ER stress induces cell death through transcriptional regulation that increases protein synthesis. This study shows that the transcription factors ATF4 and CHOP, downstream of eIF2α phosphorylation, directly induce genes involved in protein synthesis and the unfolded protein response (UPR), but not apoptosis. Forced expression of ATF4 and CHOP increases protein synthesis, leading to ATP depletion, oxidative stress, and cell death. The increased protein synthesis and oxidative stress are necessary for cell death. The study reveals that eIF2α phosphorylation reduces protein synthesis, promoting cell survival, while ATF4 and CHOP activation increases protein synthesis, leading to oxidative stress and cell death. These findings suggest that limiting protein synthesis could be therapeutic for diseases caused by ER stress. ATF4 and CHOP interact to induce their target genes, which are involved in protein synthesis and the UPR. Increased protein synthesis by ATF4 and CHOP leads to oxidative stress and cell death. The study also shows that ATF4 and CHOP increase protein synthesis in vivo, causing oxidative stress and cell death. The results highlight the importance of tightly regulating protein synthesis to prevent cell death in response to ER stress. The study provides insights into the mechanisms of ER stress-induced cell death and suggests that targeting protein synthesis could be a potential therapeutic strategy for protein-folding diseases.ER stress induces cell death through transcriptional regulation that increases protein synthesis. This study shows that the transcription factors ATF4 and CHOP, downstream of eIF2α phosphorylation, directly induce genes involved in protein synthesis and the unfolded protein response (UPR), but not apoptosis. Forced expression of ATF4 and CHOP increases protein synthesis, leading to ATP depletion, oxidative stress, and cell death. The increased protein synthesis and oxidative stress are necessary for cell death. The study reveals that eIF2α phosphorylation reduces protein synthesis, promoting cell survival, while ATF4 and CHOP activation increases protein synthesis, leading to oxidative stress and cell death. These findings suggest that limiting protein synthesis could be therapeutic for diseases caused by ER stress. ATF4 and CHOP interact to induce their target genes, which are involved in protein synthesis and the UPR. Increased protein synthesis by ATF4 and CHOP leads to oxidative stress and cell death. The study also shows that ATF4 and CHOP increase protein synthesis in vivo, causing oxidative stress and cell death. The results highlight the importance of tightly regulating protein synthesis to prevent cell death in response to ER stress. The study provides insights into the mechanisms of ER stress-induced cell death and suggests that targeting protein synthesis could be a potential therapeutic strategy for protein-folding diseases.