Proposed model of heme regulation of erythropoiesis during ID in vivo by HRI through coordinated translational control at eIF2αP and mTORC1 signaling. Left: Steady-state erythropoiesis in the BM under iron sufficiency. In iron and thus heme abundance, HRI homodimer is inactive because of full occupancies of heme onto the 4 HRI heme binding domains unable to phosphorylate eIF2α, thus permitting global protein synthesis, mainly globin proteins in erythroid cells. Sufficient hemoglobin production maintains oxygen-delivering capacity in blood without hypoxia. Middle: Activation of HRI-ISR under ID mitigates IE. Under iron/heme deficiency, HRI in BM erythroid precursors is activated by the dissociation of heme. HRI then induces ISR, phosphorylating eIF2α, which inhibits globin protein synthesis and results in a decrease of hemoglobin content and consequently induction of tissue hypoxia stress. In addition, eIF2αP selectively enhances the translation of ATF4 mRNA to alleviate ROS levels. Most important and novel here is that HRI-ISR inhibits mTORC1 signaling to mitigate IE in the spleen. Right: Elevated mTORC1 signaling and development of IE in mutant mice defective in HRI-ISR signaling in ID. Hypoxia induced by ID stimulates Epo production in the kidney and increases Epo in blood circulation. In the spleen, binding of Epo to its receptors in erythroid precursors induces AKT/mTORC1 signaling, thus phosphorylating 4EBP1 and S6K/S6 to increase protein synthesis, promote proliferation, and inhibit erythroid differentiation, which are the characteristics of IE. HRI-ISR serves as feedback to inhibit mTORC1 signaling activity inhibiting the development of IE in ID.