inhibitors for resynchronizing system-driven rhythms and alleviating circadian rhythm disorders.
    DOI:  https://doi.org/10.1126/sciadv.aec0131
  35. Nat Rev Immunol. 2026 Jul 23.
    How Big Data and AI are revolutionizing human immunology.
    Sarah A Teichmann.
      
    DOI:  https://doi.org/10.1038/s41577-026-01340-z
  36. J Med Chem. 2026 Jul 22.
    An Insight into the cGAS-STING Pathway Modulation by Metal Complexes to Initiate Immunogenic Cell Death in Cancer.
    Shilpendu Ghosh, Sujato Mukherjee, Arindam Mukherjee.
      The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of antitumor immunity, capable of converting immunologically "cold" tumors into inflamed, immune-responsive states. Cyclic dinucleotide (CDN) agonists have clinically validated the impact of targeting this axis but are limited by poor pharmacokinetics, limited tumor penetration, and delivery challenges. Non-CDN based small-molecule modulators such as MSA-2 and amidobenzimidazole (ABZI) directly modulate cGAS-STING signaling. Beyond direct receptor agonism, coupling with metals offer platforms with complementary strategies to engage and amplify cGAS-STING signaling. Complexes incorporating platinum, ruthenium, iridium, rhodium, gold, copper, manganese, or zinc exploit redox activity, coordination versatility, and photophysical properties to induce nuclear or mitochondrial DNA stress, disrupt organelle homeostasis, and promote immunogenic cell death. By coupling STING activation to ferroptosis, pyroptosis, or cuproptosis, these complexes form the foundation of self-emerging design principles with elaborate mechanistic insights, and translational challenges shaping immune modulation for therapeutics.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00727
  37. Nat Aging. 2026 Jul 20.
    Positioning TERT at the apex of aging.
    Ronald A DePinho.
      Aging is a biologically tractable process. Telomerase reverse transcriptase (TERT) has emerged as an upstream regulator coordinating several hallmarks of aging across preclinical models. Beyond maintaining telomeres, TERT influences mitochondrial health, epigenetic regulation, inflammation and stem cell function. Multiple translational strategies are being explored to modulate TERT. In mice and human cell models, restoration of physiological-range TERT expression characteristic of younger cells, or related telomere-focused interventions, has been associated with improvements in selected age-related phenotypes without a detectable increase in cancer. Simultaneously, human genetics links common variation in the TERT locus to increased risk of several cancers, underscoring the need for careful mechanistic and long-term safety evaluations. Together, mounting evidence indicates that TERT occupies an important position in aging biology with the potential to affect healthspan. This Perspective reviews current evidence for TERT's canonical and noncanonical roles and outlines a cautious therapeutic framework for evaluating TERT-directed geroprotective strategies.
    DOI:  https://doi.org/10.1038/s43587-026-01179-y
  38. Dev Cell. 2026 Jul 21. pii: S1534-5807(26)00240-6. [Epub ahead of print]
    Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.
    Adrien Grimont, David J Falvo, Whitney J Sisso, Francisco Santos, Christopher W Chan, Paul Zumbo, William B Fall, Katherine Ferrick, Grace Pan, Megan Cleveland, Tomer M Yaron-Barir, Alexa Osterhoudt, Yinuo Meng, Maria Paz Zafra, Andre F Rendeiro, Erika Hissong, Rhonda K Yantiss, Doron Betel, Mark A Magnuson, Steven D Leach, Anil K Rustgi, Lukas E Dow, Rohit Chandwani.
      Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic ductal adenocarcinoma. How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement Ptf1a-tdTomato mice and multiple KRAS mutants across several genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRASG12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRASG12R/V cannot sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. Specifically, KRASG12R/V mutants fail to invoke robust EGFR, AKT, and RAC1/VAV1 signaling and to license Pou2f3 and Vav1 in chromatin, such that only constitutive AKT activation is sufficient to rescue the tumorigenic potential of KRASG12Rin vivo. As the marked heterogeneity among KRAS variants begins early in tumorigenesis, these data are crucial to deciphering mutation-specific oncogenic trajectories and directing the implementation of KRAS-directed therapeutics.
    Keywords:  EGFR; G12R; KRAS; RAC1; VAV1; acinar-ductal metaplasia; epigenetic reprogramming; inflammation; lineage reversion; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.devcel.2026.06.016
  39. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600323123
    Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.
    Xifan Wang, Jiping Yang, Chen Jin, Xizhe Wang, Daniela Contreras, Melody Devos, Maggie M Kane, Michael G Rosenfeld, Yousin Suh.
