Sepsis is a life-threatening condition characterized by organ dysfunction, with the liver being particularly vulnerable due to inflammation triggered by Kupffer cell activation. Ferroptosis, an iron-dependent 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-induced hepatic ferroptosis and injury using in vivo and in vitro models. Sepsis was induced in mice via cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge, followed by treatment with COP, ferrostatin-1 (Fer-1, a ferroptosis inhibitor), or 2-NP. In vitro, Kupffer cells were stimulated with LPS + IFN-γ and erastin to induce inflammation and ferroptosis, then treated with COP or Fer-1. Multiple techniques were employed, including histopathology, enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), Western Blot, immunofluorescence (IF), molecular docking, bio-layer 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-induced 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-STAT1 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-associated liver injury.
Zhu et al. (Tue,) studied this question.