Cell Metabolism

Paternal exercise confers endurance capacity to offspring through sperm microRNAs Yin et al. show that paternal exercise improves offspring endurance capacity and metabolic health via sperm microRNAs that reprogram gene expression in early embryos, revealing how exercise benefits can be inherited across generations.

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The energy resistance principle Picard and Murugan introduce the energy resistance principle (ERP), a testable framework outlining how resistance to energy flow sustains life and shapes health. Excess resistance (éR) promotes hallmarks of disease, whereas restorative states minimize éR, thus linking the biophysics of energy to human health, aging, and healing.

Online now: The energy resistance principle

Catenibacterium mitsuokai promotes hepatocellular carcinogenesis by binding to hepatocytes and generating quinolinic acid Zhang et al. reveal that the gut bacterium Catenibacterium mitsuokai promotes hepatocellular carcinoma by disrupting the gut barrier, colonizing HCC cells via its surface protein Gtr1/RagA and receptor γ-catenin, and secreting quinolinic acid, which binds to TIE2 and activates the oncogenic PI3K/AKT pathway in HCC cells.

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Liver-breast communication of adipocyte-oriented exosomes drives primary mammary cancer progression Li et al. demonstrate that fatty livers foster a favorable metabolic landscape for breast cancer via adipocyte-oriented exosomes. These exosomes display tropism to mammary adipocytes through the ErbB4-Nrg4 axis. Exosomal TRMT10C triggers adipocyte ROS production, boosts IL-6 secretion, and subsequently enhances free fatty acid release, thereby facilitating tumor initiation and growth.

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Hepatic acetyl-CoA metabolism modulates neuroinflammation and depression susceptibility via acetate Cao et al. show that hepatic hydrolysis of acetyl-CoA by acyl-CoA thioesterase 12 serves as a crucial source of circulating acetate mediating liver-brain communication, which signals the brain to buffer stress via bolstering immunomodulatory checkpoint molecule expression in astrocytes to limit neuroinflammation.

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HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer Xiao et al. conducted a systematic investigation into the crucial immuno-metabolic crosstalk within triple-negative breast cancer. They found that HEBP2 promoted FOXA1 nuclear translocation to upregulate GSTP1 expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3+ macrophages, impairing antitumor immunity. Targeting GSTP1 could sensitize immunotherapy.

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Save the date for Multifaceted mitochondria!

Announcing Cell Symposia: Multifaceted Mitochondria, June 21–23, 2026, Glasgow, Scotland, UK
@CellSymposia #CSMito2026 Save the date!
Keynote speakers: Judy Hirst (University of Cambridge) & Jared Rutter (University of Utah)
Find out more: http://dlvr.it/TN9ZsM

A closed-loop cholesterol shunt controlling experimental dyslipidemia Unal et al. engineered a cholesterol-responsive genetic circuit, which was designed to sense and counteract the elevated levels of cholesterol in circulation. The circuit managed to attenuate a healthy cholesterol profile in a murine model of experimental dyslipidemia within days upon intraperitoneal implantation.

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Online now: OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis

Portal vein-enriched metabolites as intermediate regulators of the gut microbiome in insulin resistance Muñoz et al. show that circulating metabolites are differentially enriched in portal versus peripheral blood. Enrichment patterns are influenced by diet, host genetics, and the gut microbiome. These metabolites, especially mesaconate/itaconate/citraconate isomers, can directly influence hepatic insulin signaling and gene expression, highlighting an important role in obesity-linked insulin resistance.

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Polycystic ovary syndrome: A metabolic disorder with therapeutic opportunities Metabolic and reproductive abnormalities are closely interconnected in polycystic ovary syndrome (PCOS). In this perspective, Zhang et al. propose a conceptual framework positioning metabolic dysfunction as a critical contributor to PCOS pathogenesis and inheritance, highlighting emerging metabolic interventions that offer new therapeutic opportunities for this complex disorder.

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Mitochondrial dysfunction reveals H2S-mediated synaptic sulfhydration as a potential mechanism for autism-associated social defects Xian et al. report an elevation of H2S in the anterior cingulate cortex of two mouse models of autism spectrum disorders (ASDs) and their corresponding human neurons. Over-sulfhydration of synaptic proteins, e.g., mGluR5, contributes to the synaptic and social deficits of these two ASD models.

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Cell Symposia

Join us in Seville, Spain, Oct 4–6, 2026 for Cell Symposia: Hallmarks of aging!
Explore the latest in aging biology from molecules to medicine. #CSAging2026 #CellSymposia
Abstract deadline: June 5, 2026
http://dlvr.it/TMlhxk

Effect of ultra-processed food consumption on male reproductive and metabolic health This randomized controlled nutrition intervention conducted in males of reproductive age shows that, compared with an unprocessed diet, consumption of ultra-processed foods impairs metabolic and reproductive health. Effects of ultra-processed foods were independent of caloric load, providing evidence that the ultra-processed nature of food is detrimental to health.

