Hereditary Hemochromatosis: Pathophysiological Basis and Emerging Therapeutic Approaches—A Systematic Review of Clinical Evidence

Introduction: Hereditary hemochromatosis is a genetic disorder characterized by dysregulation of iron homeostasis, resulting in excessive intestinal iron absorption and progressive iron deposition in vital organs. The hepcidin–ferroportin axis plays a central role in the pathophysiology of the disease, particularly in cases associated with mutations in the HFE gene. Persistent iron overload may lead to progressive injury in target organs and functional impairment. Methods: A brief description of the pathological basis of hereditary hemochromatosis was conducted together with a systematic review of interventional clinical trials registered on ClinicalTrials.gov. Studies with available results were included regardless of clinical phase or recruitment status. Relevant data regarding therapeutic interventions and iron metabolism parameters were extracted and descriptively analyzed. Results: Three studies met the inclusion criteria: one evaluating the hepcidin mimetic Rusfertide (PTG-300), another assessing synthetic hepcidin LJPC-401, and a third investigating the iron chelator Deferasirox. Discussion: These therapies demonstrated biological activity in modulating iron metabolism parameters; however, none proved superior to therapeutic phlebotomy, which remains the standard treatment, in terms of efficacy. Conclusion: Although emerging pharmacological therapies targeting iron metabolism show promising biological effects, current clinical evidence remains limited. Therapeutic phlebotomy continues to represent the first-line treatment for hereditary hemochromatosis, and further clinical trials are necessary to determine the potential role of these novel therapeutic approaches.