NLRP3 inflammasome activation in PCOS: A novel target for managing insulin resistance and metabolic dysregulation

In this comprehensive narrative review, we systematically examine the role of the NLRP3 inflammasome in the pathogenesis of polycystic ovary syndrome (PCOS) and evaluate its potential as a therapeutic target for managing insulin resistance. We performed literature searches in PubMed, Scopus, and Web of Science up to April 2025, using keywords including "PCOS," "NLRP3 inflammasome," "insulin resistance," and "reproductive dysfunction." Only peer-reviewed studies directly addressing inflammasome activation in PCOS were included, while articles lacking mechanistic or clinical relevance were excluded. PCOS is a highly prevalent and complex endocrine-metabolic disorder characterized by chronic low-grade inflammation, insulin resistance, and reproductive dysfunction, affecting millions of women globally. Despite its widespread impact, current treatments mainly address symptoms rather than underlying disease mechanisms, highlighting the urgent need for novel, targeted therapeutic approaches. Emerging evidence implicates the NLRP3 inflammasome as a central mediator linking immune activation, metabolic dysregulation, and ovarian pathology in PCOS. Activation of NLRP3 triggers release of IL-1β and IL-18, which impair insulin signaling, disrupt glucose homeostasis, and sustain systemic inflammation. Beyond metabolic effects, NLRP3-driven inflammation contributes to anovulation, follicular atresia, and hormonal imbalance. Interactions with mitochondrial dysfunction and endoplasmic reticulum stress further amplify cellular stress responses, accelerating disease progression. This review synthesizes current mechanistic insights into how NLRP3 activation drives both metabolic and reproductive impairments in PCOS, and highlights emerging therapeutic strategies-including pharmacological inhibitors, anti-inflammatory agents, and precision medicine approaches-aimed at disrupting the inflammatory-insulin resistance cycle. By elucidating these immunometabolic mechanisms, our findings support a shift from symptom-based management toward targeted, disease-modifying interventions, advancing precision medicine in women's health.