Progesterone prevents HGSOC by promoting precancerous cell pyroptosis via inducing fibroblast paracrine.

High-grade serous ovarian carcinoma (HGSOC) is one of the most fatal gynecological cancers and has no effective prevention strategies. Herein, we demonstrated that progesterone significantly inhibited the occurrence, metastasis, and ascites of ovarian cancer in vivo, and the tumor inhibition effect of progesterone was in the tubo-ovarian intrabursal model than in the intraperitoneal or subcutaneous models. Further data demonstrated that progesterone-treated fallopian tube fibroblasts conditioned medium significantly inhibit HGSOC precancerous cell viability by inducing pyroptosis via the IL-6/ROS/NLRP3/GSDMD pathway, implying that the oviduct microenvironment may enhance progesterone's protective effects on ovarian cancer. This study elucidated progesterone inhibiting ovarian cancer mechanism and provided evidence for progesterone as a chemo-preventive role for HGSOC.