bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–07–19
58 papers selected by
Christian Frezza, Universität zu Köln
  1. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
  2. Metabolite glues as a means of purine sensing and chemotherapeutic response.
  3. Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
  4. A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
  5. Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss.
  6. A quantum interface with mitochondrial bioenergetics.
  7. Multiscale in vivo imaging of tumor evolution using a germline conditional triple-reporter mouse.
  8. ALR couples IMS redox and heme biosynthesis beyond the disulfide relay.
  9. Targeting enolase isoenzyme 2 enables precision glycolysis inhibition in VHL-mutant renal cell carcinoma.
  10. BACH1 meets its match: Heme licenses BACH1 destruction to tune ferroptosis.
  11. Decoding MASLD progression beyond histological stages.
  12. More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
  13. Endocrine-like regulation through brown fat-secreted microRNAs.
  14. Metabolic buffering restricts phenotype switching in melanoma.
  15. Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
  16. O-GlcNAcylation is a mitochondrial-nuclear signal that regulates passive transport through the nuclear pore complex.
  17. Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
  18. MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.
  19. Why do astronauts' bodies waste away? Space-station study points to mitochondria.
  20. A single chromosome 3p break initiates clear cell renal cell carcinoma evolution.
  21. Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.
  22. Lysosomes and lysosomal dysfunction in ageing biology.
  23. SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.
  24. SLC16A6 is a tyrosine transporter for the melanosome.
  25. Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
  26. ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.
  27. Vitronectin metabolically programs profibrotic macrophages in 3D cultures and idiopathic pulmonary fibrosis.
  28. Relative tension shapes embryos.
  29. The Interdependence of Carbon Substrates and Metabolic Pathways Enables the Metabolic Plasticity of Cancer Cells.
  30. Breast cancer genomic subtype-specific copy number alterations in metastases.
  31. Oncogenic Ras drives EED degradation and PRC2 dysfunction to promote aggressive squamous cell carcinoma.
  32. A data-driven framework reconstructs the molecular continuum of human MASLD progression.
  33. Whole-transcriptome-scale isoform-resolved spatial imaging of single cells in tissues.
  34. Local sensory innervation shapes anti-tumor immunity in lung cancer.
  35. Cellular hallmarks and aging clock of the human lung parenchyma.
  36. ERG preserves endothelial identity to limit atherosclerosis.
  37. PISD acts as a switch between lipophagy and fatty acid transfer to mitochondria.
  38. An encyclopedia of human enhancer-gene regulatory interactions.
  39. The Emerging Role of mTOR in Shaping the Cancer Cell Secretome and Plasticity.
  40. Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth.
  41. A cofactor-promiscuous HMGR from the Lyme disease pathogen illuminates diversity in bacterial isoprenoid biosynthesis.
  42. Lauric acid engages an O-GlcNAc-sensitive BCKDH regulatory node to modulate branched-chain amino acid oxidation in skeletal myotubes.
  43. Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
  44. Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response.
  45. Spatial metabolomics - a metabolic microscope for respiratory medicine.
  46. Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.
  47. Tanycyte BMAL1 regulates high-fat diet weight gain and shapes arcuate neurogenesis in female mice.
  48. Itaconate as a paracrine brake on thermogenesis.
  49. The kidney distal tubule potassium switch, modern diet and hypertension.
  50. Glycerol 3-phosphate activates lipid metabolism through GATOR2-dependent regulation of mTORC1.
  51. The Energetic Cost of Adrenergic Signaling in Primary Human Fibroblasts.
  52. Brain mitochondria as key drivers of cognition and behaviour.
  53. Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
  54. Colorectal cancer co-opts an epidermal wound healing program during metastasis to generate disseminated tumor cells.
  55. Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
  56. Exogenous creatine supplementation promotes tumor metastasis via megakaryocyte creatine kinase B-STAT5B signaling.
  57. Granular component sub-phases direct ribosome biogenesis in the nucleolus.
  58. Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
  1. Nature. 2026 Jul 15.
    Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J Williams, Seda Neptun, Tolga Sever, Isabela Fuentes, Sangeeta N Bhatia, Gizem Calibasi-Kocal, Matthew G Vander Heiden, Alex K Shalek, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1038/s41586-026-10779-y
  2. Nature. 2026 Jul 15.
    Metabolite glues as a means of purine sensing and chemotherapeutic response.
    Samuel R Witus, Megan M Kober, Heegwang Roh, Zhi Yang, Fouad Choueiry, Avani S Ghate, Denis V Titov, Michael Rapé.
      Molecular glues stabilize weak interactions to impart new functionalities to complexes1-3. Although molecular glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics6, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.
    DOI:  https://doi.org/10.1038/s41586-026-10790-3
  3. Nat Metab. 2026 Jul 14.
    Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
    Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.
      Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01572-2
  4. Science. 2026 Jul 16. 393(6808): eadx8675
    A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
    Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.
      The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
    DOI:  https://doi.org/10.1126/science.adx8675
  5. bioRxiv. 2026 Jul 07. pii: 2026.07.06.736733. [Epub ahead of print]
    Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss.
    Julia Urgel-Solas, Anna Benito-Ferrer, Laura Ortet, Savvas Kourtis, Etna Abad, Albert Coll Manzano, Anna Shevzov-Zebrun, Camilla Reiter Elbæk, Carlos M Martínez, Matthew G Vander Heiden, Sara Sdelci, Ana Janic.
      Metabolic adaptation is essential for cells experiencing chronic genomic stress, yet how such adaptations are organized at the nuclear level remains poorly understood. Loss of TP53 is associated with elevated genomic instability, DNA damage and altered metabolic requirements, creating context specific dependencies. Here, we identify a requirement for de novo purine biosynthesis in TP53-deficient cells, with a pronounced dependence on adenosine related metabolism. Perturbation of purine synthesis increases DNA damage and reduces nuclear ATP availability, particularly in TP53-deficient cells, and is accompanied by a rapid increase in histone methylation. This chromatin response is also induced by acute DNA damage and occurs with fast kinetics, indicating that histone methylation is an early, intrinsic feature of the nuclear stress response rather than a secondary epigenetic remodeling. Interfering with histone methylation is associated with reduced nuclear ATP levels and impaired DNA damage resolution, linking chromatin state to nuclear energy homeostasis. Genetic disruption of the purine biosynthesis enzyme PFAS selectively impairs the growth of TP53-deficient tumours in vivo , establishing the physiological relevance of this metabolic dependency. Together, these findings reveal nuclear adenosine metabolism as a compartmentalised adaptive response to genotoxic stress and highlight chromatin associated methylation as a key feature of nuclear metabolic regulation unmasked by TP53 loss.
    DOI:  https://doi.org/10.64898/2026.07.06.736733
  6. bioRxiv. 2026 Jul 09. pii: 2026.07.03.736226. [Epub ahead of print]
    A quantum interface with mitochondrial bioenergetics.
    Parisa Aghaei, Sangjun Noh, Javier Noé Ramos-Silva, Minghao Jiang, Phang-Lang Chen, Yumay Chen, Fatemeh Goodarzinia, Robert Usselman, Philip Hemmer, Douglas C Wallace, Peter J Burke.
      Recent work has shown that genetically engineered proteins can serve as quantum bits in living systems. These quantum bits arise from the photochemistry of protein-bound flavins: blue-light excitation drives electron transfer to form a spin-correlated radical pair whose coherent singlet-triplet interconversion makes the protein's fluorescence sensitive to weak magnetic fields. Because this radical-pair reaction depends on the redox state of the flavin-itself a central electron carrier in cellular metabolism-the magneto-fluorescence of a biological qubit is intrinsically coupled to the biochemistry around it. This suggests a powerful application of fundamental significance in biology, until now an unsolved problem in the field of quantum sensing. Here we show a new class of quantum sensor, mtMagLOV2, that interfaces directly to a defining feature of life itself: the bioenergetic state of the cell. We genetically engineer flavin mononucleotide (FMN)-containing, magnetic-field-sensitive fluorescent proteins ("biological qubits") to be expressed and translocated into the key bioenergetic machinery of the cell: the mitochondrial matrix. Using confocal and super-resolution microscopy, mtMagLOV2 localizes to the mitochondrial cristae, home of the electron transport chain complexes I-V and ATP synthase-the site of oxidative phosphorylation (OXPHOS). By pharmacological manipulation of OXPHOS, we show that the sensor's magneto-fluorescence tracks the redox (oxidation-reduction) state of the mitochondrial flavins, providing a quantum readout of redox status. The response differs between cancer cells (which rely heavily on glycolysis) and cardiomyocytes (which rely predominantly on OXPHOS), demonstrating "quantum bioenergetic profiling". Together, these results establish biological qubits as quantum sensors capable of probing mitochondrial bioenergetics, opening a quantum window into the energetic machinery of living cells. More broadly, we anticipate that coupling quantum redox sensitivity to specific biochemical targets will extend the reach of quantum technologies across the life sciences.
    DOI:  https://doi.org/10.64898/2026.07.03.736226
  7. Nat Biotechnol. 2026 Jul 15.
    Multiscale in vivo imaging of tumor evolution using a germline conditional triple-reporter mouse.
    Ximena L Raffo-Iraolagoitia, Abdullah Alyamani, Stephanie May, David Stevenson, Agata Mackintosh, Lynn McGarry, Jayanthi Anand, Dmitry Soloviev, Gavin Brown, Colin Nixon, Chrysa Kapeni, Maike De La Roche, Karen Blyth, Thomas Graham Bird, Douglas Strathdee, Scott K Lyons, Gilbert Fruhwirth, Leo M Carlin, David Y Lewis.
      Imaging reporter genes are essential tools in cancer research for monitoring tumor evolution, cell dissemination, gene activation and treatment response. However, germline reporter models typically rely on single imaging modalities operating over limited spatial scales. To address these limitations, we developed an inducible triple-reporter mouse model (Rosa26LSL-NRL) that integrates three reporters for complementary imaging modalities, fluorescence, bioluminescence and positron emission tomography (PET), along with inducible Cre-lox functionality for precise spatiotemporal control of reporter expression in genetically engineered mouse models. Using a multiscale, multimodal approach, we visualize deep tissue oncogenesis in models of hepatocellular carcinoma and lung adenocarcinoma and, guided by whole-body imaging with bioluminescence and [18F]tetrafluoroborate PET/magnetic resonance imaging (MRI), resolve cell-cell interactions within tumor microenvironments using in situ microscopy. This triple-reporter system enables multiscale investigation of biological processes within whole animals, facilitating sensitive, tissue-specific, in vivo cell tracking from whole-body to cellular resolution.
