Abstract
To identify the molecular targets and possible mechanisms of isoliquiritigenin (ISO) in affecting chronic obstructive pulmonary disease (COPD) by regulating the glycolysis and phagocytosis of alveolar macrophages (AM). Datasets GSE130928 and GSE13896 were downloaded from the Gene Expression Omnibus (GEO) database. Genes related to glycolysis and phagocytosis phenotypes were obtained from the GeneCards and MSigDB databases, respectively. Weighted gene co-expression network analysis (WGCNA) and differential analysis were conducted on GSE130928 to identify potential target genes for COPD (gene list 1). ISO target genes were gathered from the Traditional Chinese Medicine System Pharmacology (TCMSP) database, as well as the Comparative Toxicogenomic Database (CTD) and PubChem databases (gene list 2). COPD-related targets were gathered from the CTD and GeneCards databases, and the predicted targets of COPD were obtained by taking the intersection of these sources (gene list 3). From the three gene lists, key pathways were identified. The protein-protein interaction (PPI) network was created by extracting the common genes found in all key pathways and ISO targets. Candidate therapeutic targets were identified using the Minimum Common Oncology Data Element (MCODE) algorithm. These targets were then intersected with glycolysis and phagocytic phenotype-associated genes. The resulting intersection underwent further screening using eight distinct machine learning methods to identify phenotype-related key therapeutic targets. Clinical diagnostic evaluations-including nomogram analysis, receiver operating characteristic (ROC) analysis, correlation studies, and inter-group expression comparisons-were subsequently performed on these key targets. The research findings were validated using the independent dataset GSE13896. Additionally, gene set enrichment analysis (GSEA) was conducted to explore their functional relevance. Immune cell profiling was performed using mRNA expression data from AM in COPD patients. Molecular docking was then carried out to predict interactions between ISO and the identified key target genes. Differential expression analysis and WGCNA module analysis identified a total of 890 potential targets for COPD. Additionally, 3265 predicted targets for COPD were obtained through the intersection of two disease databases. Database searches also yielded 142 targets for ISO. Enrichment analysis identified 20 key pathways, from which three key targets (AKT1, IFNG, and JUN) were ultimately selected based on their overlap with enriched genes, ISO targets, and glycolysis- and phagocytosis-related genes. They were also validated using external datasets. Further analysis of signaling pathways and immune cell profiles highlighted the influence of immune infiltration in COPD and underscored the critical role of macrophages in disease pathology. Molecular docking simulations predicted the binding interactions between ISO and the three key targets. AKT1, IFNG, and JUN may be the key targets of ISO in regulating glycolysis and phagocytosis to affect COPD.