GPX3 improves endometrial receptivity by inhibiting ferroptosis via Nrf2/GPX4 pathway in sows

Obesity is a vital inducement of reproductive disorders during early pregnancy in mammal. However, the effect and molecular mechanism of attenuating endometrial receptivity under obesity remain largely unknown. Here, we identified that glutathione peroxidase 3 (GPX3) as a potential target for improving endometrial receptivity by integrating analysis of metabolomics and transcriptomics of uterine tissues in obese and normal sows. We demonstrate that GPX3 is significantly downregulated in the uterine tissues of obese sows, with a significant correlation to decreased endometrial receptivity. Functionally, the knockdown of GPX3 induces mitochondrial dysfunction, leading to lipid peroxidation metabolism imbalance and activation of ferroptosis, ultimately reducing endometrial receptivity in palmitic acid (PA) induced porcine endometrial epithelial cells (PEECs). Conversely, GPX3 overexpression can effectively restore endometrial mitochondrial function and reverse the ferroptosis process. Mechanistically, the reduction of GPX3 activates the endometrial ferroptosis process by inhibiting Nrf2/GPX4 axis, ultimately leading to a decrease in endometrial receptivity. Moreover, we found that the endometrial receptivity of HFD female mice decreased and GPX3/Nrf2/GPX4 signaling inhibited with mitochondrial ultrastructural damage. Overall, this study innovatively establishes GPX3 as a pivotal regulator of endometrial receptivity through Nrf2/GPX4 signaling pathway, providing novel insights for obesity-related reproductive disorders.