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

Year: 2025

Type: article

Abstract: 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. 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. 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. CUR mitigates PIICS-induced liver injury by counteracting ferroptosis through modulation of lipid metabolism, iron homeostasis, and oxidative stress, offering a promising therapeutic strategy. Schematic diagram of the protective effect of CUR on PIICS-induced liver injury. CUR administration may reduce lipid peroxidation and oxidative stress by acting on ALOX5, PTGS2 and ARC, thereby alleviating hepatic ferroptosis in PIICS-induced liver injury. • Scientific Problem of PIICS Model Significant liver injury in PlICS, driven by imbalanced oxidative stress and lipid peroxidation, is closely associated with prognosis. Despite this, its core pathogenesis and effective therapies remain unclear. • Hepatoprotective Effects of Curcumin (CUR) CUR significantly ameliorates liver injury in the PIICS model, as evidenced by reduced serum transaminase levels, alleviated hepatic histological damage, and inhibition of ferroptosis-related cell death. • Core Mechanism: Inhibition of Ferroptotic Lipid Peroxidation CUR blocks PIICS-induced hepatocyte death by suppressing iron-dependent lipid peroxidation (e.g.,decreasing malondialdehyde MDA levels, restoring GPX4 activity). • Key Targets Our analysis discovered three key targets: PTGS2, SRC and ALOX5. These targets maybe provide new directions for the clinical management of PIICS-induced liver injury.

Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

DOI: 10.1016/j.bbadis.2025.168053