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Online now: NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism

Homocysitaconate controls inflammation through reshaping methionine metabolism and N-homocysteinylation Lin et al. discover homocysitaconate, an anti-inflammatory metabolite formed during inflammation via AHCY-catalyzed adduction of homocysteine and itaconate. Homocysitaconate is recognized by MARS, inducing an N-homocysteinylation metabolic shift that leads to NLRP3 inhibition. Exogenous homocysitaconate supplementation and endogenous homocysitaconate boosting (via NAD+-dependent AHCY activation) offer novel therapeutic strategies for inflammatory disorders.

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Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism Noncanonical clock regulators bridge genetics and nutrition to mediate 3D enhancer-promoter interactions, contributing to diurnal rhythm variation and metabolic disease risk.

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Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism Hansford et al. show that GIPR, a target of new weight-loss drugs, is found in brain cells called oligodendrocytes. GIPR helps these drugs access the brain and boosts weight loss. Without GIPR in these cells, the drugs are less effective, revealing a new mechanism behind their action.

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Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development Liu et al. show that diabetes induces immunosuppressive Schwann cells via lactate-METTL16-CTCF signaling in PDAC, promoting PD-1 resistance. Targeting this pathway restores anti-tumor immunity and enhances therapy, providing key insights into metabolic-immune interactions and offering a promising strategy to improve immunotherapy outcomes in patients with high risk.

Online now: Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development

HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes Bernardo et al. uncover a transcription-splicing regulatory axis driven by HNF1A and A1CF in pancreatic β cells. Targeted perturbations, single-cell studies, and human genetic evidence demonstrate that failure of this network leads to defective β cell function and glucose homeostasis.

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Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control Glucose is required for T cell proliferation and function, but its key metabolic fates in vivo are not well defined. Longo et al. demonstrate that in CD8+ effector T cells, glucose metabolism extends beyond energy production by fueling glycosphingolipid biosynthesis, a pathway critical for T cell expansion and cytotoxic function.

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Gut substrate trap of D-lactate from microbiota improves blood glucose and fatty liver disease in obese mice D-lactate from the gut microbiota influences blood glucose and fatty liver disease. Trapping D-lactate in the gut improves blood glucose and lowers liver inflammation and fibrosis during obesity.

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Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells Shi et al. demonstrate that CD8+ T cell-mediated elimination of high-XYLB tumor cells releases relatively high Xu5P, establishing a feedforward loop to sustain Xu5P-responsive SLC35E2+ CD8+ progenitor-like exhausted T cell effector expansion and suppress metastasis. Xu5P supplementation enhances antitumor immunity and synergizes with PD-1 blockade therapy.

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Shivering, but not adipose tissue thermogenesis, increases as a function of mean skin temperature in cold-exposed men and women Dumont et al. reveal that although heat generated by shivering muscles and by the heart increases based on the degree of cold exposure, heat-producing mechanisms present in adipose tissues like brown and white fat respond in an all-or-nothing fashion. In brown fat, the heat produced likely reflects its thermogenic capacity.

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Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication Tong et al. utilize advanced imaging approaches to reveal that beta cells located next to alpha cells are specially adapted as glucagon sensors by virtue of their high expression levels of GLP1R. These beta cells respond first to rising glucose, triggering robust responses across the pancreatic islet.

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Microbial riboflavin inhibits ceramide synthase 3 to lower ceramide (d18:1/26:0) and delay colorectal cancer progression This study identifies C26 ceramide and CERS3 as critical factors in colorectal cancer progression, which is modulated by microbial metabolite riboflavin. C26 ceramide directly activates EGFR, and the FDA-approved drug AB inhibits CRC by targeting CERS3, offering new therapeutic strategies.

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RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation How cells sense nutrients to maintain homeostasis and prevent cell death is a fundamental question. Chen et al. reveal that cells use RIPK1 to sense levels of the nutrient methionine and its metabolite S-adenosylmethionine (SAM). When SAM levels drop due to metabolic changes, RIPK1 triggers apoptosis and inflammation.

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Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flaviviruses Medkour et al. demonstrate that lipids of the sphingomyelin class in mosquito saliva facilitate the transmission of multiple flaviviruses. These salivary sphingomyelins reconfigure lipid homeostasis in skin cells, disrupting cellular mechanisms for viral protein degradation, thereby promoting skin infection at the bite site—a key determinant of transmission.

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Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation Zhang et al. report that the elevation of arachidonic acid upon radiotherapy enhances tumor-to-muscle transfer of small extracellular vesicles encapsulating spermidine synthase, driving hypusination-dependent collagen deposition and skeletal muscle weakness. Losartan inhibits spermidine synthase ISGylation and its subsequent extracellular vesicle secretion to alleviate muscle weakness, suggesting a promising therapeutic approach.

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Targeting Erbin-mitochondria axis in platelets/megakaryocytes promotes B cell-mediated antitumor immunity (Cell Metabolism 36, 541–556.e1–e9; March 5, 2024)

Online now: Targeting Erbin-mitochondria axis in platelets/megakaryocytes promotes B cell-mediated antitumor immunity