Integrated Bioinformatics and Experimental Validation to Identify Shared Sialylation‐Related Signatures in Emphysematous and Fibrotic Lung Disease

Emphysema and pulmonary fibrosis represent distinct patterns of chronic lung remodeling but may share molecular and cellular abnormalities. In this study, we analyzed public transcriptomic datasets of chronic obstructive pulmonary disease, emphysema, and idiopathic pulmonary fibrosis from the Gene Expression Omnibus database to explore shared disease-related signatures. Weighted gene co-expression network analysis and differential expression analysis were used to identify common molecular alterations, followed by functional enrichment, protein-protein interaction network construction, hub gene screening, immune infiltration analysis, transcription factor prediction, and single-cell RNA-sequencing validation. The integrated analysis revealed overlapping signatures related to cell adhesion, extracellular matrix organization, vascular regulation, immune responses, and epithelial homeostasis. Five hub genes were validated, and ST6GALNAC5 was further prioritized because of its association with sialylation and predominant enrichment in epithelial cells. Given that sialylation has been rarely investigated in pulmonary fibrosis and emphysema, we therefore further investigated ST6GALNAC5-related epithelial sialylation. Experimental validation on tissue samples showed reduced Sambucus nigra agglutinin lectin signals and decreased ST6GALNAC5 expression in lungs with coexisting emphysematous and fibrotic injury. In vitro experiments confirmed that ST6GALNAC5 overexpression attenuated bleomycin-induced epithelial cell injury. Together, these findings identify convergent molecular signatures across emphysematous and fibrotic lung diseases and suggest that impaired epithelial sialylation may represent a previously underappreciated feature of chronic lung remodeling.