Lipidomic and transcriptomic remodeling underlies early retinal pathogenesis in dry age-related macular degeneration

Dry age-related macular degeneration (AMD) is initiated by retinal pigment epithelium (RPE) dysfunction, yet early metabolic mechanisms linking RPE injury to photoreceptor dysfunction remain unclear. Using a physiologically relevant mouse model, we performed cell-type–resolved lipidomic and transcriptomic profiling with ultrastructural analyses. RPE-specific loss of Chloride Intracellular Channel 4 (CLIC4) induced coordinated lipid remodeling and transcriptional rewiring compromising RPE–photoreceptor lipid homeostasis. Both RPE and neural retina exhibited shifts toward very-long-chain unsaturated phospholipids and ceramides, while mutant RPE also accumulated saturated very-long-chain ceramides and cholesterol, particularly in females, favoring drusen deposition. Strikingly, RPE and rods mounted divergent responses: RPE activated compensatory mechanisms, whereas rods exhibited transcriptomic and ultrastructural evidence of bioenergetic suppression, mitochondrial structural abnormalities, and mitochondria-derived oxidative damage, establishing a feed-forward stress cycle extending beyond canonical rod-RPE carbon-energy coupling. These findings underscore rod mitochondrial structural integrity as a potential early biomarker, positioning disrupted lipid recycling as a targetable axis in dry AMD pathogenesis.