Luspatercept decreases spleen iron content without substantial changes in liver iron content. Hypothetical mechanism(s) proposed by Denton et al,¹ which need confirmation by future studies. By improving late-stage erythropoiesis, luspatercept may negatively modulate hepcidin via multiple mechanisms, including the following: (1) increased release of mediators by erythroid progenitors (ERFE? others still unidentified?); (2) direct interference on signaling pathways activating hepcidin, which can also involve TGF-β receptor signaling; and (3) reduction of total body iron stores, to which hepcidin production is generally proportional. These dynamic changes, along with decreased erythrophagocytosis due to reduction of transfusion burden and IE, may promote ferroportin activity in splenic macrophages, leading to increased iron egress from the spleen, as well as increased iron availability in plasma, bone marrow, and liver, favoring iron redistribution and increased iron chelation efficacy. Question marks denote mechanisms that need confirmation. Figure created with BioRender.com.