Proposed mechanism of action of the erythroid regulator ERFE. After blood loss, decreased oxygen delivery is sensed in the kidneys, stabilizing HIF and inducing EPO production. Binding of EPO to its receptors on erythroid progenitors in the bone marrow and the spleen leads to the rapid production of ERFE via the JAK2/STAT5 signaling pathway. ERFE is then secreted into the circulation and acts directly on hepatocytes to signal for hepcidin suppression in order to increase the iron flow into plasma for new red blood cell synthesis.