    DOI:  https://doi.org/10.1038/s41587-026-03184-3
  8. Sci Adv. 2026 Jul 17. 12(29): eaed2430
    ALR couples IMS redox and heme biosynthesis beyond the disulfide relay.
    Julia Racho, Dylan Stobbe, Jan Jirschitzka, Marijana Croon, Carmelina Petrungaro, Muna Ali, Dario Wernet, Markus Habich, Nele Sophie Gawellek, Julian Strippel, Finn Dicke, Jörn Dengjel, Stephanie Kath-Schorr, Bent Brachvogel, Thomas Langer, Aleksandra Trifunovic, Ines Neundorf, Jan Riemer.
      Proteins in the mitochondrial intermembrane space (IMS) play essential roles in respiratory chain assembly, metabolism, signaling, and organelle dynamics. Their stability and functionality often depend on structural disulfide bonds introduced by the mitochondrial disulfide relay, mediated by MIA40 and ALR. In this system, the sulfhydryl oxidase ALR reoxidizes MIA40, which in turn oxidizes incoming substrate proteins. Although evidence has suggested that ALR can also act independently of MIA40, its endogenous substrates have remained unknown. In this study, we captured proteins directly oxidized by ALR. Among these, we found coproporphyrinogen III oxidase (CPOX), a key enzyme in heme biosynthesis. We show that ALR-mediated disulfide bond formation is crucial for maintaining CPOX stability in the IMS, thereby ensuring effective heme biosynthesis and mitochondrial functionality. Notably, while disulfide-deficient CPOX failed to rescue CPOX loss when localized to the IMS, it retained functionality when redirected to the cytosol. However, this bypass compromised pathway efficiency, leading to the accumulation of protoporphyrinogen IX, a highly hydrophobic and redox-active intermediate that sensitized cells to cell death. Together, our findings reveal that ALR has functions beyond the MIA pathway and highlight that oxidative protein folding in the IMS relies not only on a relay mechanism but also on a broader disulfide-introducing network of enzymes.
    DOI:  https://doi.org/10.1126/sciadv.aed2430
  9. Cell Death Dis. 2026 Jul 14.
    Targeting enolase isoenzyme 2 enables precision glycolysis inhibition in VHL-mutant renal cell carcinoma.
    Jiannan Yao, Xiaona Fan, Huixian Xin, Fuhui Wan, Xichen Dong, Qianqian Sun, Xuying Huang, Heshu Liu, Xiangyu Chen, Yanjun Jia, Haili Qian, Tao Wen, Jian Liu.
      Clear cell renal cell carcinoma (ccRCC) exhibits glycolytic addiction due to VHL mutation, making it vulnerable to metabolic intervention. While conventional inhibitors targeting core housekeeping glycolytic enzymes show robust antitumor efficacy, their clinical use is limited by on-target systemic toxicity. Here, we identify enolase 2 (ENO2) as an isoform-specific glycolytic vulnerability specific to VHL-deficient ccRCC. Although ENO2 is physiologically redundant (compensated by ENO1) in normal glycolysis, it becomes essential for sustaining ccRCC malignancy via VHL loss-HIF2α-driven glycolytic flux. Targeting ENO2 specifically suppressed glycolysis in VHL-deficient ccRCC cells, reducing their malignancy and enhancing their response to axitinib, doxorubicin, and gemcitabine. Importantly, pharmacological ENO2 blockade displayed superior tumor selectivity compared to traditional glycolysis inhibitors, effectively eliminating VHL-deficient ccRCC cells while sparing VHL-intact normal and malignant cells, despite causing slightly weaker glycolytic suppression. Mechanistic investigations revealed that ENO2 ablation inactivated up to ~78% of VHL loss-induced oncogenic effectors, including a pleiotropic oncoprotein MDK, through dual modulation of lactate metabolism and interferon signaling. Collectively, this work reveals ENO2 as a genotype-specific metabolic dependency in ccRCC, thereby enabling precision glycolytic therapy. Our work also suggests that targeting physiologically redundant metabolic isoenzymes may offer a precision medicine strategy for cancers with defined genetic alterations.
    DOI:  https://doi.org/10.1038/s41419-026-09102-4
  10. Cell Chem Biol. 2026 Jul 16. pii: S2451-9456(26)00237-0. [Epub ahead of print]33(7): 894-896
    BACH1 meets its match: Heme licenses BACH1 destruction to tune ferroptosis.
    Dylan Calhoon, Javier Garcia-Bermudez.
      In a recent issue of Molecular Cell, Ahmed and colleagues1 show that heme enables CRL2-FEM1B to recognize and degrade BACH1, linking metabolite-assisted substrate recruitment to ferroptosis regulation. This mechanism connects heme sensing, ubiquitin-mediated proteolysis, and transcriptional control of ferroptosis-protective genes, revealing a potential vulnerability in lung cancer.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.06.013
  11. Nat Metab. 2026 Jul 14.
    Decoding MASLD progression beyond histological stages.
      
    DOI:  https://doi.org/10.1038/s42255-026-01548-2
  12. J Cell Biol. 2026 Aug 03. pii: e202606160. [Epub ahead of print]225(8):
    More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
    Mami Sato, Florencio Porto Freitas, José Pedro Friedmann Angeli.
      Coenzyme Q (CoQ or ubiquinone) is an essential cofactor for mitochondrial energy production and a vital radical-trapping antioxidant that maintains membrane integrity. Additionally, CoQ shares an early biosynthetic pathway with cholesterol biosynthesis. In this issue, Ndoci et al. (https://doi.org/10.1083/jcb.202507174) reveal a regulatory system that preserves mitochondrial CoQ levels when the mevalonate pathway is impaired, though this prioritization leaves cells vulnerable to oxidative stress.
    DOI:  https://doi.org/10.1083/jcb.202606160
  13. Nat Metab. 2026 Jul 16.
    Endocrine-like regulation through brown fat-secreted microRNAs.
      
    DOI:  https://doi.org/10.1038/s42255-026-01570-4
  14. EMBO J. 2026 Jul 15.
    Metabolic buffering restricts phenotype switching in melanoma.
    Ana Ramírez-Sánchez, Miguel Jociles-Ortega, José Manuel García-Martínez, Irene Torrens-Martínez, Javier Martínez-Useros, Pakavarin Louphrasitthiphol, Mollie I Sweeney, Ana Morente-Carrasco, Sergio Ruiz-Reyes, Nerea Redondo-Díaz, Teresa Olmos-De Blas, María Jesús Fernández-Aceñero, José N Rodriguez-López, Tomoyoshi Soga, Richard M White, Colin R Goding, Luis Sanchez-Del-Campo, Custodia García-Jiménez, Ana Chocarro-Calvo.
      The impact of the metabolic microenvironment on epigenetically plastic cancer cells underpins phenotypic heterogeneity, a major cause of metastasis and therapy resistance. Nutrient limitation is a key microenvironmental stress, and can cause cells to transition from proliferative to invasive phenotypes, however, whether cancer cells have the capacity to delay phenotype switching remains unknown. Here, using melanoma as a model, we reveal that the ability to buffer glucose availability by accumulating and mobilizing glycogen can determine cancer cell phenotypic transitions. While proliferating cells contain high levels of glycogen, invasive cells are marked by depleted glycogen stores. Accordingly, the inability to store and metabolize glycogen leads to phenotype instability and a switch from proliferation to invasion. The amount of stored glycogen inversely correlates with tissue invasion depth in primary melanomas, and reduced expression of the glycogen phosphorylases PYGB/L and phosphoglucomutase 1 (PGM1) is associated with worse patient survival. Together, we identify metabolic glucose buffering as a determinant of invasive phenotype transitions in skin cancer, suggesting similar paradigms in other cancer types.
    DOI:  https://doi.org/10.1038/s44318-026-00857-2
  15. Nat Aging. 2026 Jul 16.
    Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
    Wei-Chieh Mu, Marine Barthez, Yufan Feng, Yibing Chen, Chih Ling Wang, Jing-Yi Huang, Jie Li, Paul Lanhart, Clair Tsui, Yang Joon Kim, Eric Verdin, Mihai G Netea, Danica Chen.
      Trained immunity is a state of heightened immune response that is initiated in hematopoietic stem cells (HSCs) and mediated mainly by their myeloid progeny. Aging-associated inflammation drives many aging-related diseases, yet its biological origin is largely unknown. Here we show that SIRT3, a mitochondrial deacetylase highly expressed in HSCs but reduced during aging, suppresses the HSC response to aging that drives maladaptive trained immunity, chronic inflammation and tissue functional decline in mice. Overexpression of SIRT3 in HSCs not only ameliorates aging-associated HSC decline, but also improves the function of distant tissues, including attenuation of age-related declines in cognition and motility, via myeloid cells with modulated inflammatory programs. These findings reveal that HSC aging is a driver of aging-associated inflammation through maladaptive trained immunity and broaden the possible clinical applications of targeting HSCs from hematological diseases to include countering aging-associated physiological decline and improving healthspan.
    DOI:  https://doi.org/10.1038/s43587-026-01175-2
  16. J Biol Chem. 2026 Jul 16. pii: S0021-9258(26)02215-5. [Epub ahead of print] 113343
    O-GlcNAcylation is a mitochondrial-nuclear signal that regulates passive transport through the nuclear pore complex.
    Talia Hart, Ashley Duke, Yifei Zhou, Alexander A Soukas, Armen I Yerevanian.
