Pyroptosis in premature ovarian insufficiency: pathogenic mechanisms, pathway crosstalk, and therapeutic strategies

Premature ovarian insufficiency (POI) is a condition characterized by loss of ovarian function in women under 40 years of age, leading to premature depletion of the follicle pool and reduced fertility. While apoptosis was long considered the main mechanism of granulosa cell death and follicle atresia, it does not fully explain the inflammatory environment and tissue fibrosis observed in POI. Pyroptosis, an inflammatory form of programmed cell death mediated by the gasdermin family, has emerged as a critical driver of ovarian damage. Key mechanisms include the NLRP3/caspase-1/GSDMD axis and the apoptosis-to-pyroptosis switch mediated by caspase-3/GSDME. Pyroptosis interacts with other forms of cell death including apoptosis, ferroptosis, and autophagy, amplifying inflammation in ovarian tissue. Emerging therapeutic approaches include mitochondrial reactive oxygen species scavengers, NLRP3/caspase-1 inhibitors, and therapies based on exosomes derived from mesenchymal stem cells.