Context-Dependent Roles of NCOA4-Mediated Ferritinophagy in Liver Diseases: From Ferroptosis to Fibrosis Reversal and Therapeutic Targeting

Abstract

Nuclear receptor coactivator 4 (NCOA4) is the cargo receptor that mediates ferritinophagy, the selective autophagic degradation of ferritin, thereby controlling iron bioavailability. In the liver, this pathway is essential for iron homeostasis, but its dysregulation contributes to ferroptosis and multiple liver diseases. This review aims to summarize the context-dependent roles of NCOA4-mediated ferritinophagy across the pathophysiological spectrum of liver diseases, including drug-induced liver injury, metabolic dysfunction-associated steatotic liver disease, alcoholic liver disease, ischemia–reperfusion injury, liver fibrosis, and hepatocellular carcinoma. We discuss how the pathological versus protective outcomes depend on the cellular redox reserve and the distance from the iron toxicity threshold. We also highlight emerging post-translational modifications that regulate NCOA4 stability and activity, and outline therapeutic strategies for either inhibiting or activating this pathway depending on the disease context. Finally, we discuss priorities for clinical translation, including cell type-specific targeting and biomarker-guided patient stratification.