      The nuclear pore complex (NPC) is the single gateway between the nucleus and the cytoplasm, and in healthy cells there is a size threshold for passive diffusion across the NPC. In aging and disease, the NPC deteriorates, leading to promiscuous passive transport. We have previously showed that NPC protein expression is required for biguanide-induced lifespan extension, mTOR inhibition, and further that biguanide treatment leads to restriction of passive nuclear transport, but the underlying changes leading to this restriction were not identified. Here, we use fluorescent dextran transport and biochemical assays in HeLa cells to clarify the mechanism by which biguanide phenformin alters NPC permeability. We find phenformin treatment in HeLa cells leads to restricted passive nuclear transport in a dose and time-dependent manner. Multiple inhibitors of the mitochondrial electron transport chain (ETC) also restrict passive nucleocytoplasmic transport. Critically, phenformin reduced expression of O-GlcNAc transferase (OGT), lowering global O-GlcNAcylation and locally decreasing O-GlcNAcylation of Nup98. OGT inhibition alone restricts passive transport, while increasing O-GlcNAcylation reverses phenformin's effects. These results identify O-GlcNAc as a mitochondrial-nuclear signal and show that ETC inhibition rapidly modulates nucleocytoplasmic transport via NPC post-translational modification in human cancer cells.
    Keywords:  Nuclear pore complex; O-GlcNAc; aging; biguanides; cancer cell biology; longevity; mitochondrial energetics; passive transport
    DOI:  https://doi.org/10.1016/j.jbc.2026.113343
  17. J Biol Chem. 2026 Jul 14. pii: S0021-9258(26)02204-0. [Epub ahead of print] 113332
    Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
    Runze Wang, Xue Li, Tongxin Zhang, Yinuo Chen, Juanjuan Liu, Yuanjing Wang, Xuanzhe Wang, Lianjing Cao, Zhimin Lu, Leina Ma.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy driven predominantly by oncogenic KRAS mutations, which enforce extensive metabolic reprogramming to support tumor progression. Although ketone body catabolism has emerged as a critical metabolic adaptation in PDAC, the signaling mechanisms that link mutant KRAS to the ketolytic machinery remain largely unexplored. Here, we identify a previously unrecognized, context-dependent role of oncogenic KRAS in driving ketone body utilization. We show that KRAS mutation alone is insufficient to fully activate ketolysis; instead, it primes the ketolytic pathway in a manner that requires cooperative input from additional tumor microenvironment signals. Mechanistically, oncogenic KRAS engages a downstream signaling cascade that leads to specific post-translational modifications of key mitochondrial enzymes. These modifications enhance the flux of ketone body catabolism, thereby increasing acetyl-CoA and ATP production and promoting pancreatic cancer cell proliferation and xenograft tumor growth. In a clinical PDAC cohort, activation of this KRAS-dependent ketolytic axis was elevated in KRAS-mutant tumors compared with KRAS wild-type cases, albeit with a trend that requires further validation. Collectively, our findings define a conditional dependency of mutant KRAS on cooperative signals to drive ketone body catabolism, linking oncogenic signaling to mitochondrial ketone metabolism in PDAC. This study expands our understanding of KRAS-driven metabolic reprogramming and highlights the ketolytic pathway as a context-dependent vulnerability for therapeutic intervention in pancreatic cancer.
    Keywords:  Ketolysis; Metabolic reprogramming; Oncogenic KRAS; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbc.2026.113332
  18. Immunity. 2026 Jul 13. pii: S1074-7613(26)00263-3. [Epub ahead of print]
    MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.
    Tanmana Mitra, Jahan Rahman, Madeline Hwee, Yan-Ting Chen, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, Pat Zanzonico, Santosha A Vardhana.
      Loss of mitochondrial function promotes CD8+ T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.
    Keywords:  NADH; RNA polymerase II; T cell exhaustion; bioenergetics; metabolism; mitochondria; nascent transcription; redox balance; terminal exhaustion; translation
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.012
  19. Nature. 2026 Jul 16.
    Why do astronauts' bodies waste away? Space-station study points to mitochondria.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-02089-0
  20. bioRxiv. 2026 Jul 10. pii: 2026.07.10.737056. [Epub ahead of print]
    A single chromosome 3p break initiates clear cell renal cell carcinoma evolution.
    Rashmi Dahiya, Ianthe A E M van Belzen, Chengheng Liao, Angad Kumar, Yu-Fen Lin, Ahyeon Ko, Amanda K Mennie, Emilija Aleksandrovic, Jin Zhou, Qing Hu, Justin L Engel, Jeffrey Miyata, Jose Espejo Valle-Inclán, Alistair G Rust, Ravikanth Maddipati, James Brugarolas, Srinivas Malladi, Siyuan Zhang, Payal Kapur, Qing Zhang, Isidro Cortés-Ciriano, Peter Ly.
      Clear cell renal cell carcinoma (ccRCC) is initiated by chromosome 3p loss, yet chromosome losses impose a profound fitness burden on normal cells. How renal epithelial cells tolerate this deleterious aneuploidy during early tumorigenesis remains unclear. Analysis of 949 ccRCC genomes reveals two major classes of chromosome 3p alterations: simple deletions and complex rearrangements surrounding a terminal breakpoint - a pattern we term breakpoint-confined chromothripsis. We modeled both alterations in non-transformed human renal proximal tubule epithelial cells by introducing a single DNA double-strand break on chromosome 3p. Despite an initial fitness disadvantage, chromosome 3p loss drives adaptive genomic evolution that recapitulates recurrent ccRCC-associated aneuploidies, including 5q gain and 14q loss. These alterations alleviate the fitness constraints of 3p loss and promote metabolic reprogramming, clonal expansion, and malignant transformation, producing tumors with features of ccRCC. Thus, a single chromosome break initiates the evolutionary trajectory of ccRCC by creating a fitness bottleneck that selects for recurrent aneuploidies.
    DOI:  https://doi.org/10.64898/2026.07.10.737056
  21. Mol Biol Rep. 2026 Jul 17. pii: 1192. [Epub ahead of print]53(1):
    Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.
    Francisco Alejandro Lagunas-Rangel.
      Metabolic competition within the tumor microenvironment shapes the availability of nutrients and metabolites that regulate both tumor progression and antitumor immunity. Among the molecules linking metabolism to gene regulation, the NAD + -dependent enzyme SIRT7 has emerged as an important regulator of ribosome biogenesis, genome stability, chromatin organization, and metabolic adaptation. Although SIRT7 is frequently associated with tumor progression, emerging evidence indicates that it also supports the metabolic fitness and effector functions of immune cells, suggesting that its biological consequences are highly cell type-dependent. However, the mechanisms underlying these apparently opposing functions remain poorly understood. A conceptual framework is presented in which differences in intracellular NAD + availability contribute to asymmetric SIRT7 activity in tumor and immune cells within the tumor microenvironment. Many tumor types preserve intracellular NAD + through metabolic rewiring, whereas infiltrating immune cells frequently experience sustained metabolic stress and progressive NAD + depletion owing to nutrient competition. Although direct evidence demonstrating that physiological fluctuations in intracellular NAD + regulate SIRT7 activity in vivo remains limited, biochemical studies indicate that SIRT7 displays a relatively high apparent Michaelis constant (Km) for NAD + compared with other mammalian sirtuins, providing a biochemical rationale for increased sensitivity to changes in intracellular NAD + availability. Current evidence from SIRT7 biology, cancer metabolism, and immunometabolism is integrated to evaluate this conceptual framework, identify key limitations in the available data, and highlight experimental questions that should be addressed to determine whether differential NAD + availability represents a fundamental mechanism underlying the context-dependent functions of SIRT7.
    Keywords:  Immune dysfunction; PD-L1; Sirtuin; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11033-026-12400-x
  22. Nat Cell Biol. 2026 Jul 15.
    Lysosomes and lysosomal dysfunction in ageing biology.
    Matthew L Steinhauser, Yuan Liu, Stacey J Sukoff Rizzo, Bill B Chen, Toren Finkel, Jay Xiaojun Tan.
      Lysosomes are essential regulators of cellular homeostasis. Emerging evidence positions lysosomes as both vulnerable targets and active drivers of ageing biology. During ageing, lysosomes exhibit impaired biogenesis, defective acidification, reduced hydrolytic activity and compromised membrane integrity. These defects impair the clearance of damaged organelles and macromolecules and promote cellular stress responses, inflammageing and senescence, causing age-dependent functional decline across tissues. Lysosomal dysfunction has been increasingly linked to age-related diseases, including neurodegeneration, cardiometabolic disorders and increased susceptibility to infection, among others. Thus, lysosomal dysfunction is a hallmark of ageing that drives age-related pathology. Here we review recent progress in lysosomal biogenesis and quality control, discuss how lysosomes intersect with fundamental ageing mechanisms and evaluate emerging therapeutic strategies that target lysosomes to promote healthy ageing and potentially ameliorate age-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-02007-6
  23. J Clin Invest. 2026 Jul 15. pii: e199709. [Epub ahead of print]136(14):
    SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.
    Haojun Yang, Vincenzo Andrea Zingaro, Kevin Boardman, Ashish Noronha, Ekin Guney, Lingru Xue, Saishma Hoigebazar, Isabelle Liu, Sohit Miglani, Siyu Chen, Hieu Vu, Kwun Wah Wen, Hao G Nguyen, Hani Goodarzi, Ralph J DeBerardinis, Davide Ruggero.
      Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model. A similar mechanism occurred after long treatment of human B cell lymphoma cells with the chemotherapeutic purine synthesis inhibitor 6-mercaptopurine (6MP). Mechanistically, we demonstrated that dipeptides containing essential amino acids activated the growth and survival mTOR complex 1 (mTORC1) signaling pathway. Notably, SLC15A3 specifically interacted with mTOR on the lysosome, boosting mTORC1 activity selectively in resistant lymphoma cells but not in parental cancer cells. Silencing SLC15A3 diminished mTORC1 activity and restored resistant lymphoma sensitivity to 6MP. Strikingly, resistant lymphomas, but not primary tumors, exhibited heightened sensitivity to the clinical mTOR inhibitor, rapamycin, in culture and in vivo. We extended these findings in human lymphoma biopsies, which revealed increased SLC15A3 expression following antimetabolite therapy. Together, our study uncovered a metabolic adaptation that fuels cancer resistance to nucleotide deficiency and positions the mTORC1 inhibitor, rapamycin, as a potential therapeutic strategy for transforming the management of chemotherapy-resistant lymphomas.
