HRI-ISR represses Epo-mTORC1 signaling in iron-restricted erythropoiesis. In Wt mice, HRI is activated, phosphorylates eIF2α, and induces ISR during ID (−Fe). At the same time, the elevated serum Epo levels resulting from ID anemia induce AKT-mTORC1 signaling to increase protein synthesis and cell proliferation. HRI-ISR is necessary to repress mTORC1 activity and cell proliferation and, thus, promote terminal differentiation. In Hri^−/−, eAA, and Atf4^−/−mice, Epo-mTORC1 signaling remains active during ID as a result of defective HRI-ISR. This active Epo-mTORC1 signaling causes IE in ISR-defective mutant mice. Repression of mTORC1 by HRI-ISR serves as 1 feedback mechanism for terminating Epo signaling in ID. Reprinted from Zhang et al.⁵⁰