      Reproductive aging in mice leads to estropause, characterized by estrous cycle irregularity and eventual cessation, yet its underlying mechanism remains unclear. Here, we present a comprehensive single-cell atlas of mouse ovaries across precisely defined reproductive stages-from young (regular cycling) through the estropausal transition (regular vs. irregular cycling) to post-estropause (acyclic)-and of ovary-specific senescent cells defined by high senescence-associated β-galactosidase activity. We mapped transcriptomic dynamics of ovarian aging and characterized the molecular features of ovarian senescent cells. Our analyses revealed that during the estropausal transition, irregularly cycling ovaries exhibited accelerated aging and cellular senescence features compared with regularly cycling counterparts, including increased transcriptional noise, altered conserved aging pathways such as oxidative phosphorylation and proteostasis, hormone dysregulation in granulosa cells, and elevated expression of the senescence marker Cdkn1a and senescence-associated secretory phenotype factors. This atlas delineates the cellular and molecular hallmarks of mouse ovarian aging and ovary-specific senescent cells, providing a resource for understanding the mechanisms underlying the estropausal transition.
    Keywords:  aging; cellular senescence; estropausal transition; ovary; single-cell RNA-seq
    DOI:  https://doi.org/10.1073/pnas.2600323123
  40. Bull Math Biol. 2026 Jul 23. pii: 142. [Epub ahead of print]88(8):
    Mathematical Modelling of the Mitochondrial Dicarboxylate Carrier (SLC25A10).
    Ramin Nashebi, Yingying Lyu, Elías Vera-Sigüenza, Daniel A Tennant, Fabian Spill.
      The mitochondrial dicarboxylate carrier SLC25A10 mediates reversible exchange among succinate, malate, and phosphate, contributing to mitochondrial metabolic regulation. Structural studies establish a ping-pong mechanism, but most mathematical models still assume sequential binding, lacking mechanistic justification and overlooking the alternation of a single binding site. Here, we present the first mechanistically derived and thermodynamically consistent model of SLC25A10 based on a ping-pong framework. The model incorporates competitive binding of succinate, malate, and phosphate, heteroexchange, reversibility, and electroneutrality, and is calibrated using experimental datasets from intact mitochondria and reconstituted proteoliposomes. To estimate kinetic parameters and quantify their uncertainty, we employed Bayesian inference, enabling statistically rigorous calibration to uptake and competition assays. The model introduces new terms that quantify which substrate and from which side of the membrane is most likely to start the transport cycle. Beyond reproducing experimentally observed exchange kinetics, the model resolves non-equilibrium transport dynamics that are difficult to access directly in classical uptake assays. In particular, the simulations reveal a two-phase response in which an initial phosphate-driven high-flux uptake regime for malate and succinate is followed by a slower redistribution phase in which the two dicarboxylates continue to readjust primarily against each other. The model also predicts that mitochondrial morphology modulates early transport behaviour, with matrix swelling increasing and matrix condensation decreasing the initial SLC25A10 flux magnitude. More broadly, the framework provides a quantitative basis for studying how substrate competition, thermodynamic driving forces, and compartment geometry shape SLC25A10-mediated exchange, and it offers a transferable modelling strategy for other carriers in the SLC25 family.
    Keywords:  Bayesian Inference; Kinetic Modeling; MCMC; Mitochondrial Dicarboxylate Carrier (SLC25A10); Ping–Pong Mechanism
    DOI:  https://doi.org/10.1007/s11538-026-01709-0
  41. Endocr Pathol. 2026 Jul 22. pii: 32. [Epub ahead of print]37(1):
    Expansion of Germline Variants in Primary Hyperparathyroidism: Fumarate Hydratase Deficiency as a Cause of Parathyroid Adenomas.
    Hussam Alkaissi, Elias Chuki, Yi Liu, James Welch, Lynn Bliss, Niharika Shah, Sunita K Agarwal, William F Simonds, Martha Quezado, Sanaz Sakiani, Thorkell Andresson, Karel Pacak, Naris Nilubol, Lee S Weinstein, Christopher A Febres-Aldana, Smita Jha.
