山东大学学报 (医学版) ›› 2026, Vol. 64 ›› Issue (7): 11-27.doi: 10.6040/j.issn.1671-7554.0.2025.1148
尹丹丹1,彦名南2,韩净净3,张伟4,崔学雷5,刘亚平6,石书龙6,季宗文6
YIN Dandan1, YAN Mingnan2, HAN Jingjing3, ZHANG Wei4, CUI Xuelei5, LIU Yaping6, SHI Shulong6, JI Zongwen6
摘要： 目的 基于网络药理学、分子对接技术及体外细胞实验探究大黄素治疗糖尿病肾病的作用机制。 方法 利用公共数据库获取大黄素和糖尿病肾病的交集靶点,建立蛋白-蛋白互作网络,对所得靶点进行基因本体(gene ontology, GO)、京都基因和基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)功能富集分析,对大黄素与核心治疗靶点进行分子对接及分子动力学模拟。将小鼠肾足细胞(mouse podocyte clone-5, MPC-5)分为对照组、高糖组和大黄素干预组,大黄素干预组分别给予5、10、20、40 μmol/L的大黄素干预24 h,检测细胞活力、铁离子、相关基因表达水平。进行非靶向代谢组学分析,筛选差异代谢物。 结果 获得80个大黄素治疗糖尿病肾病的潜在作用靶点,其中核因子E2相关因子2(nuclear factor erythroid 2-related factor 2, NRF2)是关键治疗靶点。GO分析获得190条生物过程、80条细胞组成、100条分子功能。KEGG富集分析得到铁死亡、脂质与动脉粥样硬化、白细胞介素-17(interleukin-17, IL-17)等信号通路。大黄素与NRF2之间存在强而稳定的相互作用,结合构象稳定。大黄素可显著改善高糖诱导的细胞损伤;10 μmol/L大黄素干预后,细胞内铁离子水平、肿瘤坏死因子(tumor necrosis factor, TNF)、IL-17的表达降低,铁死亡核心标志物谷胱甘肽过氧化物酶4(glutathione peroxidase 4, GPX4)、NRF2及其下游相关基因的mRNA表达升高(P<0.001)。代谢组学分析显示,大黄素干预后共鉴定出29种差异代谢物,其中10种上调、19种下调。 结论 大黄素通过关键靶点NRF2协同调控铁死亡、IL-17等多条信号通路,发挥抗铁死亡、抗炎及代谢调节作用,从而实现对糖尿病肾病的肾脏保护作用。
中图分类号:
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