    Keywords:  Drug therapy; Hematology; Lymphomas; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI199709
  24. bioRxiv. 2026 Jul 07. pii: 2026.07.06.736842. [Epub ahead of print]
    SLC16A6 is a tyrosine transporter for the melanosome.
    Corey N Cunningham, Alex J Bott, Charles H Adelmann, Matthew Shields, Katarina E Heyden, Jonathan G Van Vranken, Álvaro Jesús Narbona-Pérez, Juan A Cantres-Vélez, Guillaume Adelmant, Nathan M Krah, Steven P Gygi, David M Sabatini, Jared Rutter.
      Cells enable specialized metabolism by compartmentalizing metabolic pathways into distinct organelles, which requires the membrane transport of metabolites. In melanocytes, the amino acid tyrosine is imported into developing melanosomes for the synthesis of the UV-protective pigment melanin 1,2 . In spite of extensive biochemical characterization, the identity of the melanosomal tyrosine transporter remains unknown. Here, we identify SLC16A6 as an orphan melanosome-localized metabolite transporter. Genetic screens reveal that SLC16A6 expression is driven by the SOX10-MITF axis, the well-characterized master regulatory program governing melanogenesis and melanosomal homeostasis 3,4 . By redirecting SLC16A6 to the plasma membrane with an S240A mutation 5 , we demonstrate that SLC16A6 transports tyrosine, a process competitively inhibited by other bulky amino acids. We further determine that SLC16A6 is sufficient for in vitro melanosomal tyrosine uptake. Genetic depletion of SLC16A6 triggered loss of melanosome biogenesis and function as well as depletion of most melanosomal components. Collectively, these findings establish SLC16A6 as a melanosomal tyrosine transporter that is essential for melanosome biogenesis.
    DOI:  https://doi.org/10.64898/2026.07.06.736842
  25. bioRxiv. 2026 Jul 07. pii: 2026.07.06.736822. [Epub ahead of print]
    Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
    Helen A Jordan, Joseph A Tandurella, Vineeth Vengayil, Tanay S Parnaik, Swechha Mainali Pokharel, Kathleen Mulka, Sara Cherry, E John Wherry, Caroline R Bartman.
      During an immune response, metabolism changes dramatically. Metabolites are oxidized to power immune cell functions, serve as building blocks for proliferation, and act as effectors to regulate pathogen or host cells. Though metabolic changes in cultured cells have been studied extensively, metabolism changes in vivo are less understood. Here, we measured metabolomic changes across six mouse tissues in three models of immune activation: CpG-DNA cytokine storm, lymphocytic choriomeningitis virus infection, and polyI:C viral mimetic injection; and carried out metabolomics in cultured macrophages activated with different stimuli. We found most metabolomic changes were exclusive to either inflamed tissues or cultured macrophages, although itaconate was strongly induced in both contexts. We then mechanistically dissected the role of the soluble sialic acid N-glycolylneuraminic acid, which is highly induced in inflamed tissues yet only modestly in cultured macrophages. This metabolite rises in tissues in different models of inflammation, and the analogous human metabolite, N-acetylneuraminic acid, is increased in human patients experiencing inflammation. We found that N-glycolylneuraminic acid is produced in CD11b+ myeloid cells by cleavage of protein-bound sialic acid. However, blocking its production did not affect CpG-DNA liver inflammation or LCMV infection in mice. Therefore, these experiments identify soluble sialic acid as a conserved biomarker of inflammation in mice and humans and highlight the differences in metabolism between in vitro and in vivo models of inflammation.
    DOI:  https://doi.org/10.64898/2026.07.06.736822
  26. Cell Rep. 2026 Jul 15. pii: S2211-1247(26)00777-1. [Epub ahead of print]45(7): 117699
    ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.
    Jing Jin Gu, Kevin M Scott, Arijit Ghosh, Roberto H Barbier, Douglas C Rouse, Jacob P Hoj, Michael W Caminear, Fengqi Zhang, Boya Gao, Margaret W Barbier, Lee Zou, Li Lan, Ann Marie Pendergast.
      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine cancer that is typically metastatic upon diagnosis and has poor overall survival. Here we report that the inactivation of ABL tyrosine kinases impairs the outgrowth of metastatic SCLC tumors, resulting in prolonged animal survival. ABL inactivation increases the accumulation of transcription-replication conflicts (TRCs), compromises replication fork progression, and impairs the function of proteins implicated in transcription-coupled homologous recombination, including RAD51 and RAD52. Mechanistically, ABL-mediated tyrosine phosphorylation of RAD52 and RAD51 prevents the accumulation of TRCs and promotes replication fork progression, respectively. Because ABL inactivation increased DNA damage, we evaluated whether blocking the activity of DNA damage-repair pathways in the presence of ABL inhibitors might synergize to promote SCLC cell death. Concurrent inactivation of ABL and ATR, the primary responder to replication stress, synergistically inhibits SCLC cell growth in vitro and impairs metastatic outgrowth over single-agent-treated mice. Thus, co-inactivation of ABL and DNA damage-repair pathways might be exploited to inhibit outgrowth of SCLC metastases.
    Keywords:  CP: cancer; CP: molecular biology; abl kinase; dna damage-repair; metastasis; replication forks; small cell lung cancer; transcription-replication conflicts
    DOI:  https://doi.org/10.1016/j.celrep.2026.117699
  27. Sci Adv. 2026 Jul 17. 12(29): eaec8501
    Vitronectin metabolically programs profibrotic macrophages in 3D cultures and idiopathic pulmonary fibrosis.
    Sean W Cutter, Gang Liu, Eleanor Saunders, Bailey Cardwell, Vinzenz Hofferek, Thomas Soerianto, Kaitlyn Ritchie, Erin N S McGowan, Tien K Nguyen, Ivan K H Poon, Malcolm J McConville, Benjamin J Marsland, Glen P Westall, Mark D Hulett, Nicholas P Reynolds, Mark D Wright, Philip M Hansbro, Katrina J Binger.
      Macrophages are key drivers of inflammatory and fibrotic diseases, and their activation is shaped by interactions in their tissue microenvironment. However, dissecting the processes that drive immunopathology has proved challenging, as traditional two-dimensional (2D) culture methods fail to capture the complex molecular environment that macrophages inhabit in vivo. To address this, we generated a 3D in vitro model to better mimic the in vivo biophysical microenvironment. We show that the extracellular matrix protein vitronectin promotes a previously unknown profibrotic macrophage phenotype in 3D that is characterized by increased expression of the nicotinamide adenine dinucleotide (NAD+) ectoenzyme CD38, elevated glycolysis and mitochondrial metabolism, and synthesis of the immunomodulatory metabolite itaconate. This is validated in vivo where patients with idiopathic pulmonary fibrosis have elevated vitronectin and MRC1+CD38+ macrophages, while vitronectin-deficient mice were protected from an experimental model of lung injury and fibrosis. Thus, we uncover a previously unidentified link between the composition of tissue niches and macrophage profibrotic function via altered metabolic reprogramming.
    DOI:  https://doi.org/10.1126/sciadv.aec8501
  28. Nat Cell Biol. 2026 Jul;28(7): 1346
    Relative tension shapes embryos.
    Evan S Bardot.
      
    DOI:  https://doi.org/10.1038/s41556-026-02014-7
  29. Adv Exp Med Biol. 2026 ;1501 1-42
    The Interdependence of Carbon Substrates and Metabolic Pathways Enables the Metabolic Plasticity of Cancer Cells.
    Inês Serpa-Gonçalves, Jacinta Serpa.
      The tumor microenvironment (TME) functions as a dynamic and co-evolving ecosystem, where malignant and non-malignant cells form a metabolically interdependent community. This ecological view reimagines tumors not as isolated cell masses, but as complex biotopes in which cellular interactions are integral to tumor initiation, growth, and progression. A hallmark of this adaptive environment is metabolic plasticity-an essential mechanism that enables tumor cells, including the metastatic ones, to reprogram their metabolism in response to fluctuating nutrient availability and environmental stressors. At the core of this reprogramming lies carbon metabolism, characterized by the selective and flexible utilization of key metabolites, including glucose, lactate, glutamine, cysteine, and fatty acids. These compounds support energy production, biomass synthesis, and redox balance, while also facilitating the export and repurposing of metabolic byproducts for signaling or reuse. This chapter presents a conceptual framework that explores the interdependence of central metabolic pathways, emphasizing how tumors coordinate energy generation, biosynthesis, and redox control to support malignant progression.
    Keywords:  Gluconeogenesis; Glutaminolysis; Glycolysis; Interconnected metabolic pathways; Metabolic dependence; Metabolism-targeted therapies; Pentose phosphate pathway (PPP)
    DOI:  https://doi.org/10.1007/978-3-032-12166-0_1
  30. Sci Rep. 2026 Jul 11.
    Breast cancer genomic subtype-specific copy number alterations in metastases.
    Katherine Eason, Christopher Boursnell, Raquel Manzano, Paul A W Edwards, Suet-Feung Chin, Florian Markowetz, Oscar M Rueda, Carlos Caldas.
      Breast cancer is the second most common cancer globally, with rising incidence and poor prognosis following recurrence. Genomic analysis of primary breast tumours has identified subtypes with widely varying risk of relapse, highlighting the importance of tumour genomics in understanding metastasis. However, the genomic alterations associated with metastatic transformation-and how they differ between genomic subtypes-remain unclear due to limited sample sizes, lack of primary tumour baselines, and limited genomic coverage by panel sequencing. To address this gap, we analysed nearly 1300 whole-genome sequenced unmatched primary tumours and metastases using a unified computational pipeline. Somatic copy number profiles were classified into genomic subtypes, called the Integrative Clusters, with an improved classifier. By employing various genome-wide approaches, we identify candidate genes in regions with copy number alterations enriched or depleted in metastases, and nominate biological pathways that may contribute to metastatic disease in each genomic subtype. These subtype-specific candidates provide a framework for prioritising therapeutic hypotheses and future functional studies in metastatic breast cancer.
    DOI:  https://doi.org/10.1038/s41598-026-60972-2
  31. Nat Commun. 2026 Jul 13.
    Oncogenic Ras drives EED degradation and PRC2 dysfunction to promote aggressive squamous cell carcinoma.
