Longitudinal clinical and preclinical studies identify hetrombopag as a potent chelator for systemic iron overload.

Iron overload (IO) is a pathological condition characterized by excessive iron accumulation, leading to systemic functional impairment. It frequently occurs in patients with congenital or acquired anemia, such as aplastic anemia, who require long-term transfusions. Iron chelation therapy (ICT) is the standard approach for managing transfusion-related IO. However, the currently available iron chelators are limited by their toxicity and administration challenges. Hetrombopag (HPAG), an oral small-molecule non-peptide thrombopoietin receptor agonist (TPO-RA), has been approved for the treatment of immune thrombocytopenia and aplastic anemia. HPAG contains an iron-scavenging moiety that functions independently of its TPO-RA activity; however, its role in ICT has not been clearly defined. In this study, we conducted a longitudinal evaluation of iron burden in clinical cohorts of patients with severe aplastic anemia treated with immunosuppressive therapy alone or in combination with HPAG therapy. Complementary preclinical models mimicking transfusion-induced IO have been used to elucidate the therapeutic potential and underlying mechanisms. Our findings identified HPAG as a potent iron-chelating agent with both prophylactic and therapeutic efficacy against systemic IO. Mechanistically, HPAG functions as a potential ferroptosis inhibitor by significantly reducing toxic iron accumulation, suppressing iron-induced lipid peroxidation at the cellular level, and alleviating systemic complications. These findings advance our understanding of transfusional IO and support the idea that targeting ferroptosis is a novel therapeutic strategy for systemic IO.