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

Abstract

Premature ovarian insufficiency (POI) is characterised by pathological loss of ovarian function in women younger than 40 years, resulting in premature exhaustion of the ovarian follicle pool and impaired fertility. Although apoptosis has long been considered the dominant mechanism driving granulosa cell (GC) death and follicular atresia, it does not fully explain the severe inflammatory microenvironment and tissue fibrosis observed during POI progression. Recently, pyroptosis, a proinflammatory form of programmed cell death mediated by the gasdermin family, has emerged as a critical driver of ovarian injury. This review comprehensively summarises the core mechanisms of pyroptosis across different POI aetiologies, with particular emphasis on the role of the NLRP3/caspase-1/GSDMD axis, the caspase-3/GSDME-mediated apoptosis-to-pyroptosis switch, and their multi-layered regulation by post-translational modifications, including S-palmitoylation, ubiquitination, and phosphorylation. We further discuss the complex molecular crosstalk between pyroptosis and other programmed cell death pathways, including apoptosis, ferroptosis, and autophagy, highlighting their synergistic roles in amplifying intraovarian inflammation. Finally, we evaluate emerging therapeutic strategies targeting pyroptosis, including mitochondrial reactive oxygen species scavengers, specific NLRP3/caspase-1 inhibitors, modulators of GSDMD post-translational modifications, and mesenchymal stem cell–derived exosome therapies. Collectively, these findings provide novel insights into POI pathogenesis and support the development of precise, non-hormonal therapeutic interventions to rescue the ovarian reserve and protect female reproductive health.