Neutrophils and NETosis in polycystic ovary syndrome: unraveling the immuno-metabolic thromboinflammatory axis

Polycystic ovary syndrome (PCOS), traditionally defined by its endocrine and reproductive hallmarks-hyperandrogenism, oligo-anovulation, and polycystic ovarian morphology-is increasingly viewed as a complex disorder associated with chronic low-grade immuno-metabolic inflammation. Emerging evidence suggests that neutrophils, the most abundant innate immune cells, may play a contributory role in linking metabolic stress, inflammatory signaling, and vascular dysfunction in PCOS. In women with PCOS, hyperandrogenism, insulin resistance, and adipose-derived inflammatory cues have been associated with altered neutrophil activation profiles, including increased oxidative stress, degranulation, and markers suggestive of neutrophil extracellular trap (NET) formation. While direct evidence for NET-driven pathology in PCOS remains limited, mechanistic insights from related inflammatory and metabolic diseases indicate that NET-associated pathways can amplify thrombo-inflammatory signaling, endothelial dysfunction, and tissue injury. This review synthesizes available PCOS-specific data on neutrophil activation alongside mechanistic frameworks inferred from other disease contexts, emphasizing cytokine- and adipokine-mediated priming, neutrophil heterogeneity, and potential NET-associated effects on reproductive, metabolic, and cardiovascular outcomes. We also highlight critical knowledge gaps, including the need for longitudinal studies, standardized NET biomarker assessment, and single-cell immune profiling to define neutrophil subsets and functional states in PCOS. Finally, we discuss translational perspectives, proposing neutrophil- and NET-focused strategies as potential adjuncts to existing hormone-centric management, rather than established therapeutic targets. By reframing PCOS through an immuno-metabolic lens centered on innate immune dysregulation, this review provides a cautious yet integrative conceptual framework to guide future mechanistic and clinical investigations.