Pyroptosis in endometritis: Molecular mechanisms, pathogenic roles, and therapeutic opportunities

Endometritis is a common inflammatory disorder of the female reproductive tract caused by microbial infection or immune dysregulation that impairs endometrial function and reproductive outcomes. Growing evidence indicates that programmed cell death (PCD), particularly pyroptosis, plays a pivotal role in the pathophysiology of endometritis. Pyroptosis links cell death to inflammatory signaling through inflammasome activation and gasdermin (GSDM)-mediated membrane perforation. The canonical NLRP3-caspase-1-GSDMD axis, the noncanonical caspase-4/5/11-GSDMD pathway, and caspase-3-GSDME-dependent pyroptosis-like death all have been implicated in amplifying endometrial inflammation. Experimental and clinical studies demonstrate the upregulation of NLRP3, caspase-1, and GSDMD in affected endometrial tissues, supporting their pathological relevance. Upstream mechanisms, including the high-mobility group box 1 (HMGB1)-TLR4 axis, PI3K-AKT signaling, and microRNA (miRNA)-mediated modulation, further regulate the pyroptotic response. These insights highlight therapeutic opportunities, including pharmacological inhibitors, miRNA-based interventions, and antioxidant strategies. Nevertheless, most evidence derives from preclinical studies, and translational validation in patients remains limited. This review presents an integrated molecular framework and candidate therapeutic targets to support diagnostic stratification and precision interventions that optimize reproductive outcomes.