目的 通过网络药理学及分子对接技术探究三叶青调控糖尿病视网膜病变的关键靶点及机制。方法 通过中药系统药理学数据库与分析平台（TCMSP）获取三叶青相关作用靶点，使用GEO数据库搜索糖尿病视网膜病变相关靶点，利用FerrDb V2等数据库获取铁死亡相关靶点，汇总上述3个数据库所得靶点后，利用Venny在线平台筛选交集靶点。随后利用STRING平台构建蛋白相互作用（PPI）网络，并利用微生信平台进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。将Cytoscape排名前10的靶点和PPI软件分析所得度值排名前10的靶点取交集，并利用PyMOL及AutoDockTools软件将交集靶点与活性成分进行分子对接。结果 共筛选出562个三叶青相关作用靶点、6 007个糖尿病视网膜病变相关靶点以及471个铁死亡相关靶点，三者取交集共得到18个关键靶点。筛选前列腺素内过氧化物合成酶2（PTGS2）、肿瘤蛋白53（TP53）、还原型辅酶Ⅱ氧化酶4（NOX4）、蛋白激酶Cα（PRKCA）、缺氧诱导因子1α（HIF1A）、血红素加氧酶1（HMOX1）6个核心靶点，GO功能富集分析显示生物过程（BP）主要包括对细胞增殖负调控、血管生成、氧化应激，细胞组分（CC）主要包括胞质、核浆、细胞膜；分子功能（MF）主要包括相同蛋白结合、酶结合、锌离子结合等。KEGG结果显示潜在通路有化学致癌–活性氧、癌症通路、流体剪切与动脉粥样硬化等。分子对接结果显示三叶青中大黄素-1-O-β-D-葡萄糖苷与PTGS2的结合能力最强。结论 三叶青可能通过PTGS2、TP53、NOX4、PRKCA、HIF1A、HMOX1等靶点调节铁死亡从而发挥缓解糖尿病视网膜病变的作用。

Objective To explore the key targets and mechanisms of Tetrastigma hemsleyanum in regulating diabetic retinopathy based on network pharmacology and molecular docking. Methods The related targets of T. hemsleyanum were obtained from the TCMSP. Related disease targets of diabetic retinopathy were searched in GEO database, and ferroptosis-related targets were acquired from databases such as FerrDbV2. After summarizing the targets from the three databases mentioned above, the Venny online platform was used to screen the intersection targets. Subsequently, the PPI network was constructed using the STRING platform, and the GO and KEGG enrichment analysis were performed using the micro-bioinformatics platform. The top 10 targets of Cytoscape and the top 10 targets of PPI software were intersected, and the intersection targets were docked with the active ingredients by PyMOL and AutoDockTools software. Results A total of 562 targets of T. hemsleyanum, 6 007 targets related to diabetic retinopathy and 471 targets related to ferroptosis were screened out. A total of 18 key targets were obtained by intersection of the three targets. Six core targets of PTGS2, TP53, NOX4, PRKCA, HIF1A, and HMOX1 were screened. GO functional enrichment analysis showed that BP mainly included negative regulation of cell proliferation, angiogenesis, and oxidative stress, and CC mainly included cytoplasm, nucleoplasm and cell membrane. MF were mainly involved in identical protein binding, enzyme binding, and zinc ion binding. KEGG results showed that potential pathways included chemical carcinogenesis-reactive oxygen species, pathways in cancer, and fluid shear stress and atherosclerosis. The results of molecular docking showed that emodin-1-O-β-D-glucoside in T. hemsleyanum had the strongest binding ability with PTGS2. Conclusion Tetrastigma hemsleyanum may alleviate proliferative diabetic retinopathy by regulating ferroptosis through targets such as PTGS2, TP53, NOX4, PRKCA, HIF1A, and HMOX1.

R286.7

国家自然科学基金资助项目（82304808）；浙江省中医药科技计划项目（2026ZL0025）；浙江省医药卫生科技计划项目（2024KY877）；衢州市科技计划项目（2023K092）；浙江省中医药重点学科-药用植物学（2024-XK-06）