Long interspersed nuclear element-1 (L1)-mediated reverse transcription (RT) of AN RNA into cytoplasmic AN complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of AN cDNA-induced cytotoxicity and its relevance to human disease are unknown. Here we report that AN cDNA is highly enriched in the RPE of human eyes with geographic atrophy, an untreatable form of age-related macular degeneration. We demonstrate that the DNA sensor cGAS engages Alu cDNA to induce cytosolic mitochondria! DNA escape, which amplifies cGAS activation, triggering RPE degeneration via the inflammasome. The L1-extinct rice rat was resistant to AN RNA-inducedAlu cDNA synthesis and RPE degeneration, which were enabled upon L1-RT overexpression. Nucleoside RT inhibitors (NRTIs), which inhibit both L1-RT and inflammasome activity, and NRTI derivatives (Kamuvudines) that inhibit inflammasome, but not RT, both block AN cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.