KAT2A-Mediated excessive oxidative stress in ovarian granulosa cells Activated cell apoptosis contributes to premature ovarian failure -associated infertility

Background: Premature ovarian failure (POF) is an important cause of declined fertility in women, with hardly study focusing on post-translational modifications (PTMs). Currently, Lysine acetyltransferase 2A (KAT2A) has been reported to be essential for mammalian development and genome stability, and is associated with aging. We aimed to elucidate the role of KAT2A in POF progression and the detailed underlying mechanisms.Methods: Granulosa cells (GCs) were taken from human follicular fluid of normal and POF, and were firstly to detect the expression of GCs in oxidative stress and proliferation-related features at the clinical level. In addition, we used lentiviral vectors, cell transfection combined with in vivo microinjection to explore the role of KAT2A in POF and its regulatory pathways at the cellular and animal levels.Key findings: We first found KAT2A mediates reactive oxygen species (ROS)-induced cellular apoptosis in human granulosa cells (hGCs), and the level of KAT2A was significantly increased in human GCs, as well as in the physiologically and pathologically aged mice. RNA-sequencing and bioinformatics analysis showed that KAT2A levels affect apoptosis and hormone synthesis and secretion of mouse GCs, and also hindered the cell cycle of GCs in mice. Targeting KAT2A overexpression significantly promote GCs apoptosis, while mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) reduction in mouse GCs. Moreover, KAT2A overexpression through a microinjection of lentivirus induced cellular apoptosis, and follicular atresia in the ovaries of mice and decreased mouse fertility in vivo.Significance: Our study highlights the triggers for POF, where the augment of KAT2A, which is regulated by ROS, finally contributes to follicular atresia-associated POF via triggering granulosa cell apoptosis and inducing granulosa cell cycle arrest. Shedding light on KAT2A may represent a novel adjuvant therapy strategy for POF.