目的 通过整合血清代谢组学和网络毒理学，探究大青叶肾毒性成分及机制。方法 采用大鼠连续90 d给药评价大青叶肾毒性作用。通过血清代谢组学寻找差异代谢物及代谢通路；采用网络毒理学分析大青叶潜在肾毒性成分和靶点；整合血清代谢组学和网络毒理学，构建“成分-靶点-代谢物-代谢通路”网络。结果 大青叶具有一定肾毒性。血清代谢组学结果显示67个代谢物水平发生显著变化，涉及5条主要代谢通路；网络毒理学筛选出32个毒性成分，对应靶点422个，相关通路189条。整合分析筛选出左旋樟脑、胭木二酮、正辛醛、(-)-α-蒎烯、靛蓝、十四烷等6个毒性成分，作用于PTGS2、PTGS1、SRC、CYP2A6、CYP1A2、CYP1A1等27个靶点，干扰柠檬酸、花生四烯酸、白三烯C4、吡哆醇4种代谢物，影响丙氨酸、天冬氨酸和谷氨酸代谢，花生四烯酸代谢，氨基酸生物合成，维生素B6代谢4条代谢通路。结论 结合血清代谢组学和网络毒理学初步阐明了大青叶肾毒性成分及机制，为大青叶临床安全合理应用提供了参考。

Objective To explore nephrotoxic components and mechanisms of Isatidis Folium (IF) by integrating serum metabolomics and network toxicology. Methods The nephrotoxic effect of IF was evaluated by continuous administration in rats for 90 d. Search for differential metabolites and metabolic pathways through serum metabolomics. The potential nephrotoxic components and targets of IF were analyzed by network toxicology. Integrate serum metabolomics and network toxicology to construct a "component-target-metabolitemetabolic pathway" network. Results IF has certain nephrotoxicity. The results of serum metabolomics showed significant changes in the levels of 67 metabolites, involving five major metabolic pathways. Network toxicology screened out 32 toxic components, corresponding to 422 targets and 189 related pathways. Integrated analysis screened out six toxic components, including L-camphor, wrightiadione, octanal, (-)-α-pinene, indigo and tetradecane, which could act on 27 targets, including PTGS2, PTGS1, SRC, CYP2A6, CYP1A2, CYP1A1, etc. These targets interfered with the metabolism of citric acid, arachidonic acid, leukotriene C₄, pyridoxine, and affected four key metabolic pathways of alanine, aspartate and glutamate metabolism, arachidonic acid metabolism, biosynthesis of amino acids, and vitamin B6 metabolism. Conclusion Combined with serum metabolomics and network toxicology, the components and mechanisms of nephrotoxicity of IF were elucidated, which provided reference for safe and rational clinical application of IF.

R965.3

国家自然科学基金项目（82260681）；蒙药研发国家地方联合工程研究中心开放基金资助项目（MDK2025004）