Ferroptosis mediated by ferritinophagy is involved in liver injury caused by sepsis

Background Ferritinophagy is a type of selective autophagy mediated by nuclear receptor coactivator 4 (NCOA4), and its overactivation can promote ferroptosis. However, the role of ferritinophagy in sepsis-induced liver injury needs to be further explored. The aim of this study was to investigate the role of ferritinophagy in liver injury caused by sepsis through the regulation of ferroptosis and its underlying mechanisms. Methods The sepsis rat model was established by cecal ligation and puncture (CLP). In the CLP + Fer-1 and CLP + 3-MA groups, Fer-1 (10 mg/kg) and 3-MA (20 mg/kg) were intraperitoneally injected at 1 h and 2 h before surgery, respectively. The levels of the serum inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected. The levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. The pathological alterations in liver tissue and mitochondrial structure were examined. The levels of ferroptosis-related markers, including ferrous iron (Fe²⁺), malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), glutathione (GSH), prostaglandin endoperoxide synthase 2 (PTGS2), and acyl-CoA synthetase long-chain family member 4 (ACSL4), were quantified. The expression levels of nuclear receptor coactivator 4 (NCOA4), ferritin heavy chain 1 (FTH1), autophagy-related protein p62/SQSTM1 (p62), and microtubule-associated protein 1 light chain 3B (LC3B) in liver tissue were detected. Result (1) Ferroptosis was activated in the hepatocytes of septic rats induced by CLP. (2) In sepsis, the expression of NCOA4 in hepatocytes increased, leading to the degradation of intracellular ferritin through ferritinophagy, an increase in intracellular Fe²⁺ concentration, and the induction of ferroptosis in hepatocytes. Conclusion Ferritinophagy is involved in sepsis-induced liver injury, and inhibiting ferritinophagy can alleviate hepatocyte ferroptosis and mitigate sepsis-induced liver injury.