    Meng-Yen Li, Aubrey Houser, Pradeep Cheema, Xiang Yu Zheng, Paula Restrepo, Pooja Flora, Yudong Zhou, Gil Segal-Dalal, Eldad Silberstein, Xiaotao Zhang, Markus Schober, Deyou Zheng, Idan Cohen, Andrew L Ji, Elena Ezhkova.
      Squamous cell carcinomas (SCCs) are common epithelial malignancies frequently associated with EZH2 upregulation, which correlates with aggressive growth and poor prognosis. EZH2 functions as the catalytic subunit of Polycomb repressive complex 2 (PRC2), which deposits the repressive H3K27me3 histone mark, yet PRC2 function in SCC pathogenesis remains unresolved. Here, we uncover a paradox: although EZH2 is elevated, the PRC2-catalyzed H3K27me3 is profoundly reduced in human SCC and complementary murine models. Mechanistically, we identify that oncogenic Ras signaling causes degradation of the PRC2 subunit EED, destabilizing PRC2 and depleting H3K27me3. Loss of EED reprograms keratinocytes into an aggressive tumor-specific cell state and induces paracrine factors that remodel the tumor microenvironment, driving metastasis. Remarkably, reintroducing EED suppresses tumor growth via restoring PRC2 integrity and H3K27me3 levels, revealing the reversibility of this epigenetic collapse. These findings link oncogenic signaling to epigenetic reprogramming and uncover PRC2 reconstitution as a potential therapeutic option in epithelial cancers.
    DOI:  https://doi.org/10.1038/s41467-026-75529-0
  32. Nat Metab. 2026 Jul 14.
    A data-driven framework reconstructs the molecular continuum of human MASLD progression.
    Ioannis Kamzolas, Thodoris Koutsandreas, Charlie George Barker, Anna Vathrakokoili Pournara, Harry Weston, Naoto Fujiwara, Yujin Hoshida, Quentin M Anstee, Michele Vacca, Irene Papatheodorou, Antonio Vidal-Puig, Evangelia Petsalaki.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses along a continuum from simple steatosis to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. However, current clinical and research frameworks rely primarily on static, histology-defined stages that fail to capture the continuous nature of disease progression. Here, we present a data-driven framework that reconstructs MASLD progression as a continuous molecular trajectory from cross-sectional liver transcriptomic profiles. By positioning patients along this trajectory, we move beyond conventional stage-based classifications and resolve the ordered activation of regulatory programmes, signalling pathways and cellular remodelling processes underlying disease progression. To enable non-invasive patient stratification, we integrate the inferred molecular trajectory with paired liver-plasma proteomics data and identify a 57-gene plasma-accessible biomarker panel that accurately predicts advanced fibrosis and continuously positions patients along the disease trajectory across independent cohorts, outperforming established non-invasive clinical scores. Together, this work establishes a generalizable trajectory-based framework for understanding MASLD pathophysiology and provides a foundation for mechanistically informed biomarker discovery, precision staging and stage-aware therapeutic prioritization.
    DOI:  https://doi.org/10.1038/s42255-026-01543-7
  33. Cell. 2026 Jul 16. pii: S0092-8674(26)00747-6. [Epub ahead of print]
    Whole-transcriptome-scale isoform-resolved spatial imaging of single cells in tissues.
    Limor Cohen, Aaron R Halpern, Timothy R Blosser, Z Phil Che, Xingjie Pan, Xiaowei Zhuang.
      Cell and tissue functions arise from complex interactions among numerous genes, and a systematic understanding of these functions requires isoform-resolved transcriptomic analysis of single cells with high spatial resolution. Here, we introduce an in situ RNA amplification method and its integration with multiplexed error-robust fluorescence in situ hybridization (MERFISH) to detect short RNA sequences and enable whole-transcriptome-scale, isoform-resolved spatial transcriptomics of individual cells in intact tissues. Using this approach, we imaged ∼33,000 distinct RNAs-including ∼23,000 genes and ∼10,000 isoforms-in the mouse brain. Our data enabled systematic analyses of region- and cell-type-specific gene programs and ligand-receptor-based cell-cell communications. These data further revealed rich spatial diversity and cell-type specificity in isoform usage across numerous genes, as well as brain structures particularly rich in isoform specificity. We anticipate broad application of this method for characterizing the molecular and cellular basis of tissue functions, unlocking previously inaccessible discoveries in cell and organismal biology.
    Keywords:  MERFISH; RT&T-AMP; alternative splicing; brain; isoform; isoform-resolved spatial transcriptomics; single-cell transcriptomics; spatial genomics; spatial transcriptomics; whole-transcriptome imaging
    DOI:  https://doi.org/10.1016/j.cell.2026.06.027
  34. Nat Cancer. 2026 Jul 14.
    Local sensory innervation shapes anti-tumor immunity in lung cancer.
    Julieta Alfonso.
      
    DOI:  https://doi.org/10.1038/s43018-026-01211-5
  35. Nat Commun. 2026 Jul 15.
    Cellular hallmarks and aging clock of the human lung parenchyma.
    Ke Xu, Grace S Kim, Atharva Bhagwat, Sepideh E Meimand, Vignesh V Venkat, Giang Pham, Jing Zhang, Jamshid Abdul-Ghafar, Mohamad D Bairakdar, Komal Dolasia, Isha R Sahasrabudhe, Alter Klausner, Yijia Chen, Thinh T Nguyen, Bruno Giotti, Rachel Brody, So-Jin Kim, Jaymin J Kathiriya, Daniel J Puleston, Patty J Lee, Alexander M Tsankov.
      Aging affects lung function, predisposing older adults to respiratory diseases; however, the cellular and molecular mechanisms of lung aging are not fully understood. Leveraging single-cell and spatial transcriptomics data from 184 and 70 lung parenchyma samples, respectively, we present an analytical platform to dissect the cell composition, gene expression modules, and regulatory changes linked to multiple hallmarks of lung aging. Our findings show cell type-specific age-association of senescence markers and a decline in alveolar cell proliferation, autocrine WNT signaling, and stemness indicators with advancing age. Analysis of myeloid cells reveals a global reduction in macrophage subsets and a surge in mitochondrial dysfunction and inflammatory signaling. In contrast, lung parenchyma T cells expand with age and exhibit heightened interferon gamma expression, cytotoxic activity, and exhaustion in older lung and blood samples, indicative of age-related immune dysfunction. Cell interaction and spatial analysis demonstrate aberrant myeloid-T cell cross-talk, leading to an increase in T cell chemotaxis and activation. Lastly, we use machine learning to predict lung biological age and identify putative biomarkers of lung aging and disease risk.
    DOI:  https://doi.org/10.1038/s41467-026-75427-5
  36. Nat Commun. 2026 Jul 13.
    ERG preserves endothelial identity to limit atherosclerosis.
    Steven R Botts, Corey A Scipione, Kristen Schulz, Leandro C D Breda, Kai Ellis, Christy Ho, Sneha Raju, Kamalben Prajapati, Kai Yu, Aniqa B Khan, Chanele K Polenz, Stylianos Z Prattas, Sharon J Hyduk, Christian Cao, Joshua D Wythe, Clint S Robbins, Clint L Miller, Myron I Cybulsky, Jason E Fish, Kathryn L Howe.
      Endothelial function is a safeguard against atherosclerosis, yet endothelial‑to‑mesenchymal transition (EndMT) can occur at atheroprone sites. How endothelial identity loss contributes to atherogenesis remains unclear. Here we investigated the role of the ETS transcription factor ERG, a key regulator of endothelial identity, in atheroprogression. Inducible endothelial Erg deletion increased plaque burden in hypercholesterolemic mice. Lineage tracing and single‑cell transcriptomics showed that ERG loss drove endothelial dedifferentiation, mesenchymal fate acquisition, and migration and expansion of EndMT cells within plaques, which interacted with pro‑atherogenic cells. ERG loss also caused early disruption of barrier function, promoting lipid uptake and foam cell accumulation in normally atheroresistant regions. In human atherosclerotic plaques, ERG chromatin accessibility and expression were reduced, with transcriptional changes mirroring those in mice. Restoring ERG in cultured EndMT cells reversed mesenchymal programs and re‑established endothelial identity. These findings identify ERG as an enforcer of endothelial function that restricts EndMT to limit atherosclerosis.
    DOI:  https://doi.org/10.1038/s41467-026-75287-z
  37. J Cell Biol. 2026 Sep 07. pii: e202605090. [Epub ahead of print]225(9):
    PISD acts as a switch between lipophagy and fatty acid transfer to mitochondria.
    Hanbing Xue, Xingwen Hu, Zhenni Yang, Yiqing Cao, Qi Zhu, Hongyu Zhao, Xiaoli Ma, Tianxin Lei, Dian Zhuang, Jing Zheng, Siqi Guo, Xiaochuan Fu, Ka Kit Chung, Pingsheng Liu, Xiaohong Zhuang, Zhengyu Liang, Sicong He, Hui Jiang, Yan G Zhao.
      Fatty acids (FAs) are transported from lipid droplets (LDs) to mitochondria for β-oxidation during cell starvation. Starvation also triggers engulfment of LDs by autophagosomes and their subsequent degradation by lysosomes (lipophagy). The mechanisms coordinating these pathways remain unclear. Here, we demonstrate that PISD-LD, an LD-localized isoform of phosphatidylserine decarboxylase, facilitates FA transfer while inhibiting lipophagy. PISD-LD mediates LD-mitochondrion (LD-mito) contacts via interaction with mitochondrial PISD. In PISD-LD KD cells, LDs are larger, and FA trafficking and mitochondrial FA β-oxidation are suppressed. The lipid transfer proteins ATG2A/B are recruited by PISDs to mediate FA transfer from LDs to mitochondria. Disruption of PISD-LD-mediated LD-mito contacts activates lipophagy, aiding LD degradation. PISD-LD binds the lipophagy receptor Spartin and inhibits lipophagy by impeding Spartin-LC3 interaction. PISD-LD also regulates LD-mito contacts and lipid metabolism in mouse liver. Thus, PISD-LD serves as a switch between LD-to-mitochondrion FA transfer and lipophagy, ensuring efficient energy production.
