Ferroptosis in liver diseases: molecular mechanisms, biomarker potential, and clinical translation

Ferroptosis is a type of intracellular, iron-dependent cell death that differs from apoptosis, necrosis, and autophagy. Ferroptosis is characterized by excessive lipid peroxidation. Iron-dependent, non-apoptotic cell death is linked to several liver diseases. Although numerous ferroptosis-associated genes and pathways have been linked to liver disorders, the exact mechanisms by which ferroptosis contributes to disease initiation and progression remain incompletely understood. In this review, we discuss the initiation and role of ferroptosis in the pathophysiology of liver diseases, including acute liver injury, liver fibrosis, hepatocellular carcinoma, viral hepatitis, autoimmune hepatitis, alcohol-associated liver disease, and NAFLD/MASLD. We first describe the regulatory function of ferroptosis before highlighting its relevance and underlying processes in several distinct liver disorders. In addition, we briefly discuss the potential clinical relevance of ferroptosis-related molecules and pathways as candidate biomarkers and therapeutic targets in liver diseases, with emphasis on their possible value in biomarker discovery, patient stratification, disease evaluation, and clinical translation. We also emphasize the context-dependent role of ferroptosis, in which its induction may be therapeutically beneficial in hepatocellular carcinoma or activated hepatic stellate cells, whereas excessive hepatocyte ferroptosis may aggravate non-malignant liver injury.