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Integration of four human single\u2010nucleus transcriptomic datasets identified Coagulation Factor XIII\u2010A (F13A1)\u2010positive macrophages as the predominant subset in MASH livers, a finding validated in patient samples and murine models. Lipid\u2010stressed hepatocytes induce F13A1 expression through a sphingosine\u20101\u2010phosphate (S1P)\u2010dependent mechanism. Silencing F13A1 suppressed the pro\u2010inflammatory phenotype and alleviated hepatic injury in vivo. Mechanistically, F13A1 directly interacted with pyruvate kinase M2 (PKM2), promoting its dimerization, a process enhanced by intracellular calcium levels. Dimerized PKM2 translocated into the nucleus and upregulates interleukin\u20101 beta (IL1B) expression via the PKM2\/HIF1A (Hypoxia\u2010inducible factor 1\u2010alpha) axis. In addition, F13A1 enhanced the Warburg effect in macrophages through PKM2\u2010mediated metabolic reprogramming. Pharmacologic activation of PKM2 with DASA\u201058 abrogated F13A1\u2010driven inflammation, and PEG\u2010PLA micelle\u2010mediated delivery of DASA\u201058 ameliorated hepatic inflammation in vivo. These findings establish F13A1 as a critical driver of macrophage\u2010mediated inflammation in MASH and highlight the F13A1\/PKM2\/HIF1A pathway as a promising therapeutic target.<\/jats:p>","DOI":"10.1002\/advs.202518128","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T17:00:04Z","timestamp":1766163604000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["F13A1\u2010Mediated Macrophage Activation Promotes MASH Progression via the PKM2\/HIF1A Pathway"],"prefix":"10.1002","volume":"13","author":[{"given":"Qianrang","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"NHC Key Laboratory of Combined Multi\u2010Organ Transplantation  Hangzhou 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