Hyperandrogenism-mediated YAP activation drives ovarian inflammation and pyroptosis in PCOS: implications for follicular dysfunction
Tianyue Xu, Xiang Yu, Zichao Huang, Qi Zhu, Hong‐Hui Wu, Jieyu Cai, Linglin Weng, Hongshan Ge
Abstract
BACKGROUND: Hyperandrogenism and persistent chronic inflammation significantly contribute to ovarian dysfunction in polycystic ovary syndrome (PCOS). Although the exact connection between hyperandrogenism and inflammation in PCOS remains unclear, the Hippo pathway, also seems to be involved in the inflammatory response through YAP. METHOD: An in-vivo PCOS model of mice was constructed with dehydroepiandrosterone (DHEA) and YAP inhibitor Verteporfin (VP). YAP, inflammation and pyroptosis levels of ovarian tissues were detected in mice models. An in-vitro PCOS model of KGN cells was constructed with testosterone, and YAP was knocked down by lentivirus. RESULTS: Increased levels of YAP in the ovarian tissues of the DHEA-treated mice were observed, alongside elevations in inflammation and pyroptosis levels, whereas Verteporfin reversed these alterations. The findings in KGN cells demonstrated that testosterone treatment results in elevation of YAP, inflammation and pyroptosis levels in granulosa cells. However, knocking down YAP in KGN cells curtailed testosterone-induced inflammation and pyroptosis. CONCLUSIONS: Hyperandrogenism in PCOS promotes ovarian inflammation by upregulating nuclear YAP, disrupting the inflammatory microenvironment, leading to abnormal ovarian pyroptosis, and ultimately impairing follicular function.