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Abstract: Airway epithelial barrier dysfunction is a significant aspect of asthma, but the crucial regulatory mechanism behind epithelial barrier dysfunction remains unclear. Moreover, epithelial barrier dysfunction is also prevalent in other conditions such as atopic dermatitis and ulcerative colitis, and it is uncertain whether there are common regulatory mechanisms that contribute to epithelial functional dysregulation in these diseases. Methods: We obtained gene expression profiles of asthma, atopic dermatitis, and ulcerative colitis from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEG) were identified using the "limma" package, and a common DEG set was produced for further analysis. We conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional enrichment analysis on the common DEG and performed correlation analysis with junction molecules to identify key genes involved in epithelial barrier dysfunction. Interaction networks of the key genes were constructed, and their correlation with clinical features of asthmatic patients or immune infiltration was examined. The effects of key genes on CLDN1 expression were determined by qPCR in 16HBE. Results: Twenty common DEG were identified from the intersection of asthma, atopic dermatitis, and ulcerative colitis datasets. GO and KEGG enrichment analyses indicated their involvement in cell proliferation regulation, viral protein interaction with cytokines, and transmembrane receptor protein tyrosine kinase-related signaling pathways. Correlation analysis revealed cell division cycle 7 kinase (CDC7), peroxidasin (PXDN), transcobalamin I (TCN1), and tissue inhibitor of metalloproteinase 1 (TIMP1) as key genes, which showed upregulation in the epithelium in all three diseases and were negatively correlated with junction molecules. A chemical–gene interaction network suggested that benzo(a)pyrene could promote the expression of these key genes. Additionally, a correlation between the expression of key genes and the clinical features of asthmatic patients or immune infiltration was found. Finally, it was observed that knocking down key genes in 16HBE could promote CLDN1 expression. Conclusion: Our study reveals the pivotal genes implicated in epithelial barrier dysfunction, which may significantly aid in the treatment of asthma and other diseases associated with epithelial barrier dysfunction.