Abstract：
Diabetic retinopathy (DR), a common complication of diabetes, is characterized by inflammation and neovascularization, and is intricately regulated by the ubiquitin-proteasome system (UPS). Despite advancements, identifying ubiquitin-related genes and drugs specifically targeting DR remains a significant challenge. In this study, bioinformatics analyses and the Connectivity Map (CMAP) database were utilized to explore the therapeutic potential of genes and drugs for DR. Through these methodologies, flavopiridol was identified as a promising therapeutic candidate. To evaluate flavopiridol\'s therapeutic potential in DR, an in vitro model using Human Umbilical Vein Endothelial Cells (HUVECs) induced by high glucose (HG) conditions was established. Additionally, in vivo models using mice with streptozotocin (STZ)-induced DR and oxygen-induced retinopathy (OIR) were employed. The current study reveals that flavopiridol possesses robust anti-inflammatory and anti-neovascularization properties. To further elucidate the molecular mechanisms of flavopiridol, experimental validation and molecular docking techniques were employed. These efforts identified DDX58 as a predictive target for flavopiridol. Notably, our research demonstrated that flavopiridol modulates the DDX58/NLRP3 signaling pathway, thereby exerting its therapeutic effects in suppressing inflammation and neovascularization in DR. This study unveils groundbreaking therapeutic agents and innovative targets for DR, and establishes a progressive theoretical framework for the application of ubiquitin-related therapies in DR.
摘要：
糖尿病视网膜病变(DR),糖尿病的常见并发症，以炎症和新生血管形成为特征，并且受泛素-蛋白酶体系统（UPS）的复杂调节。尽管取得了进步，鉴定泛素相关基因和特异性靶向DR的药物仍然是一个重大挑战.在这项研究中,生物信息学分析和连接图（CMAP）数据库用于探索基因和药物对DR的治疗潜力。通过这些方法，黄酮吡啶醇被认为是一种有前途的治疗候选药物。为了评估黄酮吡啶醇在DR中的治疗潜力，使用高糖(HG)条件诱导的人脐静脉内皮细胞(HUVECs)建立体外模型。此外,使用具有链脲佐菌素(STZ)诱导的DR和氧诱导的视网膜病变(OIR)的小鼠的体内模型。目前的研究表明，黄酮吡啶醇具有强大的抗炎和抗新血管形成特性。为了进一步阐明黄酮吡啶醇的分子机制，采用实验验证和分子对接技术。这些努力将DDX58确定为黄酮吡啶醇的预测靶标。值得注意的是,我们的研究表明，黄酮吡啶醇调节DDX58/NLRP3信号通路，从而在抑制DR中的炎症和新生血管形成中发挥其治疗作用。这项研究揭示了开创性的治疗药物和DR的创新靶点，并为泛素相关疗法在DR中的应用建立了渐进的理论框架。
