Sun Xia, Zhang Jingyi, Li Xiaoxia, Li Yansheng, Zhao Xinmei, Sun Xiaowei, Li Yuanbin
The Second Clinical Medical College of Binzhou Medical University, Yantai, 264000, Shandong Province, China; Department of Ophthalmology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong Province, China.
Department of Ophthalmology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong Province, China.
Free Radic Biol Med. 2025 Aug 1;235:364-378. doi: 10.1016/j.freeradbiomed.2025.05.383. Epub 2025 May 15.
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.
环磷酸鸟苷-腺苷酸合成酶（cGAS）和干扰素基因刺激因子（STING）信号通路是炎症的关键调节因子。本研究旨在探讨cGAS-STING信号通路在糖尿病性干眼（DDE）疾病中的作用，并进一步探索非诺贝特在DDE中的治疗效果及潜在机制。利用来自基因表达综合数据库（GEO）的单细胞RNA测序（scRNA-Seq）数据，结合链脲佐菌素诱导的DDE小鼠模型以及永生化人角膜上皮细胞（HCE-T）中的高糖条件，我们观察到糖尿病角膜中的线粒体损伤以及细胞质线粒体DNA（mtDNA）显著升高，并确定cGAS-STING信号通路在DDE的发病机制中起关键作用。值得注意的是，我们发现抑制剂H151通过cGAS-STING途径逆转了眼表炎症反应。进一步研究表明，非诺贝特通过减少活性氧（ROS）的产生、恢复线粒体膜电位（MMP）、减少mtDNA细胞质泄漏，进而抑制cGAS-STING信号通路的激活，从而减轻角膜炎症反应。总之，本研究突出了cGAS-STING信号通路在DDE中的关键作用，并提出非诺贝特通过减轻线粒体损伤来抑制该通路，为DDE的治疗提供了新策略。
