目的 利用生物信息学和孟德尔随机化（Mendelian randomization，MR）分析探索慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）的潜在靶点，并预测相关干预中药。方法 从基因表达综合数据库（Gene Expression Omnibus，GEO）获得COPD微阵列数据集，鉴定差异表达基因（differentially expressed genes，DEGs）。基于表达数量性状位点数据（expression quantitative trait locus，eQTL）和COPD全基因组关联研究数据，采用MR分析筛选与COPD密切相关的基因，并与DEGs取交集以确定COPD的核心靶点。采用异质性检验、敏感性分析、水平多效性和离群值检验对结果进行质量控制。利用富集分析方法探寻核心靶点介导COPD发生的潜在机制；采用免疫浸润分析探索核心靶点与免疫细胞之间的联系；利用验证组对核心靶点的结果进行验证。基于比较毒理基因组学数据库（Comparative Toxicogenomics Database，CTD）和Coremine Medical平台筛选对核心靶点有干预作用的中药及化学成分，并对中药特征进行归纳分析。筛选核心中药，并通过分子对接验证其关键成分与核心靶点的相互作用。结果 生物信息学分析确定了289个高表达基因和1 191个低表达基因；MR分析得到了286个与COPD密切相关的基因。二者取交集后，得到5个核心靶点：Fc受体样B（Fc receptor-like B，FCRLB）、锌指蛋白101（Zinc inger protein 101，ZNF101）、髓系相关分化标志物（myeloid associated differentiation marker，MYADM）、甲基转移酶样蛋白7A（methyltransferase-like protein 7A，METTL7A）、鞘磷脂合酶2（sphingomyelin synthase 2，SGMS2）。核心靶点主要富集在JAK激酶（Janus kinase，JAK）-信号传导及转录激活蛋白（signal transducer and activator of transcription，STAT）、核苷酸结合寡聚化结构域（nucleotide-binding oligomerization domain，NOD）样受体及P53信号通路等炎症与免疫调节途径；验证组结果与MR分析的结果基本一致。共预测到42个化学成分及135味中药。预测中药四气以温、寒、平为主，五味以甘、苦、辛为主，归经以肺、肝为主，脾、胃、肾、心经次之，功效以清热、补虚、化痰止咳平喘为主，兼以活血、理气及解表等。通过CytoNCA插件进行筛选，将白果、银杏叶、人参、黄芩、黄芪、苦杏仁、冬虫夏草确定为核心中药。分子对接揭示了核心靶点与中药的关键化学成分可形成稳定的相互作用。结论 研究共确定了5个COPD核心靶点，这些靶点可能主要通过NOD样受体、P53及JAK-STAT等炎症与免疫调节途径介导COPD发生，预测到白果、银杏叶、人参、黄芩、黄芪、苦杏仁、冬虫夏草可能是调控核心靶点的关键中药。

Objective To explore potential therapeutic targets for chronic obstructive pulmonary disease (COPD) using bioinformatics and Mendelian randomization (MR) analysis and predict related traditional Chinese medicines (TCMs) for intervention. Methods Microarray datasets for COPD were obtained from the Gene Expression Omnibus (GEO)database to identify differentially expressed genes (DEGs). Based on expression quantitative trait locus (eQTL) data and COPD genome-wide association study (GWAS) data, MR analysis was employed to screen genes significantly associated with COPD. These were intersected with DEGs to identify core targets. Heterogeneity test, sensitivity analysis, horizontal pleiotropy and outlier test were used to control the quality of the results. Enrichment analysis explored potential mechanisms by which core targets mediate COPD pathogenesis. Immune infiltration analysis investigated links between core targets and immune cells. Validation sets were used to verify core target findings. The Comparative Toxicogenomics Database (CTD) and Coremine Medical platform were utilized to screen TCMs and chemical components targeting the core genes, followed by characterization analysis of TCM properties. Core TCMs were selected, and molecular docking validated interactions between their key components and core targets. Results Bioinformatics analysis identified 289 up-regulated and 1 191 down-regulated DEGs. MR analysis identified 286 genes significantly associated with COPD. Intersection yielded five core targets: Fc receptor-like B (FCRLB), Zinc inger protein 101 (ZNF101), myeloid associated differentiation marker (MYADM), methyltransferase-like protein 7A (METTL7A) and sphingomyelin synthase 2 (SGMS2). Core targets were primarily enriched in inflammation and immune regulation pathways, including the Janus kinase (JAK)-signal transducer and activator of transcription (STAT), nucleotide-binding oligomerization domain (NOD) like receptors and P53 signaling pathways. Validation set results largely corroborated the MR findings. A total of 42 chemical components and 135 TCMs were predicted. The analysis predicted that the medicinal properties of the herbs were predominantly warm, cold, and neutral; the flavors were mainly sweet, bitter, and pungent; and the meridian tropisms were primarily directed toward the lung and liver, followed by the spleen, stomach, kidney, and heart meridians. In terms of efficacy, the herbs were found to be primarily effective in clearing heat, tonifying deficiency, and resolving phlegm to relieve cough and asthma, with additional actions such as promoting blood circulation, regulating qi, and relieving exterior syndromes. Primary functions included clearing heat, tonifying deficiency, transform phlegm, relieve cough and asthma, supplemented by promoting blood circulation, resolving exterior syndromes, regulating qi. Screening by CytoNCA plug-in, Baiguo (Ginkgo Semen), Yinxingye (Ginkgo Folium), Renshen (Ginseng Radix et Rhizoma), Huangqin (Scutellariae Radix), Huangqi (Astragali Radix), Kuxingren (Armeniacae Semen Amarum) and Dongchongxiacao (Cordyceps) were identified as core TCMs. Molecular docking revealed stable interactions between core targets and key chemical components of the core TCMs. Conclusion This study identified five core targets for COPD. These targets likely mediate COPD pathogenesis primarily through inflammation and immune regulation pathways, such as JAK-STAT, NOD like receptors and P53 signaling pathways. It is predicted that Ginkgo Semen, Ginkgo Folium, Ginseng Radix et Rhizoma, Scutellariae Radix, Astragali Radix, Armeniacae Semen Amarum and Cordyceps may be the key traditional Chinese medicines to regulate the core targets.

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国家自然科学基金项目（82274462）；国家自然科学基金项目（82575036）；北京市自然科学基金项目（7232284）；国家中医药管理局第五批全国中医临床优秀人才研修项目（国中医药人教函[2022]1号）；北京市中医药管理局北京中医药新时代125工程（京中医药科字[2025]2号）；北京中医药大学第三附属医院精诚人才计划（京中三院人[2025]4号）