黄连解毒汤（HLJDD）是一种著名的传统中药方剂，广泛应用于阿尔茨海默病（AD）的治疗。然而，HLJDD中生物活性物质与AD相关靶点之间的相互作用尚未得到很好的阐明。本研究通过微生物菌群调节的方式，基于网络药理学和分子对接相结合的方法，确定了HLJDD对AD的生物活性成分、关键靶点和潜在的药理作用机理。生物活性成分和潜在靶点以及AD相关靶点从中药系统药理学分析数据库（TCMSP）中获得。通过生物信息学分析，包括蛋白质相互作用（PPI）分析、基因本体论（GO）分析和基因组学百科全书（KEGG）分析，获得了关键生物活性成分、潜在靶点和信号通路。随后，进行分子对接预测活性化合物与核心靶点的结合情况。筛选出HLJDD的102个生物活性成分和76个HLJDD-AD相关靶点。生物信息学分析表明，黄酮、木根素、β-谷甾醇、黄烷酮、丽酚素、异山梨酉鸟嘌呤、（S）-金杏碱、（R）-金杏碱可能是潜在的候选药物。AKT1、TNF、TP53、VEGFA、FOS、PTGS2、MMP9和CASP3可能成为潜在的治疗靶点。其中包括癌症通路、VEGF信号通路和NF-κB信号通路在内的15个重要信号通路可能对HLJDD对抗AD起重要作用。此外，分子对接分析表明，黄酮、木根素、β-谷甾醇、黄烷酮、丽酚素、异山梨酉鸟嘌呤、（S）-金杏碱和（R）-金杏碱与AKT1、TNF、TP53、VEGFA、FOS、PTGS2、MMP9、CASP3结合良好。本研究综合阐明了HLJDD抗AD的生物活性成分、潜在靶点和可能的分子机制，表明HLJDD可能通过多个靶点和多个途径调节微生物菌群平衡以治疗AD，并为传统中药治疗人类疾病提供了有前途的策略。版权所有©2023 Zheng、Shi、Zhang、Yuan、Guo、Guo和Jiang。

Huanglian Jiedu decoction (HLJDD) is a famous traditional Chinese medicine prescription, which is widely used in the treatment of Alzheimer's disease (AD). However, the interaction between bioactive substances in HLJDD and AD-related targets has not been well elucidated.A network pharmacology-based approach combined with molecular docking was performed to determine the bioactives, key targets, and potential pharmacological mechanism of HLJDD against AD, through the regulation of microbial flora.Bioactives and potential targets of HLJDD, as well as AD-related targets, were retrieved from Traditional Chinese Medicine Systems Pharmacology Analysis Database (TCMSP). Key bioactive components, potential targets, and signaling pathways were obtained through bioinformatics analysis, including protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Subsequently, molecular docking was performed to predict the binding of active compounds with core targets.102 bioactive ingredients of HLJDD and 76 HLJDD-AD-related targets were screened. Bioinformatics analysis revealed that kaempferol, wogonin, beta-sitosterol, baicalein, acacetin, isocorypalmine, (S)-canadine, (R)-canadine may be potential candidate agents. AKT1, TNF, TP53, VEGFA, FOS, PTGS2, MMP9 and CASP3 could become potential therapeutic targets. 15 important signaling pathways including the cancer pathway, VEGF signaling pathway, and NF-κB signaling pathway might play an important role in HLJDD against AD. Moreover, molecular docking analysis suggested that kaempferol, wogonin, beta-sitosterol, baicalein, acacetin, isocorypalmine, (S)-canadine, and (R)-canadine combined well with AKT1, TNF, TP53, VEGFA, FOS, PTGS2, MMP9, CASP3, respectively.Our results comprehensively illustrated the bioactives, potential targets, and possible molecular mechanisms of HLJDD against AD. HLJDD may regulate the microbiota flora homeostasis to treat AD through multiple targets and multiple pathways. It also provided a promising strategy for the use of traditional Chinese medicine in treating human diseases.Copyright © 2023 Zheng, Shi, Zhang, Yuan, Guo, Guo and Jiang.