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Ferroptosis, an iron\u2010dependent form of regulated cell death associated with macrophages, has emerged as a key pathogenic mechanism. This study aimed to investigate the protective effects of coptisine (COP), a natural alkaloid, against sepsis\u2010induced hepatic ferroptosis and injury using in\u00a0vivo and in\u00a0vitro models. Sepsis was induced in mice via cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge, followed by treatment with COP, ferrostatin\u20101 (Fer\u20101, a ferroptosis inhibitor), or 2\u2010NP. In\u00a0vitro, Kupffer cells were stimulated with LPS\u2009+\u2009IFN\u2010\u03b3 and erastin to induce inflammation and ferroptosis, then treated with COP or Fer\u20101. Multiple techniques were employed, including histopathology, enzyme\u2010linked immunosorbent assay (ELISA), quantitative PCR (qPCR), Western Blot, immunofluorescence (IF), molecular docking, bio\u2010layer interferometry (BLI), and cellular thermal shift assay (CETSA), to evaluate the STAT1\/IRF1\/GPX4 signaling axis. Additionally, serum markers from sepsis patients were analyzed. In septic mice, COP significantly attenuated liver injury, inflammation, and ferroptosis. In Kupffer cells, COP suppressed erastin\u2010induced ferroptosis. Mechanistically, COP directly bound to STAT1, inhibiting its phosphorylation and subsequent IRF1 activation, while restoring GPX4 expression. Overexpression of STAT1 abolished the protective effects of COP. Clinical data revealed elevated p\u2010STAT1 and IRF1 levels alongside reduced GPX4 in sepsis patients. COP exerts hepatoprotective effects in sepsis by inhibiting ferroptosis through the STAT1\/IRF1\/GPX4 pathway, highlighting its potential as a therapeutic agent for sepsis\u2010associated liver injury.<\/jats:p>","DOI":"10.1002\/ptr.70063","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T07:25:22Z","timestamp":1754983522000},"page":"4308-4326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Coptisine Improves Liver Inflammation in Sepsis by Regulating <scp>STAT1<\/scp>\/<scp>IRF1<\/scp>\/<scp>GPX4<\/scp> Signaling\u2010Mediated Kupffer Cells Ferroptosis"],"prefix":"10.1002","volume":"39","author":[{"given":"Bingwen","family":"Zhu","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"},{"name":"Department of Respiratory and Critical Care Medicine, The Tenth 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