      A substantial fraction (60-85%) of hereditary primary hyperparathyroidism (hPHPT) lacks an identifiable genetic etiology. We describe fumarate hydratase (FH) mutations as a potential cause of hPHPT, expanding the phenotypic spectrum of FH deficiency tumor predisposition syndromes. In an index patient who presented with asymptomatic hypercalcemia and a chief-to-transitional cell-dominant parathyroid adenoma, whole-exome sequencing revealed two unique heterozygous FH variants (germline p.Gln376fs*2; somatic p.Pro503_Lys504dup). Functional inactivation of FH was supported by diffuse nuclear and cytoplasmic 2-succinocysteine immunoreactivity and elevated fumarate/malate ratio in tumor tissue. This individual did not show classic HLRCC manifestations. Preserved FH protein expression suggested residual enzymatic activity, which may account for an attenuated phenotype. To assess broader relevance, no additional patients with bona fide FH-deficient parathyroid adenoma were identified among 130 individuals with suspected hPHPT of unknown etiology evaluated at our institute. In a complementary cohort of 11 patients with pheochromocytoma/paraganglioma syndrome harboring pathogenic germline heterozygous FH variants, one female (FH p.Thr234Ala) presented with multi-gland disease requiring parathyroidectomy at age 40 years, features suspicious for hPHPT. These findings support fumarate hydratase deficiency as a plausible etiology for a subset of parathyroid adenomatous disease. Thus, consideration of parathyroid function surveillance in patients with fumarate hydratase deficiency tumor predisposition syndromes may be warranted. CLINICAL TRIAL NUMBER: NCT04969926.
    Keywords:  Fumarate hydratase; Heritable primary hyperparathyroidism; Oncometabolite; Pheochromocytoma; Renal cell cancer; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s12022-026-09928-w
  42. Nat Rev Mol Cell Biol. 2026 Jul 24.
    Mitochondrial tRNA biogenesis, modifications and disease relevance.
    Wen-Yu Zhu, Ilias Skeparnias, Athanasios-Nasir Shaukat, Jinwei Zhang, Ru-Juan Liu.
      The biogenesis, modifications and function of mitochondrial transfer RNAs (mt-tRNAs) reflect the symbiotic relationship and coordinated evolution between the domesticated organelle and the outer cell. Through evolution, mt-tRNA structures have been severely degenerated, and mt-tRNA-associated proteomes have acquired additional domains and interfaces, leveraging post-transcriptional modifications to maintain functional affinity and specificity. Considerable progress has been made in the past decade in elucidating mt-tRNA structure, biogenesis, modifications and functions. In this Review, we outline how mt-tRNAs are excised from polycistronic transcripts and mature through coordinated actions of mitochondrial processing enzymes. We then examine how mitochondrial aminoacyl-tRNA synthetases and mitoribosomes have coevolved to recognize degenerated mt-tRNAs and support a streamlined genetic code. The roles of post-transcriptional modifications in mt-tRNA structure stabilization, mt-tRNA decoding and the coupling of metabolism to translation are also discussed. Moreover, we review mt-tRNA-associated pathologies and emerging therapeutic strategies, highlighting unifying principles that inform efforts to restore coherence of mitochondrial translation.
    DOI:  https://doi.org/10.1038/s41580-026-00999-5
  43. EMBO J. 2026 Jul 22.
    Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.
    Marie Palard, Gilliane Chadeuf, Maxime Carpentier, Clotilde C N Renaud, Samuel Frey, Mikael Croyal, Rola Shaaban, Samy Hadjadj, Chloe Cloteau, Naima El Khallouki, Perrine Bomme, Soazig Le Lay, Manuel Majrouh, Perrine Paul-Gilloteaux, Alexandre Humbert, Christine Durand, Nicolas Bertocchini, Laurence Dubreil, Yoann Combot, Antria Antreou, Cedric Le May, Simon Ducheix, Bertrand Cariou, Francesca Giordano, Jennifer Rieusset, Abdou Rachid Thiam, Xavier Prieur.
      Adipocyte dysfunction is a major driver of obesity-associated cardiometabolic disease, underscoring the need to understand how lipid storage and mobilization are regulated and disrupted. The ER-anchored protein Seipin governs lipid droplet (LD) biogenesis and ER-LD and ER-mitochondria (MAM) contacts, and its loss impairs calcium transfer and causes lipodystrophy. Here, we investigated whether Seipin coordinates MAM and ER-LD remodeling during adipocyte lipid handling. In subcutaneous adipose tissue from inducible Seipin-knockout mice, electron microscopy and proximity ligation assays revealed that feeding reduces MAMs while increasing ER-LD and mitochondria-LD contacts, a remodeling abolished by Seipin deficiency. Lipid loading elevated tripartite MAM-LD contacts in controls but not knockouts. Fluorescence recovery after photobleaching showed that impaired triglyceride transfer to LDs in Seipin-deficient cells was rescued by the MAM-LD-stabilizing peptide 'Linker-ER-Mi', in a calcium-dependent manner. During adipogenesis and lipid loading, MAM-LD contacts increased, whereas MAM-cytosolic mitochondria contacts declined; however, obesity blunted this remodeling. Furthermore, disrupting membrane contact sites impaired lipid flux, lipolysis, and insulin signaling. Taken together, these findings identify MAM-LD as regulators of adipocyte metabolic flexibility.
    DOI:  https://doi.org/10.1038/s44318-026-00876-z
  44. Am J Physiol Cell Physiol. 2026 Jul 21.
    Copper-dependent redox remodeling of the actin cytoskeleton regulates renal epithelial cell mechanics.
