目的 通过网络药理学、分子对接、分子动力学模拟及体外实验揭示岩藻甾醇治疗阿尔茨海默病的潜在靶点与作用机制。方法 通过网络数据库筛选阿尔茨海默病相关靶点与预测药物靶点，将获得的交集靶点取交集构建蛋白相互作用（PPI）网络并进行基因本体论（GO）功能和京都基因与基因组百科全书（KEGG）通路富集分析，采用随后进行分子对接及动力学模拟，通过Western blotting验证靶蛋白表达。结果 从数据库中筛选出36个交集靶点，PPI网络分析获得11个核心靶点。GO富集结果显示靶点参与脂肪酸代谢、脱氧核糖核酸调控等，KEGG分析提示岩藻甾醇主要通过过氧化物酶体增殖物激活受体（PPAR）及环磷酸腺苷（cAMP）信号通路发挥作用。分子对接表明，岩藻甾醇与雌激素受体1（ESR1）、细胞色素P450家族19亚家族a多肽1（CYP19A1）结合稳定；分子动力学模拟中二者的RMSD均小于0.5 nm，且在模拟过程中均存在氢键实现持续的相互作用。Western blotting结果表明，岩藻甾醇上调ESR1、CYP19A1、PPAR蛋白表达（P＜0.05）。结论 岩藻甾醇可能作用于ESR1、CYP19A1等靶点，通过激活PPAR信号通路发挥抗阿尔茨海默病作用。

Objective To reveal the potential targets and mechanism of action of fucosterol in treatment of Alzheimer’s disease by using network pharmacology, molecular docking, and molecular dynamics simulation, and in vitro experiments. Methods To screen Alzheimer’s disease-related targets and predicted drug targets through the network database, the intersecting targets obtained will be used to construct PPI network, and conduct GO and KEGG pathway enrichment analyses. To conduct molecular docking and kinetic simulation, and the expression of the target protein was verified by Western blotting. Results Thirty-six intersecting targets were screened from the database, and 11 core targets were obtained through PPI network analysis. GO enrichment revealed that the targets were involved in fatty acid metabolism and DNA regulation, and KEGG analysis suggested that fucosterol mainly functioned through PPAR and cAMP signalling pathways. The molecular docking showed that fucosterol binds stably to ESR1 and CYP19A1, the RMSD of both of them in molecular dynamics simulation was less than 0.5 nm. Hydrogen bonding existed in both of them to achieve the sustained interactions during the simulation process. Western blotting results showed that fucosterol down-regulated ESR1, CYP19A1, and PPAR protein expression. Conclusion Fagosterol may act on ESR1, CYP19A1 and other targets to exert anti-Alzheimer’s disease effects by activating the PPAR signalling pathway.

R286.1

四川省医学青年创新科研课题计划（Q22068）；成都市卫健委科研课题（2022237）；成都市科技局科技项目（2022-YF05-01457-SN）；成都医学院第二人民附属医院联合基金（2022LHFSZYB-05）；南部县人民医院联合基金（2022LHNBZYB/07）