FASN mediates crosstalk between autophagy and lipid metabolism via the AMPK-MTOR pathway in early age-related macular degeneration

Age-related macular degeneration (AMD) involves sub-retinal pigment epithelium (sub-RPE) lipid deposition in the early stage, with dysregulated lipid metabolism and impaired macroautophagy/Autophagy implicated, yet the molecular mechanisms underlying their interaction remain unclear. In this study, transcriptomic analysis of human macular tissues identified FASN (fatty acid synthase), a regulator of lipid metabolism and lysosomal function, as a significantly upregulated key hub gene in early AMD. In apoE^-/- mice fed a high-fat diet (HFD), retina-RPE-choroid complexes revealed elevated FASN alongside Autophagy suppression, lysosomal dysfunction, and lipid accumulation. In vitro, FASN protein levels increased in RPE cells treated with the Autophagy inhibitor 3-methyladenine (3-MA), but decreased with the Autophagy activator rapamycin (RAPA), without transcriptional changes; lysosomal blockade with chloroquine (CQ) induced FASN accumulation, which was significantly delayed following Autophagy inhibition. These findings indicate that FASN accumulation results from insufficient autophagic degradation. Conversely, FASN knockdown or pharmacological inhibition enhanced autophagic flux and promoted lysosomal lipid clearance in RPE cells. Mechanistically, FASN inhibition increased AMPK phosphorylation and decreased mTOR activity, thereby facilitating Autophagy and lipophagy. Collectively, our findings reveal a self-amplifying pathological circuit in early AMD: Autophagy impairment drives FASN accumulation, which in turn exacerbates lysosomal dysfunction and lipid accumulation. Targeting the FASN-AMPK-MTOR axis may offer a promising therapeutic strategy for early AMD.