目的 基于网络药理学方法和体内实验验证探讨荆防颗粒治疗高尿酸血症的作用机制。方法 通过中药系统药理学数据库与分析平台（TCMSP）筛选荆防颗粒活性成分对应靶点，通过OMIM、GeneCards和TTD等数据库收集高尿酸血症相关靶点。将交集靶点上传至STRING数据平台构建蛋白质-蛋白质相互作用（protein-protein interaction，PPI）网络，再采用Metascape数据平台进行基因本体（gene ontology，GO）功能和京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）通路富集分析。采用氧嗪酸钾诱导的高尿酸血症小鼠模型和小鼠肾脏代谢组学对网络药理学结果进行验证。结果 网络药理学结果表明，荆防颗粒109个成分中含有500个相关靶点，高尿酸血症相关靶点801个，交集靶点87个。PPI网络分析结果显示，甘油醛-3-磷酸脱氢酶（glyceraldehyde-3-phosphate dehydrogenase，GAPDH）、肿瘤蛋白p53（tumor protein p53，TP53）、肿瘤坏死因子（tumor necrosis factor，TNF）、半胱氨酸天冬氨酸蛋白酶-3（cystein-asparate protease-3，Caspase-3）、白细胞介素-6（interleukin-6，IL-6）可能是荆防颗粒治疗高尿酸血症的关键靶点。KEGG通路富集分析获得凋亡信号通路、坏死性凋亡、低氧诱导因子-1（hypoxia-inducible factor-1，HIF-1）信号通路等。通过氧嗪酸钾诱导的高尿酸血症小鼠模型结果显示，荆防颗粒显著降低血清尿酸、尿素氮及血肌酐水平（P＜0.01、0.001），显著抑制肾组织Bcl-2相关X蛋白（Bcl-2 associated X protein，Bax）、cleaved Caspase-3蛋白表达（P＜0.01），升高B细胞淋巴瘤（B-cell lymphoma-2，Bcl-2）蛋白表达（P＜0.05、0.01）。肾脏代谢组学结果显示，荆防颗粒能够通过改善高尿酸血症小鼠丙氨酸、天冬氨酸和谷氨酸的代谢、糖酵解/糖异生途径、柠檬酸循环等途径改善代谢。结论 荆防颗粒能够基于多成分、多靶点、多通路的特点相互协同治疗高尿酸血症。

Objective To explore the mechanism of Jingfang Granules (荆防颗粒, JF) on hyperuricemia (HUA) based on network pharmacological method and in vivo experiments. Methods The corresponding targets of active components in JF were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the related targets of HUA were collected by OMIM, GeneCards, TTD and other databases. Intersection targets were upload in STRING data platform to build protein-protein interaction (PPI) network, and Metascape data platform was then used to conduct gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. HUA model induced by oteracil potassium and renal metabonomics of mice were used to verify the results of network pharmacology. Results The results of network pharmacology showed that there were 500 targets corresponding to 109 compounds detected by JF, 801 targets matching HUA and 87 intersection target. The results of PPI network analysis showed that glyceraldehyde-3-phosphate dehydrogenase (GAPDH), tumor protein p53 (TP53), tumor necrosis factor (TNF), cystein-asparate protease-3 (Caspase-3) and interleukin-6 (IL-6) may be the key targets of JF in treatment of HUA. The apoptotic signaling pathway, necroptosis and hypoxia-inducible factor-1 (HIF-1) signaling pathway were obtained by KEGG pathway enrichment analysis. The results of HUA mouse model induced by oteracil potassium showed that JF significantly reduced the serum uric acid, blood urea nitrogen and serum creatinine level (P < 0.01, 0.001), significantly inhibited Bcl-2 associated X protein (Bax) and cleaved Caspase-3 protein expressions in renal (P < 0.01), and increased B-cell lymphoma-2 (Bcl-2) protein expression (P < 0.05, 0.01). The results of renal metabolomics showed that JF could regulate the metabolism of alanine, aspartic acid and glutamic acid, glycolysis/gluconeogenesis, tricarboxylic acid cycle and other pathways in HUA mice. Conclusion JF can treat hyperuricemia synergistically based on the characteristics of multi-component, multi-target and multi-pathway.

R285.5

国家自然科学基金青年科学基金资助项目（81600601）；山东省自然科学基金面上项目（ZR2021MH363）