ATF4 Activation Promotes All-trans-Retinal-Driven Retinopathies in Mice

Impaired clearance of all-trans-retinal (atRAL) during the visual cycle leads to retinal degeneration, which is closely associated with autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (dry AMD). Transient activation of activating transcription factor 4 (ATF4) generally supports cellular adaptation to stress, whereas excessive ATF4 expression or prolonged activation can become maladaptive and promote oxidative and metabolic disturbances. Here, we reported that activation of ATF4 promoted atRAL-induced photoreceptor damage through mitochondria-caspase/DNA damage-dependent apoptosis and gasdermin E (GSDME)-dependent pyroptosis and apoptosis, and identified ATF4 as an upstream transcriptional regulator of GSDME. Genetic ablation of Atf4 or pharmacological attenuation of ATF4 signaling with the integrated stress response inhibitor ISRIB visibly preserved the viability and morphology of atRAL-treated 661W cone photoreceptor cells. Both interventions lowered GSDME N-terminal fragment (GSDME-N) abundance, decreased intracellular and mitochondrial reactive oxygen species (ROS) production, and blunted damage to mitochondria and DNA. Notably, pharmacologically suppressing ATF4 expression in the neural retina effectively prevented retinal function loss and structural injury as well as photoreceptor apoptosis and pyroptosis in light-exposed Abca4^-/-Rdh8^-/- mice, which exhibit severe defects in atRAL clearance and recapitulate key features of STGD1 and dry AMD. Our findings demonstrate that ATF4 is a critical mediator of atRAL-induced retinal atrophy, suggesting that ATF4 inhibition represents a promising therapeutic strategy for STGD1 and dry AMD.