Hyperandrogenism triggers mtDNA release to participate in ovarian inflammation via mPTP/cGAS/STING in PCOS

Hyperandrogenism induced ovarian inflammation is associated with the pathogenesis of polycystic ovary syndrome (PCOS), but the specific mechanism behind it remains unclear. The aim of this study was to elucidate the association between mitochondrial DNA-cGAS-STING pathway and PCOS inflammatory response. RNA sequencing analysis and other experiments showed that inflammatory pathways were activated, mitochondria were damaged, and mtDNA-cGAS-STING pathways were activated in PCOS women. <i>In vitro</i>, after stimulation of KGN cells with testosterone, the expression of pro-inflammatory factors was enhanced and the cGAS-STING pathway was activated. Stimulator of the interferon genes (STING) knockout can reduce testosterone-induced inflammatory response and improve follicular function. Cyclosporin A therapy reduces cytoplasmic mtDNA, blocks cGAS-STING pathway activation, alleviates inflammatory markers, and reverses abnormal follicular function. <i>In vivo</i> experiments have shown that inhibiting STING can reduce ovarian dysfunction and inflammation in PCOS patients. Hyperandrogenism in PCOS can trigger mitochondrial permeability transition pore (mPTP) overopening, leading to mtDNA release and cGAS-STING pathway activation, causing inflammation and follicle damage.