Ferroptosis: A Key Mechanism in Alcohol-Induced Mitochondrial Dysfunction and Oxidative Stress

Abstract

Alcoholic liver disease (ALD) is a complex condition marked by mitochondrial dysfunction, oxidative stress, and hepatocellular death. Among the various mechanisms involved, ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical contributor. Alcohol metabolism increases reactive oxygen species (ROS), depletes glutathione, and promotes lipid peroxidation, which jointly trigger ferroptosis and exacerbate liver injury. Recent studies highlight the significant role of hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α, in regulating ferroptosis during ALD. HIF-1α promotes iron accumulation by enhancing iron uptake and reducing iron export, thereby sensitizing hepatocytes to ferroptosis. In contrast, HIF-2α demonstrates a context-dependent influence on iron homeostasis and cellular responses to hypoxic stress. These findings point to a complex regulatory network involving mitochondrial damage, ROS generation, and iron metabolism. Despite growing evidence, the interplay among ROS, HIFs, and ferroptosis in ALD pathogenesis remains insufficiently defined. The dual roles of HIF isoforms and their effects on mitochondrial function and iron regulation require further investigation. Additionally, therapeutic strategies targeting ferroptosis or HIF activity remain largely unexplored in clinical practice. Continued research is needed to clarify the molecular pathways connecting HIFs and ferroptosis in ALD. Developing ferroptosis inhibitors and modulators of HIF activity may offer promising therapeutic options, and preclinical and clinical studies should determine the appropriate dosing and safety profiles. A deeper understanding of these mechanisms may enable targeted interventions that reduce liver injury and improve outcomes in individuals with ALD.