Protective Effects of Estradiol on Disease Progression in a Murine Model of Fuchs Endothelial Corneal Dystrophy.

Purpose: The purpose of this study was to investigate the protective effects of estradiol (E2) on disease progression in Fuchs endothelial corneal dystrophy (FECD) and to explore potential underlying mechanisms. Methods: E2-supplemented drinking water was administered to Col8a2Q455K/Q455K mice, a mouse model of FECD. The corneal endothelial phenotype was evaluated using contact specular microscopy. In vitro studies were performed using immortalized FECD (iFECD) cells derived from patients with and without TCF4 triplet repeat expansion to assess the effects of E2 on extracellular matrix (ECM) production and protein aggregation through immunofluorescence, whereas transforming growth factor-beta (TGF-β) signaling and epithelial-mesenchymal transition (EMT)-related factors were evaluated by Western blot analysis. Results: E2 treatment significantly reduced guttae formation (0.55 ± 0.23% vs. 0.97 ± 0.22%, P < 0.001) and maintained higher endothelial cell density (2263 ± 177 vs. 2058 ± 118 cells/mm², P = 0.004) in FECD mice compared with untreated controls at 20 weeks of age. In vitro studies demonstrated that E2 suppressed TGF-β2-induced upregulation of ECM proteins (fibronectin, biglycan, and collagen I) and reduced protein aggregation in both iFECD cell lines. Mechanistically, E2 inhibited TGF-β signaling by suppressing Smad2/3 phosphorylation and downregulating EMT-related factors (Snail and ZEB1). Conclusions: E2 ameliorates FECD progression by suppressing excessive ECM production. Our in vitro data suggest this protective effect is mediated through the inhibition of the TGF-β-Smad signaling pathway. These findings provide critical in vivo evidence for the therapeutic potential of E2, establishing a strong rationale for its clinical investigation as a novel treatment for FECD.