During the absorption of dietary nonheme iron in the proximal small intestine, iron traverses the enterocyte cytosol, where it may be stored in ferritin complexes. NCOA4, a cargo receptor that promotes the autophagic degradation of ferritin, is expressed in enterocytes and is upregulated by HIF-2α. NCOA4 activity enhances iron uptake in the context of systemic iron overload, because loss of NCOA4 in enterocytes attenuates systemic iron loading in a mouse model of hemochromatosis caused by hepcidin gene disruption.