Therapeutic strategies targeting iron homeostasis or heme synthesis. Hamp agonist(s) block TMPRSS6 function (SLN124, sapablursen), resulting in Smad phosphorylation and nuclear translocation. This ends in upregulation of Hamp expression. Hamp mimetics (LJPC-401, PTG300) increase Hamp level. Hamp inhibits the iron export activity of FPN in enterocytes and macrophages. FPN blocker(s) (VIT-2763), mimic Hamp function. Apotransferrin binds circulating free iron (Fe2+). Collectively, these strategies targeting iron homeostasis have been proposed to reduce free iron to rebalance iron/heme synthesis and globin synthesis in β-thalassemia, which is characterized by ineffective erythropoiesis. Bitopertin as Glyt1 inhibitor blocks the import of glycine, which is the first step in the metabolic cascade of heme biosynthesis. Bitopertin treatment has been shown to reduce PPIX erythroblast content. BMP6, bone morphogenic protein 6; BMPR, bone morphogenic protein-receptor; HJV, hemojuvelin; Smad, suppressor of mothers against decapentaplegic; TMPRSS6, transmembrane protease serine 6.
