Abstract

Tahira Asgarova*, Huseyn Abiyev, Nigar Malikova, Elshad Novruzov

ABSTRACT

Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism characterized by excessive systemic iron accumulation resulting from dysregulation of the hepcidin–ferroportin axis. Persistent iron overload promotes oxidative stress, mitochondrial injury, chronic inflammation, and progressive damage to the liver, pancreas, heart, endocrine glands, and other organs. In recent years, ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and impaired antioxidant defenses, has emerged as a key mechanism linking iron accumulation to tissue injury. Growing evidence suggests that ferroptosis contributes substantially to the pathogenesis and clinical manifestations of hereditary hemochromatosis. This review summarizes current knowledge regarding the molecular mechanisms of iron overload and ferroptosis in hereditary hemochromatosis, emphasizing the roles of reactive oxygen species, mitochondrial dysfunction, lipid peroxidation, glutathione metabolism, and glutathione peroxidase 4 (GPX4). The review also discusses emerging therapeutic strategies targeting iron metabolism and ferroptotic pathways, including iron chelation, hepcidin replacement therapies, ferroptosis inhibitors, and antioxidant approaches. A better understanding of the relationship between iron overload and ferroptosis may provide new opportunities for precision medicine and the development of targeted interventions for hereditary hemochromatosis.[1–5]