Dual Roles of Natural Products in Regulating Ferroptosis in Acute and Chronic Liver Diseases: A Review

Liver diseases, both acute and chronic, are a major global health burden with limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key contributor to liver pathology and a potential therapeutic target. This review examines how plant-derived natural products modulate ferroptosis across acute liver failure (ALF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma (HCC). These compounds show dual effects, suppressing ferroptosis to protect hepatocytes in ALF, NAFLD, and NASH, and inducing ferroptosis to eliminate activated hepatic stellate cells and cancer cells in liver fibrosis and HCC. Mechanistically, they act on major ferroptosis regulators, including nuclear factor erythroid 2-related factor 2 (NRF2), solute carrier family 7 member 11 (SLC7A11), glutathione (GSH) peroxidase 4 (GPX4), heme oxygenase 1 (HMOX1), acyl-CoA synthetase long-chain family member 4 (ACSL4), lipid metabolism enzymes including arachidonate lipoxygenases (ALOXs) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), and tumor protein p53 (p53). They influence transcriptional and epigenetic programs to regulate gene expression related to ferroptosis. Some natural products modulate noncoding RNAs and chromatin-modifying enzymes to suppress genes promoting ferroptosis, while others affect RNA methylation to stabilize antioxidant defenses. Additionally, these compounds regulate iron metabolism and impact key upstream signaling pathways, collectively shaping ferroptosis control. Despite promising preclinical results, translation to clinical use is challenged by context-dependent effects, bioavailability limitations, and potential toxicity. Further mechanistic studies, in vivo validation, and clinical trials are warranted. Overall, natural product-based modulation of ferroptosis offers a promising therapeutic avenue in liver disease.