目的 基于代谢组学和网络药理学探讨玄参大极性环烯醚萜苷（HPISN）防治阴虚火旺型甲亢的潜在作用机制。方法 雄性SD大鼠随机分为对照组、模型组、HPISN(205 mg·kg^-1)组，每组10只，分别饲养于代谢笼中。除对照组外，采用优甲乐诱导阴虚火旺甲亢模型，90 min后ig给药，每天1次，连续15 d；采用超高效液相色谱-飞行时间质谱（UPLC-TOFMS）技术对大鼠尿液进行代谢组学分析，筛选差异代谢物。基于文献研究筛选得到玄参大极性环烯醚萜苷类活性成分，利用网络药理学、分子对接技术预测玄参大极性环烯醚萜苷防治阴虚火旺甲亢的潜在作用机制。将代谢组学中获得的差异代谢物与网络药理学中获得的“HPISN-甲亢”交集靶点导入Cytoscape 3.9.1软件，并使用Metscape插件构建“化合物-反应-酶-基因”网络，以寻找基因和代谢物之间的重要关联。结果 与对照组相比，模型组中有13个差异代谢物显著下调（P<0.05）,11个差异代谢物显著上调（P<0.05）；与模型组相比，HPISN组大鼠上述指标水平均显著逆转（P<0.05）。网络药理学筛选出HPISN作用于甲亢的8个核心靶点，分别为ALB、INS、TP53、EGFR、CTNNB1、IL10、STAT3、ANXA5；核心活性成分有5个，分别为哈巴苷（harpagide）、二氢梓醇（dihydrocatalpol）、8-O-阿魏酰基哈巴苷（8-O-feruloylharpagide）、球花苦苷（globularin）、6-O-α-L-rhamnopyranosylaucubin;GO功能富集结果显示核心靶点影响的生物过程主要包括RNA聚合酶II启动子转录的正调控、信号转导、基因表达的正向调节等；KEGG富集分析结果表明，HPISN可能调控缺氧诱导因子1（HIF-1）等信号通路。代谢组学联合网络药理学分析发现关键靶点为琥珀酸脱氢酶复合体A亚基（SDHA）、柠檬酸合成酶（CS）。结论 HPISN防治阴虚火旺甲亢的机制可能与作用于SDHA、CS等靶点，干预HIF-1等信号通路，引起差异代谢物变化有关。

Objective Exploring the potential mechanism of action of highly polar iridoids from Scrophularia ningpoensis（HPISN） in preventing and treating hyperthyroidism based on metabolomics and network pharmacology. Methods Male SD rats were randomly divided into the control group, the model group, and the HPISN(205 mg·kg^-1) group, with 10 rats in each group, and were respectively raised in metabolic cages. Except for the control group, the hyperthyroidism model of yin deficiency and hyperactivity of fire was induced by eumetronil. The drug was administered by ig once a day after 90 min for 15 consecutive days. Used UPLC-TOFMS technology to perform metabolomics analysis on rat urine, screening for differential metabolites. Based on literature research, the active ingredients of HPISN were screened, and network pharmacology and molecular docking techniques were used to predict the potential mechanism of action of HPISN for preventing and treating hyperthyroidism. The differential metabolites obtained in metabolomics and the intersection target of "HPISN-hyperthyroidism" obtained in network pharmacology were imported into the Cytoscape 3.9.1 software, and the "compound-reaction-nzyme-gene" network was constructed using the Metscape plugin to search for important associations between genes and metabolites. Results Compared with the blank group, 13 differential metabolites were significantly down regulated（P ＜0.05） and 11 differential metabolites were significantly up-regulated（P ＜0.05） in the model group. Compared with the model group, the levels of the above indicators were significantly reversed in the treatment group of rats with HPISN（P ＜0.05）. Network pharmacology identified 8 core targets of HPISN in treating hyperthyroidism, namely ALB, INS, TP53, EGFR, CTNNB1, IL10, STAT3, and ANXA5. There were 5 core active components, including harpagide, dihydrocatalpol, 8-Oferuloylharpagide, globularin, and 6-O-α-L-rhamnopyranosylaucubin. GO functional enrichment results indicated that the biological processes affected by the core targets mainly included positive regulation of RNA polymerase II promoter transcription, signal transduction, and positive regulation of gene expression. KEGG enrichment analysis suggested that HPISN might regulate signaling pathways such as hypoxia-inducible factor 1（HIF-1）. Combined metabolomics and network pharmacology analysis identified succinate dehydrogenase complex subunit A（SDHA） and citrate synthase（CS） as key targets. Conclusion The mechanism of HPISN in preventing and treating hyperthyroidism due to yin deficiency and excessive internal heat may be related to its action on targets such as SDHA and CS, intervention in signaling pathways such as HIF-1, and causing changes in differential metabolites.

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国家自然科学基金资助项目(82060830); 贵州省科技计划项目(黔科合基础-ZK[2024]重点073); 贵州省中药炮制技术传承基地建设项目[黔中医药函(2024)22号]; 王建科全国老药工传承工作室(国中医药人教函[2024]255号); 中医药(民族医药)中药文化与大健康传承创新人才团队(GZYYFY2025007)