目的 采用网络药理学和分子对接技术系统探讨左归丸“异病同治”阿尔茨海默病（AD）和骨质疏松（OP）的潜在作用机制。方法 借助中药系统药理学数据库与分析平台（TCMSP）、HERB等数据库检索和筛选左归丸中8味组方中药（熟地黄、山药、枸杞子、山茱萸肉、川牛膝、菟丝子、鹿角胶，龟甲胶）的活性成分，并对其活性成分进行靶点预测。通过OMIM、DrugBank、GeneCards等数据库进行AD和OP疾病相关靶点的收集。对疾病相关靶点与活性成分作用靶点取交集，得到左归丸“异病同治”AD和OP的潜在作用靶点。使用STRING数据库和Cytoscape软件分别构建潜在作用靶点的蛋白质-蛋白质相互作用（PPI）网络和“药物-成分-靶点”网络，通过网络拓扑分析筛选出核心活性成分和核心靶点。并运用Metascape数据库并结合微生信平台，对潜在作用靶点展开基因本体（GO）注释及京都基因与基因组百科全书（KEGG）通路富集分析。为深入验证核心活性成分与关键作用靶点间的结合模式及相互作用强度，运用AutoDock软件进行分子对接实验。结果 对左归丸组方中药进行靶点检索其包含的91种活性成分，能够作用于329个蛋白靶点。将上述靶点与4 019个AD相关靶点及1 368个OP相关靶点进行比对分析后，最终筛选出97个交集靶点。通过GO功能富集分析进一步揭示，这些潜在作用靶点主要参与多种生物学过程，涵盖细胞对脂质的响应、细胞迁移的正向调控、对外源性物质刺激的响应、细胞因子刺激的响应、激素刺激的响应以及细胞凋亡信号通路的调控等环节。在KEGG通路富集分析中，发现关键通路包括AGE-RAGE、IL-17、TNF、雌激素、HIF-1及MAPK等信号通路。通过PPI网络及“药物-成分-靶点”网络拓扑分析，进一步筛选出10个核心靶点（如PGR、PTGS2、PTGS1、PRKACA、PPARG、DPP4、NOS3等）以及10个核心活性成分（如山柰酚、薯蓣皂苷元、染料木黄酮等）。分子对接实验证实，这些核心活性成分与对应靶点之间存在较强的结合能力。结论 左归丸可能是借助其核心活性成分，例如山柰酚、薯蓣皂苷元、染料木黄酮等，进而对PGR、PTGS2等关键靶点产生影响，同时参与AGE-RAGE、TNF以及MAPK等信号通路的调控过程，最终在AD和OP治疗方面展示“异病同治”作用。

Objective To explore the “treating different diseases with the same therapy” mechanism of Zuogui Pill for Alzheimer’s disease（AD） and osteoporosis（OP） via network pharmacology and molecular docking. Methods The active ingredients of eight Chinese medicines in Zuogui Pill（Rehmanniae Radix Praeparata, Dioscoreae Rhizoma, Lycii Fructus, Corni Fructus, Cyathulae Radix, Cuscutae Semen, Cervi Cornus Colla, Testudinis Carapacis et Plastri Colla） were searched and screened with the help of TCM systematic pharmacology database and analysis platform（TCMSP）, HERB and other databases, and the target prediction of their active ingredients was carried out. Collect AD and OP disease-related targets through databases such as OMIM, DrugBank, GeneCards, etc. By taking the intersection of disease-related targets and active ingredient targets, potential targets for AD and OP in Zuogui Pill’s “treating different diseases with the same treatment” approach were identified. Construct protein-protein interaction（PPI） networks and "drug component target" networks for potential targets using STRING database and Cytoscape software, respectively, and screen for core active ingredients and core targets through network topology analysis. And by utilizing the Metascape database and combining it with the bioinformatics platform, gene ontology（GO） annotation and Kyoto Encyclopedia of Genes and Genomes（KEGG） pathway enrichment analysis was conducted on potential target genes. In order to further verify the binding mode and interaction strength between the core active ingredients and key targets, molecular docking experiments were conducted using AutoDock software. Results Analysis of Zuogui Pill revealed that it contained 91 active ingredients that can act on 329 protein targets. After comparing and analyzing the above targets with 4 019 AD related targets and 1 368 OP related targets, 97 potential targets（i.e. intersecting targets） were ultimately screened. Through GO functional enrichment analysis, it was further revealed that these potential targets were mainly involved in various biological processes, including cell response to lipids, positive regulation of cell migration, response to exogenous stimuli, response to cytokine stimulation, response to hormone stimulation, and regulation of apoptosis signaling pathways. In KEGG pathway enrichment analysis, key pathways were found to include AGE-RAGE, IL-17, TNF, estrogen, HIF-1, and MAPK signaling pathways. Through PPI network and “drug component target” network topology analysis, 10 core targets（such as PGR, PTGS2, PTGS1, PRKACA, PPARG, DPP4, NOS3, etc.） and 10 core active ingredients（such as kaempferol, diosgenin, genistein, etc.） were further screened. Molecular docking experiments have confirmed the strong binding ability between these core active ingredients and their corresponding targets. Conclusion Zuogui Pill may utilize its core active ingredients, such as kaempferol, diosgenin, and genistein, to affect key targets such as PGR and PTGS2, while also participating in the regulation of signaling pathways such as AGERAGE, TNF, and MAPK. Ultimately, it demonstrates a "different disease treatment" effect in the treatment of AD and OP.

R285.5

国家自然基金区域创新发展联合基金集成项目(U24A6013); 省部共建中医湿证国家重点实验室专项(SZ2021ZZ14)