Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

Biochemistry and Molecular Biology Graduate Program Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN 55905 USA

Cardiovascular Research Center Yale University New Haven CI 06510 USA

Department of Biochemistry and Molecular Genetics College of Medicine University of Illinois at Chicago Chicago IL 60607 USA

Department of Cardiovascular Medicine Mayo Clinic Rochester MN 55905 USA

Department of Computer Science Hanyang University Seoul 04763 Republic of South Korea

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN 55905 USA

Department of Medical Biochemistry Faculty of Medicine Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Pathology Division of Anatomic Pathology Mayo Clinic Rochester MN 55905 USA

Department of Quantitative Health Sciences Mayo Clinic Rochester MN 55905 USA

Department of Urology Mayo Clinic Rochester MN 55905 USA

Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN 55905 USA

Lab of Gastroenterology and Hepatology State Key Laboratory of Biotherapy; Department of Gastroenterology West China Hospital Sichuan University Chengdu China

Metabolomics Core Mayo Clinic Rochester MN 55905 USA

Proteomics Core Mayo Clinic Rochester MN 55905 USA

School of Computational Sciences Korea Institute for Advanced Study Seoul 02455 Republic of South Korea

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