Annexin A3 mediates senescence-associated inflammation and collagen metabolism disorder in pelvic organ prolapse

Pelvic organ prolapse (POP) is a prevalent condition whose pathogenesis mainly involves extracellular matrix dysregulation and inflammation responses. However, the key molecular mediators linking these processes remain incompletely understood. Our study aimed to investigate the role of Annexin A3 (ANXA3) in POP. We generated a single-cell transcriptomic atlas of the human anterior vaginal wall utilizing public datasets, and identified ANXA3 as a candidate gene mediating inflammation and collagen metabolism disorder in POP. Its response to inflammatory stimulation was examined in primary human vaginal wall fibroblasts (hVWFs). Subsequently, the functional roles of ANXA3 in collagen metabolism, oxidative stress, proliferation, senescence, and inflammation were evaluated via overexpression and knockdown strategies. Statistical significance was assessed using appropriate tests. Single-cell analysis revealed a remodeled microenvironment in POP, characterized by expanded fibroblast populations and enhanced inflammatory signals, leading us to focus on ANXA3 as a potential mediator. Immunohistochemical staining (n = 9 per group) and Western blot analysis (n = 5 per group) demonstrated the upregulation of ANXA3 in the anterior vaginal wall tissues of POP patients. In vitro, treatment with pro-inflammatory cytokine directly induced ANXA3 expression in hVWFs. Functionally, overexpression of ANXA3 in hVWFs from patients without POP disrupted collagen metabolism by tilting the balance between matrix metalloproteinases and tissue inhibitors of metalloproteinases toward degradation ( P < 0.05), induced oxidative stress, suppressed proliferation, and promoted cellular senescence with pro-inflammatory senescence-associated secretory phenotype ( P < 0.05). Conversely, ANXA3 knockdown in hVWFs from patients with POP attenuated these pathological alterations. ANXA3 may link inflammation to collagen dysregulation in POP, suggesting its potential as a novel candidate biomarker or a promising therapeutic target requiring further validation.