Taurochenodeoxycholic Acid Activates Calcium Signaling to Protect Against Fuchs' Endothelial Corneal Dystrophy.

Abstract

PURPOSE: Fuchs' endothelial corneal dystrophy (FECD) is the leading cause of corneal endothelial dystrophy. This study aimed to investigate the protective effects and mechanism of taurochenodeoxycholic acid (TCDCA) in FECD. METHODS: TCDCA levels were quantified in aqueous humor from patients with FECD and ultraviolet A (UVA)-induced FECD mice. Corneal endothelial cell (CEC) morphology and function were evaluated by optical coherence tomography (OCT) and ZO-1 staining following TCDCA treatment. In vitro, UVA-induced human corneal endothelial cells (HCECs) were treated with TCDCA, and cell viability, mitochondrial membrane potential, ATP, and reactive oxygen species (ROS) levels were measured. RNA sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) were used to explore molecular mechanisms, and the role of Ca²⁺ signaling was validated using the inhibitor 2-APB in vivo. RESULTS: Analysis of FECD aqueous humor revealed significantly elevated TCDCA levels. In UVA-induced mouse model, TCDCA administration ameliorated corneal endothelial dysfunction, as evidenced by reduced corneal thickness, increased endothelial cell density, and a lower percentage of abnormal cells. Further, in vitro studies revealed a concentration-dependent effect of TCDCA, with 100 µM TCDCA significantly enhancing cell viability, reducing ROS production, restoring mitochondrial membrane potential, and promoting ATP synthesis. RNA-seq and functional studies identified that TCDCA exerts its beneficial effects on corneal endothelial function by activating the calcium signaling pathway. CONCLUSIONS: TCDCA demonstrated a protective effect on corneal endothelial cells during the pathogenesis of FECD. Therefore, TCDCA may be a promising novel therapeutic target for attenuating the progression of FECD.