Abstract
Background: This study pioneers the exploration of the role of cuproptosis (a novel form of regulated cell death) in the pathogenesis of atopic dermatitis (AD). Methods: We integrated two datasets (GSE157194 and GSE193309) from the GEO database and employed weighted gene co-expression network analysis (WGCNA) to identify disease-related modules. Through multi-dimensional approaches, including differential gene expression analysis, functional enrichment analysis, GeneMANIA network construction, GSEA/GSVA pathway enrichment analysis, and immune infiltration analysis, we systematically elucidated the regulatory mechanisms of cuproptosis-related genes (CRGs) in AD. Results: The findings reveal novel mechanisms underlying AD pathogenesis. We identified 14 co-expression modules and 1173 differentially expressed genes, among which SPTLC2, AMD1, and IGSF3 were identified as key hub genes (AUC > 0.75). In-depth mechanistic analysis uncovered critical pathophysiological features of AD, including significant enrichment in chemokine signaling pathways (p < 0.001) and copper-dependent metabolic reprogramming. Notably, immune infiltration analysis demonstrated abnormal activity in 20 out of 21 immune cell types, particularly Th2 cells and macrophages, which showed strong correlations with CRG expression patterns. These findings establish an innovative "metabolic checkpoint" model for AD progression, highlighting dysregulation of the sphingolipid-immune axis as a key pathogenic mechanism. Conclusions: This study provides novel evidence, suggesting a potential link between AD and copper metabolism dysregulation, and identifies several promising targets that may aid in diagnosis and treatment. Our findings contribute to the growing understanding of AD pathogenesis and hint at possible new therapeutic directions, including copper chelation or sphingolipid-modulating approaches for difficult-to-treat AD cases. The identified CRG signatures may serve as potential biomarkers and therapeutic targets for personalized management strategies of this complex skin disorder.