    DOI:  https://doi.org/10.1083/jcb.202605090
  38. Nature. 2026 Jul 15.
    An encyclopedia of human enhancer-gene regulatory interactions.
    Andreas R Gschwind, Kristy S Mualim, Alireza Karbalayghareh, Maya U Sheth, Kushal K Dey, Evelyn Jagoda, Ramil N Nurtdinov, Wang Xi, Anthony S Tan, James Galante, Hank Jones, X Rosa Ma, David Yao, Dulguun Amgalan, Judhajeet Ray, Chad J Munger, Joseph Nasser, Žiga Avsec, Benjamin T James, Muhammad S Shamim, Neva C Durand, Suhas S P Rao, Ragini Mahajan, Benjamin R Doughty, Kalina Andreeva, Jacob C Ulirsch, Kaili Fan, Elizabeth M Perez, Tri C Nguyen, David R Kelley, Hilary K Finucane, Jill E Moore, Zhiping Weng, Manolis Kellis, Michael C Bassik, Berk Ustun, Alkes L Price, Michael A Beer, Roderic Guigó, John A Stamatoyannopoulos, Erez Lieberman Aiden, William J Greenleaf, Christina S Leslie, Lars M Steinmetz, Anshul Kundaje, Jesse M Engreitz.
      Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease1-6. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.
    DOI:  https://doi.org/10.1038/s41586-026-10781-4
  39. Mol Cell Biol. 2026 Jul 14. 1-22
    The Emerging Role of mTOR in Shaping the Cancer Cell Secretome and Plasticity.
    Tyler T Cooper, Ivan Topisirovic, Lynne M Postovit.
      As tumors expand and encounter hypoxia and nutrient deprivation, cancer cells must establish tight coordination between metabolic reprogramming, protein synthesis and secretory activity to enable effective adaptation. The mechanistic target of rapamycin (mTOR) pathway plays a major role in coordinating protein synthesis and energy metabolism. Dysregulation of mTOR signaling is a hallmark of neoplasia and it contributes to tumorigenesis, metastasis, and therapeutic resistance. In this review, we discuss the emerging role of mTOR in shaping the cancer secretome and examine the implications of mTOR-dependent secretory regulation within the tumor microenvironment. Specifically, we highlight how alterations in secretory output downstream of mTOR influence extracellular matrix remodeling, angiogenesis, immune evasion, and the development of chemoresistance. This review integrates current evidence to provide a comprehensive perspective on the intersection between mTOR signaling, metabolism, protein synthesis and secretory remodeling in cancer. Specifically, we emphasize emerging links between aberrant mTOR function in cancer and secretory programs in the context of cancer cell plasticity and therapeutic resistance.
    Keywords:  cancer; chemoresistance; extracellular vesicles; mTOR; metabolism; microenvironment; plasticity; protein synthesis; secretion; stress-response
    DOI:  https://doi.org/10.1080/10985549.2026.2699146
  40. Cell Rep Med. 2026 Jul 14. pii: S2666-3791(26)00338-1. [Epub ahead of print] 102921
    Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth.
    Ximena Diaz Olea, Kristin Beede, Gabriel Pereira, David Scott, Christopher Petucci, Eric Martens, Dmitri Rodionov, Aagam Shah, Miguel P Martinez, Hyungsoo Kim, Ashok Kumar Sharma, Anthony Martin, Tongwu Zhang, Mark B Faries, Omid Hamid, Suzanne Devkota, Andrei Osterman, Simon Knott, Emile E Voest, Nadim J Ajami, Jennifer Wargo, Amanda E Ramer-Tait, Ze'ev A Ronai.
      Study of gut microbiota control of anti-tumor immunity (ATI) identifies Bacteroides rodentium and the human-related Bacteroides uniformis species to be capable of inducing ATI and limiting melanoma development in germ-free (GF), complex microbiome, or wild-type (WT) mice. Enhanced CD8+ T cell infiltration within tumors of mice harboring B. rodentium coincides with increased expression of immune-stimulating pathways. Metabolomic analyses identify lower tryptophan levels in the cecal samples of GF mice harboring B. rodentium. In silico genomic reconstruction reveals that B. rodentium and B. uniformis harbor tryptophanase A (TnaA) and aromatic aminotransferase genes, which degrade tryptophan to indoles. Administration of B. uniformis harboring TnaA mutant fails to inhibit melanoma growth. Notably, administration of indoles effectively induces ATI and inhibits melanoma development. Correspondingly, the levels of bacterially encoded tryptophan-degrading enzymes are higher in cohorts of patients with melanoma responding to immunotherapy. These findings identify indoles as tryptophan breakdown products capable of inducing ATI resulting in melanoma inhibition.
    Keywords:  Bacteroides rodentium; Bacteroides uniformis; anti-tumor immunity; indoles; melanoma; tryptophan
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102921
  41. bioRxiv. 2026 Jul 07. pii: 2026.07.06.735745. [Epub ahead of print]
    A cofactor-promiscuous HMGR from the Lyme disease pathogen illuminates diversity in bacterial isoprenoid biosynthesis.
    Isaac A Paddy, Joshua McCausland, Madelyn Frazier, Poulami Chatterjee, Mekedlawit Setegne, Oliv Eidam, Christine Jacobs-Wagner, Laura M K Dassama.
      The Lyme disease pathogen Borrelia burgdorferi contains a highly reduced genome lacking many primary metabolic pathways. However, B. burgdorferi retains the mevalonate pathway that synthesizes isopentenyl pyrophosphate (IPP), the precursor to the peptidoglycan carrier lipid. While the mevalonate pathway and the enzyme that catalyzes its rate-limiting step (3-hydroxy-3-methyl glutaryl coenzyme A reductase, HMGR) are well studied in vertebrates, little is known about the pathway in B. burgdorferi and many pathogenic bacteria. In this work, we reveal that HMGR is a critical metabolic enzyme in B. burgdorferi . We demonstrate that loss of HMGR causes morphological defects and muted de novo synthesis of peptidoglycan; these defects are ameliorated by exogenous mevalonate and IPP. Biochemical characterization unveiled the HMGR as a highly unusual cofactor-promiscuous oxidoreductase that functions with both nicotinamide cofactors. Bioinformatics and biochemical characterization uncovered examples of similarly promiscuous HMGRs and revealed a previously unrecognized evolutionary link to cofactor choice. Moreover, structures of the enzyme reveal a highly divergent active site architecture. Together, these findings firmly establish HMGR as an opportunity target for the development of antibacterials for a diderm pathogen while highlighting cofactor promiscuity as an evolutionary acquired feature in HMGRs.
    DOI:  https://doi.org/10.64898/2026.07.06.735745
  42. J Biol Chem. 2026 Jul 16. pii: S0021-9258(26)02217-9. [Epub ahead of print] 113345
    Lauric acid engages an O-GlcNAc-sensitive BCKDH regulatory node to modulate branched-chain amino acid oxidation in skeletal myotubes.
    Koichiro Sumi, Miho Shioyama, Kinuyo Munakata, Satoshi Takasugi, Masashi Morifuji, Kentaro Nakamura.
      Branched-chain amino acid (BCAA) catabolism is controlled by the phosphorylation state of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which is regulated by the opposing actions of BCKDH kinase (BDK) and the phosphatase PPM1K. Although fatty acids and amino acids both contribute to skeletal muscle energy metabolism, how fatty acid availability influences BCAA catabolic regulation remains incompletely understood. Here we examined the effects of lauric acid (C12), a medium-chain fatty acid abundant in dietary lipids, on BCAA metabolism in differentiated skeletal myotubes. Lauric acid increased phosphorylation of the BCKDH E1α subunit at Ser293 during nutrient perturbation in both mouse and human skeletal myotubes. Stable isotope tracing with U-[ˆ13C6]-leucine revealed that C12 reduced incorporation of leucine-derived carbon into downstream tricarboxylic acid (TCA) cycle-associated metabolites, indicating suppression of BCAA oxidative flux, whereas incorporation of labeled leucine into protein was not significantly altered. Mechanistically, genetic and pharmacological perturbation experiments indicated that the C12 effect requires PPM1K and is sensitive to O-GlcNAc cycling. Knockdown of O-GlcNAc transferase attenuated the C12-induced increase in BCKDH phosphorylation and reversed suppression of leucine-derived carbon flux. Dual-tracer experiments further showed that carbon derived from lauric acid and leucine converges in shared TCA cycle-associated metabolite pools, including glutamate and glutamine. Together, these findings identify a nutrient-sensitive regulatory node linking fatty acid availability, O-GlcNAc signaling, and BCKDH phosphorylation that modulates BCAA oxidation in skeletal myotubes.
    Keywords:  BCAA; Medium chain fatty acid; Myotubes; flux; lauric acid; metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2026.113345
  43. Science. 2026 Jul 16. 393(6808): eaea3075
    Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
    Yuting Jessy Tan, Travis E Conley, Fuwen Yao, Fernando J García-Marqués, Damilola E Akinyemi, Van Vuong Dinh, Qian Wang, Abel Bermudez, Jieun Kim, Julia A Belk, Oliver Soehnlein, Sharon J Pitteri, Katrin I Andreasson.
      Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.
    DOI:  https://doi.org/10.1126/science.aea3075
  44. EMBO J. 2026 Jul 11.
    Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response.
    Onur Deniz, Ying Liu, Tuuli Kirkinen, Krista Kokki, Kateryna Gaertner, Pau Clavell-Revelles, Jaakko Mattila, Ville Hietakangas.
      Anabolic and catabolic processes are coordinated by a conserved regulatory network, which includes the nutrient-sensing protein kinase mTOR complex 1 (mTORC1) and the insulin- and stress-responsive transcription factor FoxO. In a physiological setting, these regulators align growth, storage, reproduction, and aging with nutrient availability. Here, we identify transcription factor Spalt-related (Salr), previously implicated in organogenesis, as a negative regulator of growth and lipid storage in Drosophila melanogaster. Salr activates catabolic gene expression and restricts mTORC1-mediated cell growth in the Drosophila fat body. The genomic binding of Salr overlaps extensively with that of FoxO, and a similar convergence is observed for their mammalian homologs, SALL1 and FOXO1. Both Salr and FoxO are activated upon fasting, but respond to distinct cues: while FoxO displays transient activation and is responsive to AKT inhibition, Salr is activated in a slow and sustained manner through the integrated stress response. Once activated, Salr counters nuclear localization of FoxO. Taken together, we show that Salr and FoxO are growth-inhibitory transcription factors that act in a convergent manner to respond to nutrient stress through distinct cues.
