CXCL12: a key gene in IPF-COPD pathogenesis and its therapeutic potential

Shared core genes and molecular mechanisms relevant to the pathological overlap between idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) were investigated to inform future diagnostic and therapeutic research. Gene expression profiles were analysed using differential expression gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment. A random forest (RF) model incorporating a multi-feature selection mechanism was used to identify core genes in IPF patients with COPD. The expression levels, diagnostic performance, and immune cell relationships of these genes were analysed, and single-cell RNA sequencing (scRNA-seq) was used to assess the expression patterns of the core genes. Finally, drug predictions were made based on the core genes. Molecular docking and 100-ns molecular dynamics simulations were further performed to evaluate candidate CXCL12-ligand interactions, and CXCL12 expression was experimentally validated in BEAS-2B cells after cigarette smoke extract, bleomycin, and combined stimulation. CXCL12 was identified as a core gene for IPF combined with COPD. This gene exhibited high expression levels in the dataset, with receiver operating characteristic (ROC) curve area under the curve (AUC) values of 0.78, 0.67, 1.00, and 0.86, respectively. Exploratory analysis of CIBERSORT-estimated immune-cell proportions showed significant differences in CD8 + T cells and resting memory CD4 + T cells between the CXCL12-high and CXCL12-low groups. Single-cell RNA sequencing (scRNA-seq) indicates that CXCL12 exhibits significantly increased expression in endothelial cells of COPD and fibroblast cells of IPF, providing valuable insights into the molecular mechanisms. Molecular docking results suggested that sitagliptin and LY-294,002 could serve as therapeutic candidates for IPF combined with COPD. Molecular dynamics simulations supported the sustained binding stability of both CXCL12-ligand complexes. In vitro validation further showed that CXCL12 was induced at the mRNA and protein levels after epithelial injury stimulation. CXCL12 plays a key role in the pathogenesis of IPF combined with COPD and holds promise as a potential target for the diagnosis and treatment of this disease.