Sestrin2 protects ovarian granulosa cells by regulating oxidative stress and p53-mediated apoptosis.

Reactive Oxygen Species (ROS) accumulation disrupts cellular homeostasis, leading to lipid peroxidation, mitochondrial dysfunction, DNA damage, and apoptosis. Sestrin2 (Sesn2) is a critical antioxidant protein that regulates intracellular oxidative stress and protects cells from oxidative damage and apoptosis. However, the role of Sesn2 in ovarian reproductive function remains unclear. In this study, we examined Sesn2 expression in response to oxidative stress using granulosa-like KGN cells derived from human ovarian granulosa cell tumors, mouse granulosa cells, and an oxidative stress mouse model. Additionally, we investigated the protective Sesn2 functions and its mechanisms of action in promoting granulosa cell survival. The results showed that Sesn2 expression markedly increased in granulosa cells exposed to hydrogen peroxide (H2O2) and in oxidative stress models induced by 3-nitropropionic acid (3-NP). Oxidative stress in ovarian granulosa cells increases ROS levels, decreases cell viability, and triggers apoptosis. Sesn2 silencing further aggravates granulosa cell damage, whereas targeting Sesn2 under oxidative stress conditions reduces ROS levels and modulates apoptosis through the p53/Caspase-3 signaling pathway. These findings highlight the pivotal role of Sesn2 in protecting cells against ROS-induced damage, preserving follicular health, and supporting ovarian function and reproductive capacity.