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基于孟德尔随机化(Mendelian randomization, MR)分析、网络药理学及多组学数据整合分析,系统筛选瓜蒌薤白半夏汤(Gualou Xiebai Banxia decoction, GLXBBX)治疗慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)的核心调控基因与关键细胞亚群,通过探索核心靶点所在的细胞亚群特征,揭示该方剂整体干预COPD的分子与细胞学作用机制。运用公共数据库获取COPD的转录组及单细胞RNA测序数据,通过差异表达基因(differentially expressed genes, DEGs)和加权基因共表达网络分析(weighted gene co-expression network analysis, WGCNA)鉴定COPD相关基因。构建“中药-活性成分-靶点”网络,联合模块识别算法识别筛选GLXBBX-COPD核心基因,并对其进行功能富集分析。采用MR分析验证核心基因与COPD发病之间的因果关联,通过受试者工作特征(receiver operating characteristic, ROC)曲线与外部验证集评估因果基因的诊断效能;并利用分子对接、分子动力学(molecular dynamics, MD)模拟及ADMETlab平台评估关键活性成分与靶蛋白的结合稳定性及毒理药代特征。通过DEGs、 WGCNA和拓扑算法,共筛选获得144个GLXBBX-COPD核心基因,显著富集于磷脂酰肌醇3-激酶/蛋白激酶B(phosphatidylinositol 3-kinase/protein kinase B, PI3K-AKT)信号通路。单细胞及免疫浸润分析显示,m TOR在巨噬细胞中高表达且关联显著。MR证实m TOR与COPD发病具有显著因果关系, ROC曲线验证曲线下面积(area under the curve, AUC)为0.503。分子对接和分子动力学模拟证实GLXBBX核心成分(如维生素E和卡维丁等)能与m TOR稳定结合,鉴定m TOR和巨噬细胞是GLXBBX干预COPD的关键靶标及效应细胞,揭示了该方剂可能通过调控PI3K-AKT通路、下调m TOR以影响巨噬细胞极化,进而缓解COPD。该发现为GLXBBX的临床应用提供了理论依据。
Abstract：Based on Mendelian randomization( MR), network pharmacology, and multi-omics data integration analysis, systematically screen the core regulatory genes and key cell subpopulations associated with Gualou Xiebai Banxia decoction( GLXBBX) in the treatment of chronic obstructive pulmonary disease( COPD). By exploring the characteristics of the cell subpopulations harboring these core targets, we reveal the molecular and cytological mechanisms underlying the holistic intervention of this decoction in COPD. Transcriptomic and single-cell RNA sequencing data of COPD were retrieved from public databases. COPD-associated genes were identified by utilizing differentially expressed genes( DEGs) profiling and weighted gene co-expression network analysis( WGCNA). Subsequently, a "Traditional Chinese Medicine-active ingredient-target" network was constructed. Combined with module identification algorithms, the core GLXBBX-COPD genes were screened and subjected to functional enrichment analysis. MR analysis was employed to validate the causal relationship between these core genes and the pathogenesis of COPD. The diagnostic efficacy of the causal genes was evaluated using receiver operating characteristic( ROC) curves and external validation sets. Furthermore, molecular docking, molecular dynamics( MD) simulations, and the ADMETlab platform were utilized to assess the binding stability and the toxicological and pharmacokinetic profiles of the key active ingredients with the target proteins. A total of 144 GLXBBX-COPD core genes were screened and identified by integrating DEGs, WGCNA, and topological algorithms. These genes were significantly enriched in the phosphatidylinositol 3-kinase/protein kinase B( PI3K-AKT) signaling pathway. Single-cell and immune infiltration analyses revealed that m TOR were highly expressed in macrophages with significant correlations. MR analysis confirmed a significant causal relationship between m TOR and the onset of COPD, with the ROC curve validation yielding an area under the curve( AUC) of 0. 503. Molecular docking and MD simulations demonstrated that the core components of GLXBBX( such as vitamin E and cavidine) could stably bind to m TOR. m TOR and macrophages were thereby identified as the critical targets and effector cells for GLXBBX′s intervention in COPD. This suggests that the decoction may alleviate COPD by modulating the PI3K-AKT pathway and downregulating m TOR to influence macrophage polarization. These findings provide a solid theoretical basis for the clinical application of GLXBBX.
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基本信息:
DOI：10.13417/j.gab.045.000922
中图分类号:R285
引用信息:
[1]罗成,叶远航,覃琬婷.多组学研究揭示瓜蒌薤白半夏汤治疗慢性阻塞性肺疾病的关键基因[J].基因组学与应用生物学,2026,45(04):922-944.DOI:10.13417/j.gab.045.000922.
基金信息:
国家自然科学基金项目(82505509); 四川省自然科学基金项目(2025ZNSFSC1853); 中国博士后科学基金第75批面上资助“地区专项支持计划”(2024MD753905); 成都市卫生健康委员会-成都中医药大学委校院联合科技创新基金项目(WXLH202403266)共同资助
2026-05-25
2026-05-25
2026-05-25