Molecular code of ferroptosis: emerging multi-dimensional modifications and therapeutic targets in hepatic disorders

Ferroptosis, a distinct form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a pivotal regulator in the pathogenesis of liver diseases. It functions both as a driver of hepatocyte injury in chronic liver disorders and as a therapeutic vulnerability in hepatocellular carcinoma. This review provides a comprehensive analysis of the regulatory networks of ferroptosis, shaped by both epigenetic and post-translational modifications. Specifically, we detailed how RNA and DNA methylation, non-coding RNAs, histone acetylation and post-translational modifications dynamically modulated the expression, stability and activity of ferroptosis-related molecules, especially for glutathione peroxidase 4, solute carrier family 7 member 11, acyl-CoA synthetase long-chain family member 4 and transferrin receptor 1. By dissecting these multilayered regulatory mechanisms, we delineated how distinct modifications operated, either promoting or suppressing ferroptosis across various liver diseases. Furthermore, we summarized recent advances in therapeutic interventions targeting ferroptosis-related pathways, including their pharmacological mechanisms, efficacy in preclinical models and limitations in clinical translation. Special emphasis was also placed on the complexity of modifications, disease-stage specificity and the topology of modification sites in shaping ferroptosis sensitivity. Collectively, this review highlights ferroptosis as a dynamic and therapeutically actionable within liver pathology and underscores the potential of targeting regulatory modifications to refine strategies for disease intervention.