Role of ferroptosis in liver diseases and its implications for therapeutic strategies

Ferroptosis, a novel form of regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides and subsequent plasma membrane rupture, is fundamentally distinct from traditional cell death modalities such as apoptosis, necrosis, and autophagy. Accumulating preclinical and clinical evidence indicates that ferroptosis is intricately intertwined with the pathogenesis and progression of a broad spectrum of acute and chronic liver diseases, including acute liver injury (ALI), metabolic dysfunction-associated steatotic liver disease (MASLD), alcoholic liver disease (ALD), viral hepatitis (HBV/HCV infection), liver fibrosis, and hepatocellular carcinoma (HCC). Notably, the role of ferroptosis in liver diseases is pleiotropic: it accelerates disease progression in most acute and early-stage chronic liver diseases by exacerbating hepatocellular damage and inflammatory responses, while exerting a tumor-suppressive effect in advanced liver fibrosis and HCC by selectively eliminating malignant or activated pathogenic cells (e.g., hepatic stellate cells). This review systematically elaborates on the core molecular mechanisms of ferroptosis, with a focus on the regulatory networks of iron metabolism, lipid peroxidation cascades, and endogenous antioxidant defense systems. Subsequently, it systematically summarizes the context-dependent regulatory role of ferroptosis in different types of liver diseases, integrating the latest preclinical findings and clinical correlative evidence, aiming to provide new theoretical insights and translational therapeutic strategies for the clinical management of liver diseases. • Ferroptosis is a novel iron-dependent regulated cell death featured by lipid peroxide accumulation and plasma membrane rupture, which is fundamentally distinct from apoptosis, necrosis, and autophagy. • Mounting evidence demonstrates that ferroptosis is closely involved in the pathogenesis and progression of a wide spectrum of acute and chronic liver diseases, including ALI, MASLD, ALD, viral hepatitis, liver fibrosis, and HCC. • Ferroptosis plays a pleiotropic role in liver diseases: it aggravates hepatocellular injury and inflammation in most acute and early-stage liver diseases, but exerts a tumor-suppressive function in advanced fibrosis and HCC. • This review summarizes the core molecular mechanisms of ferroptosis and its context-dependent roles in liver diseases, aiming to provide novel theoretical insights and translational therapeutic strategies for clinical liver disease management.