Free Radic Biol Med. 2025 May 6:S0891-5849(25)00658-6. doi: 10.1016/j.freeradbiomed.2025.05.383. Online ahead of print.
ABSTRACT
The cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING) signaling pathway are critical regulators of inflammation. This study aims to investigate the role of the cGAS-STING signaling pathway in diabetic dry eye disease (DDE) and further explore the therapeutic efficacy and underlying mechanism of fenofibric acid in DDE. Using single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database, combined with the STZ-induced DDE mouse model and high-glucose conditions in immortalized human corneal epithelial cells (HCE-T), we observed mitochondrial dysfunction in the diabetic cornea, and identified that the cGAS-STING signaling pathway plays a pivotal role in the pathogenesis of DDE. Notably, we found that the inhibitor H151 reversed the ocular surface inflammatory response via the cGAS-STING pathway. Further investigation revealed that fenofibrate alleviated corneal inflammation in diabetic mice by inhibiting reactive oxygen species (ROS) production, restoring mitochondrial membrane potential, and suppressing the activation of the cGAS-STING signaling pathway. In conclusion, this study highlights the crucial role of the cGAS-STING signaling pathway in DDE and proposes that fenofibrate alleviates mitochondrial damage to inhibit this pathway, offering novel strategy for the treatment of DDE.
PMID:40339725 | DOI:10.1016/j.freeradbiomed.2025.05.383