    DOI:  https://doi.org/10.1038/s44318-026-00858-1
  45. Am J Respir Cell Mol Biol. 2026 Jul 11. pii: aanag143. [Epub ahead of print]
    Spatial metabolomics - a metabolic microscope for respiratory medicine.
    Matthew J Smith, Jesper Säfholm, Craig E Wheelock.
      Spatial metabolomics enables in situ, pixel-resolved mapping of small molecules across tissues, providing a powerful complement to conventional bulk metabolomics, which lacks cellular and anatomical resolution. By adapting mass spectrometry (MS) ionization approaches such as matrix-assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI), spatial metabolomics generates high-resolution metabolic maps that link metabolite distributions to defined tissue regions, cellular niches, and biological functions. This "metabolic microscopy" enables localization of biosynthetic pathways, identification of region-specific metabolic signatures, and integration with histology and other spatial omics modalities. High-resolution MS platforms support untargeted discovery, while targeted approaches enable sensitive detection of low-abundance metabolites. In respiratory research, spatial metabolomics has begun to reveal regional heterogeneity in lung metabolism, including surfactant remodeling, lipid mediator localization, fibrosis-associated metabolic reprogramming, infection-specific airway responses, and tumor-associated phospholipid dysregulation. These studies highlight the capacity of the method to connect localized biochemistry with pulmonary physiology and disease mechanisms. However, challenges remain, including limited sensitivity, difficulties in metabolite identification and isomer discrimination, restricted quantification strategies, and incompatibility with commonly used FFPE tissue preservation, underscoring the need for standardized fresh-frozen tissue workflows. Future integration of spatial metabolomics with spatial transcriptomics and proteomics promises comprehensive, multi-layered metabolic mapping of the airways, enabling the cross talk between multiple orders of biology to be understood from specific tissue microenvironments. As part of a multimodal spatial biology framework, spatial metabolomics has strong potential to define disease endotypes, inform therapeutic target discovery, and generate spatial metabolic atlases that advance mechanistic understanding and precision medicine in respiratory disease.
    DOI:  https://doi.org/10.1093/ajrcmb/aanag143
  46. Genes Dev. 2026 Jul 17.
    Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.
    Devesh Raizada, Ana P Gomes.
      Cancer progression is shaped not only by tumor-intrinsic programs and the local microenvironment but also by profound metabolic rewiring of the host at the organismal scale. Tumors engage in dynamic cross-talk with distant organs, immune and neuroendocrine networks, and systemic nutrient pools, generating a metabolically permissive macroenvironment that fuels tumor growth, supports metastatic dissemination, and undermines therapeutic efficacy. In this review, we synthesize emerging evidence showing how cancer-driven systemic metabolic remodeling reshapes glucose, lipid, and protein metabolism, perturbs immune and hematopoietic homeostasis, and hijacks neuroendocrine circuits governing energy balance and stress responses. We further highlight how these adaptations fuel cellular energetics within tumor cells as well as promote premetastatic niche formation, immune evasion, and therapy resistance, while leaving durable metabolic and inflammatory scars that accelerate biological aging and compromise long-term health in cancer survivors. Together, these findings position tumor-host metabolic cross-talk as a central, targetable axis in cancer biology with broad implications for therapy and survivorship care.
    Keywords:  cancer progression; metabolism; tumor macroenvironment
    DOI:  https://doi.org/10.1101/gad.353830.126
  47. Cell Rep. 2026 Jul 13. pii: S2211-1247(26)00763-1. [Epub ahead of print]45(7): 117685
    Tanycyte BMAL1 regulates high-fat diet weight gain and shapes arcuate neurogenesis in female mice.
    Daniel Maxim Iascone, Pavel Pivarshev, Jianing Yang, Mariela Lopez Valencia, Sara B Noya, Hongtong Lin, Corey D Holman, Ron C Anafi, Joseph L Bedont, Amita Sehgal.
      The hypothalamic radial-glia-like tanycyte population plays important and intertwined roles in metabolism, reproduction, and seasonality. Although these processes are circadian-regulated, the role of the molecular clock in tanycytes themselves has not yet been examined. We report that clock genes cycle with much higher amplitude in ventral tanycytes compared to more dorsal ependymocytes and that adult, tanycyte-specific knockout of core clock gene Bmal1 reduces diet-associated weight gain and fat mass in female mice. Fate mapping studies show that female mice have higher baseline tanycyte-derived neurogenesis than males, with many of the resulting neurons localizing to the feeding-relevant arcuate nucleus. Female but not male mice show reduced tanycyte-derived arcuate neurogenesis after adult Bmal1 deletion, with an increased proportion of newborn neurons acquiring a feeding-suppressing POMC neuropeptidergic fate. Together, our data support a role for tanycyte BMAL1 as a sex-specific regulator of body composition and hypothalamic adult neurogenesis.
    Keywords:  Bmal1; CP: neuroscience; arcuate; circadian; feeding; glia; hypothalamus; neurogenesis; sex; tanycyte; weight
    DOI:  https://doi.org/10.1016/j.celrep.2026.117685
  48. Nat Metab. 2026 Jul 14.
    Itaconate as a paracrine brake on thermogenesis.
    Lei-Lei Chen, Dan Ye.
      
    DOI:  https://doi.org/10.1038/s42255-026-01573-1
  49. Nat Rev Nephrol. 2026 Jul 14.
    The kidney distal tubule potassium switch, modern diet and hypertension.
    Paul A Welling, Eric Delpire, David H Ellison, Olivier Staub, Michael Stowasser, Robert A Fenton.
      Hypertension is the leading contributor to premature death and disability in the world. Genetic susceptibility and high dietary salt (NaCl) consumption have long been considered to be the primary culprits but growing evidence indicates that low dietary potassium consumption has an equally important role. Although the underlying mechanisms are complex and multifactorial, the potassium switch signalling mechanism in the kidney distal convoluted tubule represents a crucial pathway with implications for preventing and treating hypertension. Comprising a Kir4.1 and Kir5.1 channel potassium-sensing mechanism, a WNK kinase-induced phosphorylation cascade, and the thiazide-diuretic-targeted sodium chloride co-transporter, the potassium switch orchestrates a physiological response in the distal nephron that maintains sodium-potassium balance over wide variations in dietary potassium intake. The potassium switch is ideally adapted for the low-salt, feast-and-famine diets of hunter-gatherers. However, low potassium consumption, which is common in high-sodium modern diets, promotes potassium conservation at the expense of increasing sodium reabsorption, exacerbating salt-sensitive hypertension and its associated cardiovascular complications. Here, we discuss current understanding of the potassium switch and how its role in kidney adaptation to the modern diet can contribute to hypertension.
    DOI:  https://doi.org/10.1038/s41581-026-01099-5
  50. Sci Signal. 2026 Jul 14. 19(946): eaeb7989
    Glycerol 3-phosphate activates lipid metabolism through GATOR2-dependent regulation of mTORC1.
    Hyokjoon Kwon, Sayaka Yamada, Lingqiong Meng, Mijung Kwon, Huiting Xu, Jinhua Chi, Sally Radovick, Haiwei Gu, Ling He, Fredric E Wondisford.
      Triglycerides can be formed by fatty acid esterification of glycerol 3-phosphate (G3P) and by de novo lipogenesis (DNL). We identified G3P as a stimulus that activated mTORC1, a nutrient-sensing protein complex that promotes DNL in the liver. We found that the major source of G3P in primary mouse hepatocytes was glycerol kinase (GK), which generates G3P from glycerol. Mice with a liver-specific GK deficiency showed reductions not only in hepatic triglyceride production and storage but also in mTORC1-dependent DNL. Sequentially blocking hepatic pathways for G3P metabolism and analysis of hepatocytes and mice deficient in glycerol phosphate dehydrogenases, alternative enzymatic sources for G3P, showed that mTORC1 activation positively correlated with G3P amounts and was not mediated by a G3P precursor or other glycerol metabolites. G3P generated by wild-type GK in glycerol-treated cells induced mTORC1 activation through GATOR2, a complex that also activates mTORC1 in response to amino acids. In contrast, GK with inactivating mutations found in GK deficiency did not induce activation of mTORC1 in response to glycerol. These results show that by coordinating the production of substrates needed for esterification, G3P stimulates hepatic DNL through mTORC1 activation. In obesity, higher glycerol levels and enhanced GK-mediated metabolism drive hepatic TG accumulation, contributing to metabolic dysfunction-associated fatty liver disease.
    DOI:  https://doi.org/10.1126/scisignal.aeb7989
  51. bioRxiv. 2026 Jul 10. pii: 2026.07.09.737569. [Epub ahead of print]
    The Energetic Cost of Adrenergic Signaling in Primary Human Fibroblasts.
    Janell L M Goode, Gabriel Sturm, Martin Picard.
