Decoding Cuproptosis-Sphingolipid-Immune Crosstalk in Atopic Dermatitis: A Multi-Omics Network Analysis

Area of Science:

• Biochemistry
• Immunology
• Dermatology

Background:

• Atopic dermatitis (AD) pathogenesis involves complex cellular and molecular mechanisms.
• Cuproptosis, a newly identified form of regulated cell death, has not been previously investigated in AD.

Purpose of the Study:

• To explore the role of cuproptosis-related genes (CRGs) in the pathogenesis of atopic dermatitis (AD).
• To identify potential biomarkers and therapeutic targets for AD based on cuproptosis mechanisms.

Main Methods:

• Integrated two GEO datasets (GSE157194, GSE193309) for analysis.
• Employed weighted gene co-expression network analysis (WGCNA) to identify disease-related gene modules.
• Conducted differential gene expression, functional enrichment, pathway analysis (GSEA/GSVA), and immune infiltration analyses.

Main Results:

• Identified 14 co-expression modules and 1173 differentially expressed genes in AD.
• SPTLC2, AMD1, and IGSF3 emerged as key hub genes associated with AD.
• Uncovered significant enrichment in chemokine signaling pathways and copper-dependent metabolic reprogramming.
• Revealed abnormal immune cell infiltration, particularly Th2 cells and macrophages, correlated with CRG expression.
• Proposed a novel "metabolic checkpoint" model for AD progression involving the sphingolipid-immune axis.

Conclusions:

• Cuproptosis plays a significant role in AD pathogenesis, linked to copper metabolism and sphingolipid-immune axis dysregulation.
• Identified potential diagnostic biomarkers and therapeutic targets, including SPTLC2, AMD1, and IGSF3.
• Suggests novel therapeutic strategies such as copper chelation or sphingolipid modulation for AD treatment.