Multiple roles of HRI in attenuating the severity of thalassemia phenotypes. In β-thalassemia, HRI is activated to inhibit excess α-globin synthesis and, thus, reduces proteotoxicity. HRI-induced translation of ATF4 mRNA activates downstream gene expression to mitigate oxidative stress. Furthermore, the HRI-ATF4 axis represses Epo-mTORC signaling to reduce IE. In human erythropoiesis, HRI is implicated in fetal γ-globin expression in an opposing manner. On one hand, HRI was reported to increase translation of γ-globin mRNA^32,33 ; however, on the other hand, it was shown to inhibit transcription of γ-globin gene by increasing Bcl11A mRNA.³⁴