Work

Integrative Single-Cell and Bulk RNA Sequencing Analysis Identifies Ion Channel-Related Biomarkers in Chronic Obstructive Pulmonary Disease

Year: 2026

Type: article

Abstract: Background: Human ion channel genes (HICGs), as core effectors of transmembrane signal transduction, play a critical role in the initiation and progression of chronic obstructive pulmonary disease (COPD); however, the underlying mechanisms remain largely unclear. This study aimed to investigate the potential value of ion channel genes in COPD. Methods: Differential expression analysis was performed to screen HICGs in COPD datasets. A total of 107 machine learning models were employed to identify hub HICGs and evaluate their diagnostic performance, and SHAP analysis was used to assess feature contributions. GSEA, immune cell infiltration, and inflammatory cytokine correlation analyses were conducted on the hub HICGs. Consensus clustering and WGCNA were used to define two disease subtypes and key modules. Single-cell RNA-seq data were used to examine the expression patterns of the hub HICGs. Subsequently, virtual knockout, virtual drug screening, and molecular docking were performed. Results: The nine hub HICGs showed high diagnostic performance in cross-dataset validation, with LRRC8D ranking first in the SHAP analysis. These HICGs were significantly correlated with immune cells and inflammatory cytokines. Consensus clustering revealed significant gender differences between the two subtypes (BH-adjusted P = 0.01), and the two subtypes were enriched in phagocytosis and MAPK signaling pathways, respectively. Single-cell RNA-seq analysis using the Ro/e index suggested enrichment of macrophages and a reduction in smooth muscle cells in the disease group. Virtual knockout of LRRC8D was predicted to preferentially affect CD68 and the affected genes were enriched in human cytomegalovirus infection. Virtual screening prioritized Tezacaftor as a potential therapeutic agent, and molecular docking predicted that Tezacaftor may exhibit high binding affinity for the hub HICGs. Conclusion: We identified potential HICGs in COPD and suggested a potential role for LRRC8D, as well as the potential utility of hub HICGs in disease subtyping, particularly with respect to gender, and Tezacaftor may serve as a candidate therapeutic agent.

Source: International Journal of COPD

DOI: 10.2147/copd.s638940