Targeting iron metabolism or IE to improve anemia and iron overload in BT. (A) Iron restriction can be achieved by using hepcidin agonists or activators or inhibitors of ferroportin, HIF2α, and erythroferrone to reduce iron intake and increase iron sequestration into macrophages, decreasing TSat. This limits hemichrome formation, ROS, and, potentially, free α-globin chain accumulation, resulting in improvements to RBC lifespan, anemia, extramedullary erythropoiesis and also iron overload. (B) Improvement of IE with drugs that inhibit JAK2 or modulate TGFβ/SMAD (eg, luspatercept) and GATA-1 activity. Use of JAK2 inhibitors will only decrease the number of erythroid progenitors and improve splenomegaly. In the event of the use of TGFβ/SMAD and GATA-1 modulators, it is expected that, as the differentiation of erythroid progenitors increases and the relative number of RBC increases, iron consumption improves and, as a consequence, hemichrome formation is reduced. In this last case, the end points are similar to those observed with the use of iron-restrictive agents, although the extent of each improvement can vary based on the activity and characteristics of each drug. Of note, the challenge in the development of GATA-1 modulators would require identifying compounds that protect GATA-1 in cells in which HSP70 is sequestered by the excess of α-globin chains, but not in cells in which GATA-1 is fully active, to prevent undesirable effects.