      Stress involves the activation of cellular, physiological, and emotional processes that cost energy-nothing is free in biology. In mammals, the stress response involves hormone release, including norepinephrine (NE), which increases energy expenditure. To quantify the energetic cost of NE signaling in a simple cellular system, we interrogated the dose (0 - 10 μM NE) and time-dependent (up to 10 hours) effects of adrenergic signaling in primary human fibroblasts. Oxygen consumption rates (OCR, reflecting ATP generated by mitochondria) and extracellular acidification rate (ECAR, reflecting ATP generated by glycolysis) were measured continuously using extracellular flux analysis, allowing us to estimate the ATP turnover rates, and thus cellular energy expenditure. Within the first 18 minutes (early phase), glycolysis increases up to 47% whereas respiration decreased 2-5%. Both parameters normalized within 1-2 hours for low NE concentrations. This was followed by an increase in oxidative phosphorylation (OxPhos), peaking around 9-12% by 2-6 hours (mid or late-phase). These minutes-to-hours data reveal the temporal dynamics whereby NE increases cellular energy expenditure in fibroblasts. Blocking OxPhos with oligomycin or piericidin A abolished OxPhos changes post-NE addition while conserving the glycolytic response. Withdrawal of glucose from the media significantly dampened the absolute rise in ECAR in response to NE, and instead increased OxPhos, revealing the metabolic flexibility in fibroblasts. Finally, cells with genetic defects impairing OxPhos exhibited a 50% blunted NE-driven metabolic response, consistent with the existence of an energy constraint in mitochondrial diseases. In summary, we have resolved the dynamics and flexible bioenergetic recalibrations associated with NE-driven hypermetabolism in primary human fibroblasts. Mapping the nature and magnitude of these recalibrations in humans would advance our understanding of the potential energetic forces underlying the damage to health by chronic stress.
    DOI:  https://doi.org/10.64898/2026.07.09.737569
  52. Nat Rev Neurosci. 2026 Jul 13.
    Brain mitochondria as key drivers of cognition and behaviour.
    Carmen Sandi, Mary Kay Lobo, Fiona Hollis, Yusuke Hirabayashi, Jaime de Juan-Sanz, Juan P Bolaños.
      Cognition and behaviour arise from computations in neural circuits, which can differ in their readiness for recruitment or in the computations and behavioural outputs that they generate. Mitochondria contribute to both circuit properties and their variability by shaping the cellular processes on which circuit function depends. Across neurons and glia, mitochondria provide bioenergetic support, regulate Ca2+ dynamics and reactive oxygen species levels, influence neurotransmitter synthesis and turnover, and sustain quality control programmes that preserve cellular integrity. The capacity of mitochondria to provide this support and their plasticity have been linked to circuit architecture, engagement and adaptation, with implications for learning and memory, reward and reinforcement, state-trait anxiety and motivation. Here we describe two complementary modes of mitochondrial support: a baseline mode, in which mitochondria sustain circuit architecture and physiological properties over long timescales, and an activity-evoked mode, in which local mitochondrial outputs support synaptic transmission and plasticity. Distinguishing these two modes helps to explain how behavioural modulators, including stress hormones, immune activity and metabolic signals, can shape behaviour by altering either baseline mitochondrial control of circuit readiness or activity-evoked mitochondrial support during circuit engagement.
    DOI:  https://doi.org/10.1038/s41583-026-01061-1
  53. Cell Metab. 2026 Jul 14. pii: S1550-4131(26)00246-9. [Epub ahead of print]
    Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
    Dandan Wang, Mark Li, Tian Lu, Mami Matsushita, Juro Sakai, Masayuki Saito, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less explored. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a critical role for BAT in the clearance of circulating branched-chain amino acids and triglycerides. We also identified a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced primarily by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress.
    Keywords:  bioenergetics; brown adipose tissue; inter-organ communication; metabolic health; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.020
  54. Nat Commun. 2026 Jul 11.
    Colorectal cancer co-opts an epidermal wound healing program during metastasis to generate disseminated tumor cells.
    Mizuho Sakahara, Takuya Okamoto, Kohei Kumegawa, Yasuko Natsume, Daisuke Kusama, Hitomi Yamanaka, Rie Komatsuzaki, Katsuyuki Yaginuma, Upasna Srivastava, Atsushi Takahashi-Kanemitsu, Etsuo A Susaki, Kazutaka Obama, Satoshi Nagayama, Reo Maruyama, Ryoji Yao.
      Metastasis is the principal cause of death from colorectal cancer (CRC), yet the cellular states that enable tumor dissemination remain poorly defined. Disseminated tumor cells (DTCs) are rare, transient, and clinically inaccessible, limiting mechanistic insight into their biology. Here we show that CRC cells transiently adopt a wound-healing program normally used by epidermal keratinocytes during tissue repair to enable metastatic dissemination. Using serial orthotopic transplantation of patient-derived organoids to model metastasis, we find that DTCs lose cancer stem cell features and instead express wound-inducible keratins, including KRT17, before metastatic outgrowth. This state is reversible, as cells reacquire primary tumor-like characteristics upon colonization of distant organs. Mechanistically, this transition is associated with reduced EZH2 activity and activation of YAP signaling. Clinically, KRT17⁺ cells localize to the invasive front of primary CRCs and are absent from adjacent normal tissue. These findings uncover unexpected lineage plasticity across distinct developmental origins and identify a transient, targetable state critical for metastatic progression.
    DOI:  https://doi.org/10.1038/s41467-026-75296-y
  55. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00158-5. [Epub ahead of print]209 91-103
    Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
    Jiashuo Zheng, Weijia Zhang, Marcus Conrad.
      Unlike apoptosis, necroptosis, or pyroptosis which are executed by dedicated proteins, ferroptosis is a distinct form of regulated cell death driven by lipid peroxidation downstream of metabolic dysfunction. In most physiological settings, the cyst(e)ine/glutathione/glutathione peroxidase 4 (GPX4) axis constitutes the central anti-ferroptotic machinery, and disruption of this axis is usually sufficient to trigger ferroptosis. For in vitro studies, commonly employed ferroptosis inducers include erastin, which blocks cystine uptake by targeting system xc-, and (1S,3R)-RSL3, which inhibits GPX4 activity. However, both compounds exhibit off-target effects - erastin can activate voltage-dependent anion channels in mitochondria, whereas (1S,3R)-RSL3 affects other selenoproteins in addition to GPX4. Thus, genetic approaches to induce ferroptosis provide a valuable complement to chemical inducers by excluding off-target concerns. Here, we describe an efficient CRISPR/Cas9-based strategy to generate SLC7A11- and GPX4-knockout HT1080 cells. These knockout lines require routine culture in medium supplemented with β-mercaptoethanol or liproxstatin-1, while withdrawal of these supplements readily induces ferroptosis.
    Keywords:  CRISPR/Cas9; Ferroptosis; GPX4; HT1080 cells; Knockout; SLC7A11
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.002
  56. Nat Commun. 2026 Jul 15.
    Exogenous creatine supplementation promotes tumor metastasis via megakaryocyte creatine kinase B-STAT5B signaling.
    Sisi Xie, Ruibo Chen, Xiaoting Sun, Xiaolei Ni, Yuting Wu, Linli Cai, Yangyi Chen, Shuangming Lin, Mei Rao, Liling Chen, Yintao Li, Yanyong Xu, Minfeng Chen, Dongmei Zhang, Shun Zhu, Ling Yang, Wen Liu, Ji Zuo, Yunlong Yang.
      Creatine supplementation is widely used in sports and increasingly popular among exercising individuals. Although the physiological role of creatine has been extensively studied, the creatine biology in pathological conditions remains poorly understood. Here we report that exogenous creatine supplementation promotes tumor metastasis via platelet activation mechanism in various mouse models and humans. Mechanistically, creatine supplementation increases megakaryocyte creatine levels and upregulates creatine kinase B (CKB). Unbiased phosphoproteomics reveals that a CKB-downstream, non-canonical STAT5B phosphorylation instigates various platelet functional genes, leading to hyperactive, metastasis-promoting platelets. Megakaryocyte-specific knockout of the creatine transporter Slc6a8 or Stat5b, as well as pharmacological inhibition of STAT5, ablates the creatine-augmented platelet hyperactivity and prevents consequent metastasis in mice. Importantly, creatine supplementation in healthy volunteers results in hyperactive peripheral platelets that increase metastasis risks. Together, our study sheds mechanistic insights into the creatine-induced metastasis and provides an anti-metastatic therapeutic paradigm by targeting megakaryocyte creatine metabolism.
    DOI:  https://doi.org/10.1038/s41467-026-74639-z
  57. Mol Cell. 2026 Jul 15. pii: S1097-2765(26)00424-7. [Epub ahead of print]
    Granular component sub-phases direct ribosome biogenesis in the nucleolus.
    Priyanka Dogra, Mylene C Ferrolino, Suparna Khatun, Qi Miao, Michele Tolbert, Aaron Pitre, Shondra M Pruett-Miller, Swarnendu Tripathi, David W Baggett, Jaison John, George E Campbell, Katelyn Jackson, Richa Bajpai, Toler Freyaldenhoven, Eric Gibbs, Cheon-Gil Park, Richard W Kriwacki.
      The hierarchical, multiphase organization of the nucleolus underlies ribosome biogenesis. Ribonucleoprotein particles that regulate ribosomal subunit assembly are heterogeneously distributed in the nucleolar granular component (GC). However, the molecular origins of the GC's spatial heterogeneity and their link to ribosome subunit assembly remain poorly understood. Here, using super-resolution microscopy in DLD-1 cells, we uncover that key GC biomolecules-NPM1, SURF6, and ribosomal RNA (rRNA)-are heterogeneously localized within GC sub-phases. In vitro reconstitution with E. coli- and human-derived rRNA revealed that these GC biomolecules form multiphase condensates with a SURF6/rRNA-rich core and NPM1-rich shell, providing a mechanistic basis for this heterogeneity. SURF6's association with rRNA weakens upon ribosome subunit assembly, enabling NPM1 to extract assembled subunits from condensates, suggesting an assembly-line-like mechanism of subunit efflux from the GC. Our results establish a framework for understanding the GC's heterogeneous structure and reveal how its distinct sub-phases facilitate ribosome subunit assembly.
    Keywords:  assembly factor; granular component; intrinsically disordered region; multiphase condensate; nucleolus; phase separation; ribonucleoprotein assembly; ribosome biogenesis; spatial heterogeneity; structured illumination microscopy
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.035
  58. Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00106-7. [Epub ahead of print] 102422
    Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
    Emma Frank, Kaspar W Persson, Pauline Morigny, Zakarias Kefil Jensen Ogueboule, Tang Cam Phung Pham, Jonas R Knudsen, Maria Rohm, Lykke Sylow, Steffen H Raun.
       PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
    METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
    RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice with anorexia compared to weight stable C26-cancer mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
    CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.
    Keywords:  Cancer cachexia; food restriction; glucose metabolism; insulin sensitivity; muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102422
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