Abstract

Premature ovarian insufficiency (POI), a major cause of female infertility, is a condition where the ovaries lose their function before the age of 40. Growing evidence suggests that lysine acetyltransferase 2A (KAT2A) has been identified as a critical factor for mammalian development and the maintenance of genome stability and is associated with aging. However, the function of KAT2A in POI remains unclear. Our objective was to elucidate the role of KAT2A in the progression of POI and the intricate underlying mechanisms involved. KAT2A expression was significantly increased in human granulosa cells (hGCs) isolated from POI patients, as well as in the ovaries of aged mice. KAT2A overexpression aggravated estrous cyclicity irregularity, hormonal imbalances, follicular development disorders, increased follicular atresia, and decreased ovarian reserve in mice. Meanwhile, KAT2A overexpression exacerbates reactive oxygen species–induced cellular apoptosis in mouse GCs. Mechanistically, gene set enrichment analysis revealed that KAT2A upregulation significantly enriched apoptosis and p38 mitogen-activated protein kinase (MAPK) signaling pathway. Using a p38/MAPK-specific inhibitor in rescue experiments confirmed that the inhibition of p38/MAPK is essential for KAT2A-mediated ovarian dysfunction. In summary, the current study elucidated the molecular network of KAT2A-p38/MAPK in pathogenesis of POI, KAT2A promotes the progression of premature ovarian insufficiency (POI) via the p38/MAPK signaling pathway, thereby implying it to be a potential therapeutic target for female reproductive aging.