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It frequently occurs in patients with congenital or acquired anemia, such as aplastic anemia, who require long\u2010term transfusions. Iron chelation therapy (ICT) is the standard approach for managing transfusion\u2010related IO. However, the currently available iron chelators are limited by their toxicity and administration challenges. Hetrombopag (HPAG), an oral small\u2010molecule non\u2010peptide thrombopoietin receptor agonist (TPO\u2010RA), has been approved for the treatment of immune thrombocytopenia and aplastic anemia. HPAG contains an iron\u2010scavenging moiety that functions independently of its TPO\u2010RA 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\u2010induced IO have been used to elucidate the therapeutic potential and underlying mechanisms. Our findings identified HPAG as a potent iron\u2010chelating 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\u2010induced 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.<\/jats:p>","DOI":"10.1002\/hem3.70331","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T15:18:06Z","timestamp":1773069486000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Longitudinal clinical and preclinical studies identify hetrombopag as a potent chelator for systemic iron overload"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0391-4375","authenticated-orcid":false,"given":"Yufei","family":"Zhao","sequence":"first","affiliation":[{"name":"Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology &amp; Blood Diseases Hospital Chinese Academy of 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