Daprodustat augments red blood cell and γ-globin production in models of sickle cell disease

Sickle cell disease (SCD) causes erythrocyte sickling and downstream sequelae, including hemolysis, iron mishandling, and subclinical renal dysfunction, thereby reducing erythropoietic drive. These effects result in chronic anemia that drives SCD-related complications. Treatment of severe anemia in SCD with frequent subcutaneous injections of erythropoiesis-stimulating agents is often poorly tolerated by patients, underscoring the need for oral treatments. Here, we provide key insights into how daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates red cell production, may serve as a targeted treatment for anemia in SCD. In a mouse model of SCD, daprodustat increases red blood cell production, reduces sickling, and improves iron mobilization by suppressing hepatic hepcidin expression, thereby enhancing iron availability for erythropoiesis and ameliorating chronic anemia. In addition to these systemic, non-cell-autonomous effects on iron homeostasis, daprodustat directly induces γ-globin expression and increases the production of fetal hemoglobin-containing erythroid cells (F-cells) derived from CD34+ hematopoietic stem and progenitor cells of patients with SCD, conferring cell-autonomous therapeutic benefits. These findings demonstrate that HIF-PHIs act on multiple therapeutic targets in SCD and represent a promising oral treatment option for chronic anemia in this disease.