Novel insights into the role of Annexin A2 signaling pathway in female reproductive system diseases: from mechanisms to advanced therapies.

Annexin A2 (ANXA2) is a calcium-dependent protein with high affinity for phospholipids, and its multifunctional nature has drawn increasing attention in the onset and progression of various disorders of the female reproductive system (FRS). Beyond its canonical roles in endocytosis, cytoskeletal dynamics, angiogenesis, and extracellular matrix (ECM) remodeling, ANXA2 signaling integrates phosphorylation events, interactions with S100A10, and fibrinolytic activity to shape reproductive biology. Emerging evidence demonstrates that aberrant ANXA2 expression is implicated in gynecological cancers, endometriosis, adenomyosis, infertility, and pregnancy-related complications, where it modulates processes such as epithelial-mesenchymal transition (EMT), trophoblast invasion, vascular integrity, and immune homeostasis. Elevated ANXA2 levels have been correlated with tumor aggressiveness, recurrence risk, chemoresistance, and poor prognosis, whereas circulating ANXA2 and exosome-derived ANXA2 show promise as minimally invasive biomarkers for benign reproductive system disorders. Despite these advances, the precise molecular mechanisms and context-specific functions of ANXA2 remain incompletely understood, and significant gaps persist regarding its clinical translation. This review synthesizes current knowledge of ANXA2 signaling in female reproductive diseases, highlights its potential diagnostic and therapeutic value, and identifies key challenges and research priorities. A deeper understanding of ANXA2 biology may not only refine disease stratification and prognosis but also open new avenues for targeted interventions, positioning ANXA2 as a promising node for precision medicine in reproductive health.