Fenofibrate inhibits activation of cGAS-STING pathway by alleviating mitochondrial damage to attenuate inflammatory response in diabetic dry eye.

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 (DDE) disease and further explore the therapeutic efficacy and underlying mechanism of fenofibrate in DDE. Using single-cell RNA sequencing (scRNA-Seq) 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 damage and significantly elevated cytoplasmic mitochondrial DNA (mtDNA) 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 inflammatory response by reducing the production of reactive oxygen species (ROS), restoring mitochondrial membrane potential (MMP), decreasing mtDNA cytoplasmic leakage, and subsequently 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.