Objective To explore the genetic causal relationship between gastro-esophageal reflux disease (GERD) and chronic obstructive pulmonary disease (COPD) by Mendelian randomization (MR) analysis based on the theory of “gather in stomach and focus on lung”, and to predict potential Chinese herbal medicines that may intervene in GERD-related COPD. Methods The genome-wide association study (GWAS) datasets for GERD and COPD were obtained from the IEU Open GWAS database. A bidirectional two-sample Mendelian randomization (MR) analysis was applied to evaluate the causal relationship between the two conditions, followed by a series of quality control procedures. Subsequently, proximal genes of the instrumental variables were extracted using the Ensembl database, and functional enrichment analysis was performed to explore the potential mechanisms by which GERD influences COPD risk. Furthermore, protein-protein interaction (PPI) analysis was conducted on these proximal genes to identify core genes involved in this process. Potential intervention chemical components and Chinese herbal medicines were predicted using the Comparative Toxicogenomics Database (CTD) and the Coremine Medical database, respectively, and statistical analysis was carried out on the medicinal properties and functions of the identified herbs. The CytoNCA plugin was used to screen core Chinese herbal medicines, and molecular docking of traditional Chinese medicine components with core genes to preliminarily verify the prediction results. Results Forward MR analysis indicated that GERD was causally associated with a significantly increased risk of COPD onset; quality control results confirmed the robustness of this finding. Reverse MR analysis did not reveal evidence supporting a causal effect of COPD on GERD. A total of 135 proximal genes of the instrumental variables were identified, which were primarily enriched in biological pathways such as the regulation of Nuclear Factor-Kappa B (NF-κB) signal transduction, the Interleukin-17 (IL-17) signaling pathway, the Tumor Necrosis Factor (TNF) signaling pathway, the Phosphatidylinositol 3-Kinase-Protein Kinase B (PI3K-Akt) signaling pathway, and natural killer cell-mediated cytotoxicity. The top five genes identified through PPI analysis were determined as core genes. Using the CTD and Coremine Medical databases, 163 chemical components and 167 Chinese herbal medicines were predicted. Statistical analysis of the medicinal properties of the herbs showed that among the Four Natures, cold and warm properties predominated, followed by neutral; among the five flavors, bitter, sweet, and pungent were most common; the primary meridian tropism was the lung meridian, followed by the liver, spleen, and stomach meridians; in terms of functions, tonifying deficiency and resolving phlegm, relieving cough and asthma were primary, followed by clearing heat, relieving exterior syndrome, and regulating qi. After calculation with CytoNCA, key herbs were screened out, including Mahuang (Ephedrae Herba), Baiguo (Ginkgo Semen), Banxia (Pinelliae Rhizoma), Chenpi (Citri Reticulatae Pericarpium), Sangbaipi (Mori Cortex), Gancao (Glycyrrhizae Radix et Rhizoma), Ganjiang (Zingiberis Rhizoma), Shengjiang (Zingiberis Rhizoma Recens), Huangqi (Astragali Radix), Renshen (Ginseng Radix et Rhizoma), Fuling (Poria), and Baizhu (Atractylodis Macrocephalae Rhizoma). Molecular docking demonstrated favorable binding affinity between the core genes and the key components of these Chinese herbal medicines. Conclusion Based on the theory of "accumulation in the stomach and its connection with the lungs," this study not only confirms from a genetic perspective that GERD is a risk factor for COPD, but also reveals that its potential mechanisms are closely associated with inflammatory and immune signaling pathways such as NF-κB, IL-17, TNF, and PI3K-Akt. The predicted Chinese herbal treatment strategies primarily focus on tonifying deficiency, resolving phlegm, relieving cough, and calming asthma.

gastroesophageal reflux disease  /  chronic obstructive pulmonary disease  /  gather in stomach and focus on lung  /  Mendelian randomization  /  Pinelliae Rhizoma  /  Ginseng Radix et Rhizoma  /  Poria  /  Atractylodis Macrocephalae Rhizoma