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

Yirong Ding, Yue Chen, Yu Pan, Ruiqi Fu, Wenjie Wang, Xiwen Wang, Yu Liu, Suya Bao, Ying Chen, Hengwei Liu
American journal of physiology. Endocrinology and metabolism · 2026 · doi:10.1152/ajpendo.00462.2025 · PMID:41979667
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This review synthesizes current knowledge on Annexin A2 signaling in female reproductive diseases, highlighting its mechanisms, diagnostic potential, and therapeutic implications.

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This review synthesizes evidence on Annexin A2 (ANXA2) signaling in disorders of the female reproductive system, describing its calcium-dependent roles in processes such as endocytosis, cytoskeletal dynamics, angiogenesis, and extracellular matrix remodeling, as well as its links to phosphorylation, S100A10 interactions, and fibrinolytic activity. It reports that aberrant ANXA2 expression has been implicated across conditions including gynecological cancers, endometriosis, adenomyosis, infertility, and pregnancy-related complications, where it is associated with epithelial–mesenchymal transition, trophoblast invasion, vascular integrity, and immune homeostasis. The paper highlights findings that elevated ANXA2 correlates with tumor aggressiveness, recurrence risk, chemoresistance, and poor prognosis, and notes that circulating and exosome-derived ANXA2 may serve as minimally invasive biomarkers for benign disorders. It also states that key molecular mechanisms and context-specific functions remain incompletely understood, with major gaps in clinical translation. This paper is centrally about endometriosis and adenomyosis— it reviews ANXA2 signaling as implicated in both conditions alongside other female reproductive diseases.

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Abstract

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, trophoblast invasion, vascular integrity, and immune homeostasis. Elevated ANXA2 levels have been correlated with tumor aggressiveness, recurrence risk, chemoresistance, and poor prognosis, while 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.
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Abstract

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, trophoblast invasion, vascular integrity, and immune homeostasis. Elevated ANXA2 levels have been correlated with tumor aggressiveness, recurrence risk, chemoresistance, and poor prognosis, while 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. Formats available You can view the full content in the following formats: Information & Authors Information Published In American Journal of Physiology-Endocrinology and Metabolism Articles in Press Copyright Copyright © 2026 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society. History Received: 21 October 2025 Revised: 13 November 2025 Accepted: 23 February 2026 Published online: 14 April 2026

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endometriosisadenomyosisinfertility

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