IL-24 and S100A2 as Novel Immune Drivers for Therapeutic Targeting and Precision Subtyping in Atopic Dermatitis
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Background Atopic dermatitis (AD) is a heterogeneous inflammatory skin disorder driven by immune dysregulation. This study aimed to identify novel immune-related signatures and molecular subtypes to advance precision medicine in AD. Methods Transcriptomic datasets were retrieved from the Gene Expression Omnibus (GEO). Functional enrichment and protein-protein interaction (PPI) network analyses were conducted to elucidate biological pathways. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms were utilized to identify and validate hub differentially expressed immune-related genes (DEIRGs) through receiver operating characteristic curve (ROC) analysis, as well as in vivo and in vitro experiment validations. CIBERSORT and single sample gene set enrichment analysis (ssGSEA), and consensus clustering analysis were employed to evaluate immune cell infiltration and classify AD subtypes. Results Among 25 DEIRGs associated primarily with cytokine-cytokine receptor interaction and chemokine signaling pathway, IL-24 and S100A2 were identified as hub DEIRGs with high diagnostic sensitivity and specificity. Both genes were upregulated in AD lesions, MC903-induced AD mouse models, and TNF-α/IFN-γ-stimulated HaCaT cells. Immune infiltration analysis showed that their expression correlated with dendritic cells activated. Subtype analysis revealed two distinct AD clusters characterized by differential immune cell infiltration and pathway activation. Functional studies confirmed that knockdown of IL-24 or S100A2 in HaCaT cells attenuated the secretion of pro-inflammatory mediators (IL-1β, IL-6, TSLP, CCL17). Conclusion IL-24 and S100A2 represent crucial DEIRGs involved in AD pathogenesis, demonstrating strong potential for patient stratification and diagnosis. These findings offer new perspectives for developing targeted diagnostic and therapeutic strategies in AD.
