The study investigates the unfolded protein response (UPR) in human cells under persistent endoplasmic reticulum (ER) stress, focusing on the roles of IRE1, ATF6, and PERK signaling pathways. The UPR is a set of signaling pathways that adjust the cell's ER protein folding capacity in response to stress. The research found that IRE1 and ATF6 activities were attenuated over time in the presence of persistent ER stress, while PERK signaling remained active. This attenuation of IRE1 and ATF6 activities was linked to a switch from cytoprotective to proapoptotic cell fate. Artificially sustained IRE1 activity enhanced cell survival, suggesting a causal link between IRE1 activity duration and cell fate. The findings were validated in animal models of retinitis pigmentosa, where misfolded rhodopsin induced changes in UPR activity similar to those observed in cells under prolonged ER stress. The study provides insights into how the UPR integrates cytoprotective and proapoptotic outputs to determine cell fate in response to ER stress.The study investigates the unfolded protein response (UPR) in human cells under persistent endoplasmic reticulum (ER) stress, focusing on the roles of IRE1, ATF6, and PERK signaling pathways. The UPR is a set of signaling pathways that adjust the cell's ER protein folding capacity in response to stress. The research found that IRE1 and ATF6 activities were attenuated over time in the presence of persistent ER stress, while PERK signaling remained active. This attenuation of IRE1 and ATF6 activities was linked to a switch from cytoprotective to proapoptotic cell fate. Artificially sustained IRE1 activity enhanced cell survival, suggesting a causal link between IRE1 activity duration and cell fate. The findings were validated in animal models of retinitis pigmentosa, where misfolded rhodopsin induced changes in UPR activity similar to those observed in cells under prolonged ER stress. The study provides insights into how the UPR integrates cytoprotective and proapoptotic outputs to determine cell fate in response to ER stress.