Hepatic Hepcidin/Intestinal Hif-2 Alpha Axis Maintains Iron Absorption During Iron Deficiency And Overload

Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin, a liver-derived hormone that controls iron mobilization through its molecular target ferroportin (FPN), the only known mammalian iron exporter. This pathway is perturbed in diseases that cause iron overload. Additionally, intestinal HIF-2 alpha, is essential for the local absorptive response to systemic iron deficiency and iron overload. Our data demonstrate a heterotissue crosstalk mechanism, whereby hepatic hepcidin regulated intestinal HIF-2 alpha in iron deficiency, anemia, and iron overload. We show that FPN controlled cell-autonomous iron efflux to stabilize and activate HIF-2 alpha by regulating the activity of iron-dependent intestinal prolyl hydroxylase domain enzymes. Pharmacological blockade of HIF-2 alpha. using a clinically relevant and highly specific inhibitor successfully treated iron overload in a mouse model. These findings demonstrate a molecular link between hepatic hepcidin and intestinal HIF-2 alpha that controls physiological iron uptake and drives iron hyperabsorption during iron overload.