N-Acetyltransferase 2 Inhibits Myopia by Maintaining Mitochondrial Metabolism in Scleral Fibroblasts

The excessive elongation of eye axis is a primary contributing factor of myopia, yet the underlying genetic mechanisms remain not fully understood. The study was to explore risk-associated genes of myopia and identified that N-acetyltransferase 2 (NAT2) acted as a regulator in the pathological process of myopia. The genome-wide association study analysis was performed for axial length of eyes in a Chinese population aged 4 to 18 years (n = 6,345), and the most significant locus was 8p22, with NAT2 identified as a potential risk-associated gene for myopia. NAT2 was down-regulated by hypoxia in form deprivation-induced murine myopia, and the adeno-associated virus-induced genetic intervention of NAT2 in sclera influenced myopia progression. For mechanism, NAT2 could regulate the phenotypic transition and extracellular matrix remodeling of scleral fibroblasts by maintaining mitochondrial metabolism and inhibiting the ROS/TGF-β pathway, which also had effects on choroidal vascular function. Additionally, administration with α-ketoglutarate, a downstream metabolite of NAT2, effectively suppressed myopia progression in murine models. These findings highlight NAT2 as a critical regulator of myopia pathogenesis, offering new insights into potential therapeutic strategies targeting mitochondrial metabolism.