Neutrophil extracellular traps in gynecological disease: pathogenic mechanisms and therapeutic opportunities

Gynecologic disorders, including infections, sterile inflammatory diseases, endocrine abnormalities, and malignancies, share a common signature of dysregulated immunity within a uniquely hormone-responsive reproductive tract. Neutrophil extracellular traps (NETs) are increasingly recognized as central effectors at this interface of innate immunity, endocrine signaling, tissue remodeling, and thrombosis. In this review, we first outline the mechanistic basis of NET formation and emphasize how the cyclical anatomy, fluctuating sex hormones, and regional microbiota of the female reproductive tract shape NET induction, localization, and clearance. We then synthesize evidence across disease spectra. In infectious conditions such as pelvic inflammatory disease, genital tuberculosis, and vaginal dysbiosis, NETs confine pathogens but also drive epithelial injury, fibrosis, and infertility. In sterile inflammatory and endocrine-related disorders, including endometriosis, polycystic ovary syndrome, premature ovarian insufficiency, and primary dysmenorrhea, NET-associated oxidative stress, inflammasome activation, and profibrotic signaling link hormonal and metabolic imbalance to chronic pain and organ dysfunction. In gynecologic cancers, NETs promote tumor cell adhesion, invasion, immune escape, and thromboembolic complications within hormone-conditioned microenvironments, while circulating and tissue NET markers, as well as NET-related gene and lncRNA signatures, hold diagnostic and prognostic value. Finally, we discuss how biomaterial-based strategies in vaginal reconstruction exploit antimicrobial NET functions yet risk excessive fibrosis if NETs are not tightly controlled. Across these contexts, we highlight an emerging NET-sex hormone axis and propose endocrine-aware, biomarker-guided strategies that combine NET-targeting agents with hormonal and microbiome-based interventions to achieve more precise diagnosis, risk stratification, and therapy for gynecologic diseases.