FGF10 Protects the Corneal Epithelium From Dry Eye-Induced Oxidative and ER Stress Via Upregulation of SLC7A11.

PURPOSE: To investigate the protective effect of fibroblast growth factor 10 (FGF10) on the corneal epithelium in dry eye disease (DED) and reveal the underlying mechanism.

METHODS

DED mouse model was induced via scopolamine injections and low-humidity airflow to evaluate the therapeutic effects of FGF10. Mice received topical FGF10 (5, 25, or 125 µg/mL) or vehicle for seven days. Corneal fluorescein staining, oxidative stress (ROS levels), endoplasmic reticulum (ER) stress, and apoptosis were evaluated. To investigate protective mechanisms on corneal epithelium cells, hyperosmolar-stressed HCE-2 cells were treated with 100 ng/mL FGF10, and RNA sequencing was performed. Transcriptomic analysis identified SLC7A11, a key regulator of cellular antioxidant defense, as significantly upregulated by FGF10. SLC7A11's functional importance was validated through siRNA-mediated silencing in HCE-2 cells and AAV-mediated overexpression in mouse model.

RESULTS

FGF10 treatment significantly improved corneal epithelial integrity in dry eye mice, reducing fluorescein staining, ROS level, and ER stress markers, while increasing Bcl-2 and decreasing BAX. RNA sequencing revealed that FGF10 stimulated antioxidant signaling pathways and upregulated SLC7A11 expression. FGF10 also increased SLC7A11 protein levels in HCE-2 cells and dry eye corneas. Silencing of SLC7A11 in vitro prevented FGF10-induced reductions in ROS, ER stress, and apoptosis. Furthermore, AAV-mediated overexpression of SLC7A11 in dry eye mice recapitulated the protective effects observed with FGF10 treatment.

CONCLUSIONS

FGF10 protects mouse corneal epithelium and HCE-2 cells from oxidative stress, ER stress, and apoptosis, partially through SLC7A11 upregulation. The FGF10-SLC7A11 pathway represents a promising therapeutic target in dry eye.