    Pedro Pompeu, Juliana Soares, Íris Ávila Dos Santos, Giuliano Martins Pinheiro, Nicole Jacinto Damasceno, Romênia Ramos Domingues, Glória M R S Grelle, Marcelo Einicker-Lamas, Bruno Pontes, Rafael H F Valverde.
      Copper is essential for cellular function but can become toxic in excess. Although its redox and enzymatic roles are well established, how copper availability affects cytoskeletal organization and cell mechanics remains unclear. Here, we show that elevated copper availability increases membrane tether force and F-actin anisotropy in HK-2 proximal tubule cells, consistent with actin cytoskeletal remodeling. Co-treatment with the membrane-permeable ROS scavenger Tiron reversed copper-induced ROS accumulation and mechanical changes without affecting cell viability, supporting a ROS-dependent mechanism. Quantitative proteomics and post-translational modification profiling (ProteomeXchange: PXD072220) identified coordinated changes in actin-regulatory proteins, including Rab35, MsrB2, CK2 subunits, and Septin2, together with reduced actin methionine oxidation and copper-sensitive phosphorylation shifts. These findings identify copper-driven redox signaling as a modulator of renal epithelial cell mechanics associated with remodeling of actin-regulatory pathways.
    Keywords:  Cellular mechanics; Copper; Cytoskeleton; Kidney; Reactive oxygen species
    DOI:  https://doi.org/10.1152/ajpcell.00311.2026
  45. Science. 2026 Jul 23. 393(6809): eadx0673
    Human body single-cell atlas of three-dimensional genome organization and DNA methylation.
    Jingtian Zhou, Yue Wu, Hanqing Liu, Wei Tian, Rosa G Castanon, Anna Bartlett, Zuolong Zhang, Guocong Yao, Dengxiaoyu Shi, Ben Clock, Samantha Marcotte, Joseph R Nery, Michelle Liem, Naomi Claffey, Lara Boggeman, Cesar Barragan, Rafael Arrojo E Drigo, Annika K Weimer, Minyi Shi, Johnathan Cooper-Knock, Sai Zhang, Michael P Snyder, Sebastian Preissl, Bing Ren, Carolyn O'Connor, Shengbo Chen, Chongyuan Luo, Jesse R Dixon, Joseph R Ecker.
      Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multiomic profiling of three-dimensional (3D) genome structure and DNA methylation for 86,689 single nuclei across 16 tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, which indicates that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers a reference for exploring gene regulation in human health and disease.
    DOI:  https://doi.org/10.1126/science.adx0673
  46. NPJ Aging. 2026 Jul 20.
    Geroprotective insights into the natural metabolite spermidine in aging and age-related diseases.
    Zhirui Jiang, Sen Tong, James L Kirkland, Yu Sun.
      Aging is associated with increased oxidative stress, which leads to pathological vulnerability. Spermidine is a ubiquitous natural polyamine found across all living organisms studied so far and present in multiple food sources. In humans, spermidine levels decline with aging, and a possible connection between reduced endogenous spermidine concentration and age-related organ degeneration has been proposed. We outline recent studies that address the potential contribution of spermidine to geroprotection, with a perspective of advancing spermidine towards clinical trials.
    DOI:  https://doi.org/10.1038/s41514-026-00448-9
  47. Epigenomics. 2026 Jul 24. 1-8
    Understanding and making sense of epigenetic age misalignment across different aging clocks.
    Adiv A Johnson, Maxim N Shokhirev.
      The output of an epigenetic aging clock can vary depending on the training method utilized, cell type composition, the nature of the training dataset, the technology used to generate the methylomic data, acute stressors, and other factors. On an individual level, epigenetic age can fluctuate across different clocks purely due to differences in model training. Among aging clock researchers, it is well-known that the epigenetic age of a single sample can vary across different models. Based on our observations and conversations with longevity scientists and stakeholders, however, this fact is often unappreciated among non-aging clock experts. To help bring more awareness to this important topic, we highlight key literature and, as an illustrative example, use eight blood-trained clocks to show that epigenetic age is frequently misaligned in a publicly available whole blood dataset. Our simple analysis revealed that the average sample difference between the youngest and oldest predicted ages across these clocks was 17 years. The smallest and largest individual-level differences observed were 4 and 45 years, respectively. Clock misalignment has implications for choosing which clock to utilize, interpreting the impact of an intervention on epigenetic age, personalized tracking, and relating epigenetic age to the abstract concept of biological age.
    Keywords:  Aging clocks; DNA methylation; aging biomarker; epigenetic age; epigenetic clocks; predicted age
    DOI:  https://doi.org/10.1080/17501911.2026.2708567
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