基于整合网络毒理学和分子对接的补骨脂酚致肝毒性机制探讨

目的 基于网络毒理学和分子对接技术探究补骨脂酚致肝毒性的潜在机制。方法 通过TCM-BATMAN挖掘补骨脂酚靶点，DisGeNET挖掘肝毒性基因；Cytoscape 3.7.0分别构建补骨脂酚靶点和肝毒性基因蛋白互作关系（PPI）网络，并Merge取交集，运用软件中插件分析获得关键靶点，构建生物学总调控网络，并对其进行基因本体论（gene ontology，GO）和京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）富集分析；分子对接评价补骨脂酚与潜在关键靶点结合的亲和力。结果 共获得补骨脂酚靶点3 952个，肝毒性基因6 025个和交集基因2 221个。经分析，补骨脂酚主要作用于TP53、HSP90AA1、EP300等关键靶点，参与氧化应激反应与细胞增殖、分化、凋亡过程的调控，涉及多种酶调控等生物过程，主要通过PI3K-Akt、MAPK、细胞周期等信号通路引起肝毒性。补骨脂酚与EP300、HSP90AA1靶点的亲和力最强，能够与二者的结合口袋形成较强的疏水作用，total score值为8.858 2、7.217 8。结论 补骨脂酚致肝毒性具有多靶点、多途径的作用规律，主要通过PI3K-Akt、MAPK、细胞周期等信号通路引起肝毒性。

Mechanism of bakuchiol induced hepatotoxicity based on network toxicology and molecular docking

Objective To explore the potential mechanism of bakuchiol induced hepatotoxicity based on network toxicology and molecular docking. Methods TCM-BATMAN was used to mine drug targets, and DisGeNET was used to mine disease genes. Cytoscape3.7.0 was used to construct bakuchiol targets and hepatotoxic genes PPI network respectively, and Merge was used to obtain the intersection. The key targets were obtained by plug-in analysis of the software, and the overall regulatory network of biology was constructed. GO and KEGG were performed on key targets. The binding affinity of bakuchiol to potential target genes was evaluated by molecular docking. Results There were 3 952 component targets, 6 025 hepatotoxic genes and 2 221 intersection genes. Through in-depth analysis, bakuchiol mainly acted on TP53, HSP90AA1, EP300 and other key targets. It was mainly involved in the regulation of oxidative stress response and cell proliferation, differentiation and apoptosis, involving a variety of enzyme regulation and other biological processes, regulating PI3K-Akt, MAPK and cell cycle signaling pathways, causing hepatotoxicity. Bakuchiol had the strongest affinity with EP300 and HSP90AA1 target genes, and could form strong hydrophobic interaction with their binding pocket. The total score was 8.858 2 and 7.217 8. Conclusion Psoralen induced hepatotoxicity has the law of multi-target and multi-channel action, mainly through PI3K-Akt, MAPK, cell cycle and other signal pathways.