Activation of cGAS/STING Drives Inflammation and Cellular Senescence of Macrophages in Ovarian Endometrioma Induced by Endometriotic Cyst Fluid

Abstract Ovarian endometrioma (OE) is a common gynecological condition characterized by the formation of “chocolate cysts”. Recent research indicates that the cyst fluid acts as a “toxic environment” for the ovary and plays a significant role in the development of OE, with macrophages being pivotal. However, the specific molecular and cellular mechanisms of it are not fully understood. In this study, clinical samples are integrated, single‐cell sequencing, in vivo and in vitro experimental models to comprehensively investigate the effects of OE fluid on ovarian function and the mechanisms of it. Combined with bioinformatics analysis and experimental validation, the findings demonstrate that OE fluid can cause ovarian function decline, which associated with inflammatory response, and mitochondrial dysfunction and cellular senescence, while activating the cGAS/STING signaling pathway. As a STING inhibitor, H‐151 effectively alleviates ovarian dysfunction, inflammatory state and cell apoptosis induced by OE fluid. Furthermore, it is also discovered that H‐151 can inhibit OE fluid‐induced mitochondrial dysfunction and cellular senescence. These findings provide important theoretical and experimental foundations for further research and development of STING inhibitors as potential drugs for treating ovarian dysfunction.