Figure 6. Schematic diagram of mitapivat actions in β-thalassemic mouse model.

The downstream effects of mitapivat on erythropoiesis and iron homeostasis. Mitapivat improves anemia, hemolysis, and red cell survival, and ameliorates the ineffective erythropoiesis seen in Hbb^th3/+ mice. The mitapivat-induced improvement in erythropoiesis modulates the ERFE-Hamp axis, resulting in reduction of liver iron overload. In duodenums, mitapivat increases pyruvate kinase activity with reduced expression of PKM2, redirecting cells to a “nonhypoxic” metabolic condition. This reduces the expression of HIF2α and the activation of NF-κB p65, both targeting Dmt1 gene expression. Thus, mitapivat treatment blocks both iron absorption and iron release from duodenum, contributing to the reduction of iron overload in Hbb^th3/+ mice.