Annexin A1 at the Interface of Immunometabolism and Vaginal Tissue Homeostasis in Menopause

Menopause is associated with hormonal, metabolic, and inflammatory changes that contribute to mucosal atrophy and impaired tissue homeostasis, particularly in the vagina. Despite its clinical relevance, the immunometabolic mechanisms underlying menopausal vaginal dysfunction remain poorly understood. Annexin A1 (AnxA1) is an endogenous anti-inflammatory mediator involved in immune regulation and metabolic homeostasis, but its role in menopausal vaginal alterations remains unexplored. We investigated the effects of menopause on vaginal structure, inflammation, and metabolism, and evaluated the contribution of endogenous AnxA1 using wild-type and AnxA1-deficient (AnxA1-/-) mice subjected to 4-vinylcyclohexene diepoxide (VCD)–induced menopause. Vaginal morphology, collagen remodeling, oxidative stress, systemic leukocyte profiles, inflammasome signaling, cytokine production, and untargeted metabolomic profiles of plasma and vaginal tissue were analyzed. VCD-induced menopause promoted vaginal epithelial atrophy, lamina propria thinning, and collagen remodeling, effects that were exacerbated in AnxA1-/- mice. Menopause also increased vaginal reactive oxygen species and altered systemic leukocyte profiles. At the molecular level, menopause enhanced NLRP3 inflammasome signaling and disrupted local cytokine balance, particularly in the absence of AnxA1. Metabolomic analyses revealed pronounced systemic and local metabolic remodeling, with genotype-dependent alterations involving amino acid, lipid, redox, nitrogen, and steroid hormone metabolism. Pathway enrichment analyses identified distinct immunometabolic adaptations in plasma and vaginal tissue, with AnxA1 deficiency amplifying disturbances in nitrogen metabolism, redox homeostasis, and lipid-derived inflammatory pathways. Together, these findings demonstrate that menopause drives immunometabolic remodeling of vaginal tissue and identify AnxA1 as a key endogenous regulator of vaginal homeostasis during the menopausal transition, highlighting AnxA1-related pathways as potential non-hormonal therapeutic targets.