Oxidative stress mediates retinal damage after corneal alkali burn through the activation of the cGAS/STING pathway.

Retinal damage accounts for irreversible vision loss following ocular alkali burn (OAB), but the underlying mechanisms remain largely unexplored. Herein, using an OAB mouse model, we examined the impact of oxidative stress (OS) in retinal damage and its molecular mechanism. Results revealed that OS in the retina was enhanced soon after alkali injury. Antioxidant therapy with N-acetylcysteine (NAC) preserved the retinal structure, suppressed cell apoptosis and decreased retinal inflammation, confirming the role of OS. Moreover, enhanced OS was linked to mitochondrial dysfunction, mtDNA leakage and initiation of the cytosolic DNA-sensing signaling. The activation of the major DNA sensors cyclic GMP-AMP Synthase (cGas) and cGAS-Stimulator of Interferon Genes (cGAS/STING) pathway was then identified. Notably, inhibiting cGAS/STING signaling with C-176 markedly reduced inflammation and cell apoptosis and ultimately protected the retina against OAB. Overall, our study reveals the vital function of OS in the occurrence of OAB-induced retinal damage and the involvement of cGAS/STING activation. Furthermore, our provides preclinical validation of the use of an antioxidant or a STING inhibitor as a potential therapeutic approach to protect the retina after OAB.