Curcumin protects against PIICS-induced liver injury by suppressing iron-induced lipid peroxidation: Insights from network pharmacology and experimental validation.

Abstract

BACKGROUND: Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) drives severe metabolic dysregulation and hepatic injury, characterized by hepatocyte damage and fibrosis. While curcumin (CUR) exhibits hepatoprotective properties, its role in PIICS-induced liver injury remains unexplored. METHODS: This study investigates the efficacy and mechanisms of CUR against PIICS-induced hepatic damage. Murine PIICS models underwent hepatic histopathology (H&E staining, TEM), RNA sequencing, and targeted metabolomics to identify injury markers. CUR's effects were assessed via biochemical, transcriptomic, and metabolomic analyses. Network pharmacology, molecular docking, and qPCR were employed to validate CUR targets. RESULTS: PIICS mice exhibited elevated serum ALT, AST, IL-6, and TNF-α levels, alongside histopathological evidence of inflammatory infiltration. Transcriptomics revealed dysregulation in lipid metabolism, redox homeostasis, and iron-binding pathways. Metabolomics identified hepatic polyunsaturated fatty acid (PUFA) depletion, increased ferrous ions, lipid peroxidation (4-HNE, MDA), and reduced antioxidants (GSH, SOD). CUR treatment alleviated liver injury, restored redox balance, and suppressed ferroptosis markers. Integrated analyses demonstrated that CUR targets ferroptosis-related pathways, modulating lipid metabolism, iron homeostasis, and oxidative stress. CONCLUSION: CUR mitigates PIICS-induced liver injury by counteracting ferroptosis through modulation of lipid metabolism, iron homeostasis, and oxidative stress, offering a promising therapeutic strategy.