Scheme of the mechanism by which HIF-PHI induces erythropoiesis and iron mobilization. This study, using mutant mouse lines in which the Epo gene is modified, demonstrates that HIF-PHIs induce erythropoiesis primarily by activating renal Epo gene expression. Hepatic EPO induction contributes marginally to the therapeutic effects of HIF-PHIs. HIF-PHIs directly regulate neither hepcidin expression in the liver nor the mobilization of stored iron. Hepatic hepcidin expression is fundamentally suppressed by erythroferrone, which is secreted from erythroblasts stimulated by EPO. Hepcidin suppression results in the induction of iron release from iron-storage cells. Erythroblasts use serum iron for hemoglobin synthesis without hepcidin suppression. Regardless of EPO induction, HIF-PHIs directly drive the duodenal induction of duodenal cytochrome b and divalent metal transporter 1, which promote iron intake from food in coordination with hepcidin suppression.