In this study, HFD feeding has significantly increased the hepatic lipid accumulation; however, P2Y2R deficiency reduced lipogenesis and mitochondrial dysfunction by enhancing FAO and PGC-1α activity through AMPK signaling, suggesting P2Y2R as a promising therapeutic target for NAFLD (Figure 6). This evidence concerns the gene PPARGC1A and metabolic dysfunction-associated steatotic liver disease.