Ceapin-A7 Suppresses UPR Signaling and Mitigates Retinal Neovascularization in Vldlr-/- Mice.

Pathological neovascularization drives blinding retinal diseases, including diabetic retinopathy, retinopathy of prematurity, and neovascular age-related macular degeneration. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling are key mechanisms underlying neovascularization. Mice lacking the UPR regulator Activating Transcription Factor 6 (ATF6) show normal retinal vasculature yet are resistant to pathologic neovascularization, suggesting that ATF6 inhibition may mitigate retinal damage and vision loss from aberrant retinal angiogenesis. We tested Ceapin-A7, a selective ATF6 inhibitor, in Vldlr-/- mice, a genetic model of retinal neovascularization. Intravitreal Ceapin-A7 reduced ectopic vascular projections into the outer retina and significantly increased scotopic b-wave amplitude, while a-wave and photopic responses showed no significant difference between groups. Single-nucleus RNA sequencing revealed suppressed ATF6/UPR gene programs and angiogenic pathways in retinal endothelial cells and reduced Müller cell gliosis. These findings demonstrate that pharmacologic ATF6 inhibition mitigates retinal neovascularization in Vldlr-/- mice and identifies ATF6/UPR as a therapeutic target for neovascular retinal diseases.