Schematic of HIF-2 regulation in response to cellular iron deficiency and overload in duodenal enterocytes. When cytosolic iron levels are elevated, IRP1 incorporates an iron-sulfur cluster, which interferes with the ability of IRP1 to bind IRE. This promotes translation of HIF-2 mRNA but also increases the degradation of HIF-2 mediated by the PHDs. When cytosolic iron levels are low, IRP1 binds to IRE in the 5′-UTR of HIF-2 mRNA, blocking HIF-2 translation. However, decreased activity of PHDs prevents the degradation of HIF-2 by the proteasome.