Single-Cell Transcriptomic Analysis Reveals Copper Metabolism Heterogeneity and Phenotypic Remodeling in Vaginal Anterior Wall Stromal Cells in Pelvic Organ Prolapse

Pelvic organ prolapse (POP) is a common disease characterized by disordered extracellular matrix (ECM) remodeling of pelvic support tissues. Copper dysregulation drives fibrosis in multiple diseases, whereas its function in POP remains unclear. We analyzed single-cell transcriptomes of 90,578 cells from 21 vaginal wall samples (5 controls, 16 POP). ECM remodeling was the most robustly upregulated module in POP fibroblasts, accompanied by decreased copper metabolism and senescence scores. Fibroblasts resolved into nine subpopulations, with copper metabolism activity decreased in eight, most prominently in p53/senescence-like states. High-copper fibroblasts were enriched for TNFα/NF-κB, inflammatory, hypoxic, and EMT programs. Copper metabolism correlated with senescence (rho = 0.56, p = 0.010) but not ECM remodeling (rho = −0.02, p = 0.92). Smooth muscle cells shifted toward a synthetic phenotype, negatively correlating with copper metabolism. CellChat and trajectory inference revealed ECM ligand-driven interactions and temporal copper–ECM gene dynamics. Elesclomol reduced fibroblast viability and induced apoptosis and senescence in a copper-dependent manner. These findings suggest that copper metabolism dysregulation contributes to POP stromal remodeling and may serve as a potential therapeutic target.