Regulation of the PERK pathway attenuates hypoxia-induced apoptosis in a 661W photoreceptor cell model.

High-altitude retinopathy (HAR), characterized by retinal dysfunction under hypobaric hypoxia, remains mechanistically unclear. This study explored hypoxia-induced molecular injury in retinal photoreceptor cells using a hypoxic 661W cell model and identified potential therapeutic targets. Hypoxia triggered endoplasmic reticulum (ER) stress in 661W photoreceptor cells, marked by increased phosphorylation of PERK and eIF2α, upregulation of ATF4, and elevated CHOP expression. Both Salubrinal (Sal) and PERK-targeting siRNAs (PERK-siRNAs) attenuated ER stress via the PERK/eIF2α/ATF4/CHOP pathway, reducing apoptosis and reactive oxygen species (ROS) production by suppressing HIF-1α. Sal further preserved ER morphology, alleviating ultrastructural abnormalities such as ER dilation and mitochondrial swelling observed via transmission electron microscopy. In a HAR mouse model under simulated 5,000 m altitude conditions, Sal improved retinal function, as evidenced by enhanced a- and b-wave amplitudes in electroretinogram (ERG) recordings. These findings suggest that ER stress modulation through PERK pathway inhibition mitigates hypoxia-induced retinal damage, highlighting its potential as a therapeutic strategy for HAR and related retinal disorders.