Transcriptomic Analysis Reveals Mitochondrial-Driven Subgroups in Atopic Dermatitis Lesions.

Atopic dermatitis (AD) is a common and chronic inflammatory skin disease with global prevalence. Its clinical heterogeneity and complex molecular mechanisms pose significant challenges for the development of effective therapies. To explore AD molecular heterogeneity using lesional skin transcriptomic data, characterize their biological and immune profiles, and identify key genes underlying the differentiation. Differentially expressed genes were identified using DESeq2, followed by pathway and co-expression analyses via GSEA and WGCNA, respectively. Mitochondrial-related genes were extracted by intersecting DEGs and WGCNA modules with the MitoCarta3.0 database, and their functional relevance was assessed through GO and KEGG enrichment. Hub genes were identified by protein-protein interaction network analysis, which were subsequently used to construct a classification model. Transcriptional regulators were predicted using hTFtarget, while immune cell infiltration was quantified using CIBERSORT. Two molecular subgroups were identified. Cluster 1 was enriched in cell signaling and adhesion pathways, whereas Cluster 2 exhibited upregulation of oxidative phosphorylation and proteasome-related processes. A total of 85 mitochondrial-associated genes, primarily involved in energy metabolism, were differentially expressed between clusters. PPI network analysis identified four hub genes (BAD, BOLA1, CHCHD5, and ISOC2), which were significantly upregulated in Cluster 1. A hub gene-based classifier demonstrated strong discriminatory power (area under the curve > 0.7). Predicted key transcriptional regulators included ATF3, BRD2, BRD4, and CEBPA. Immune profiling revealed higher regulatory T cell infiltration in Cluster 1 and increased follicular helper T cells in Cluster 2. This study reveals two molecularly and immunologically distinct AD subtypes, characterized by differential mitochondrial function and immune microenvironment signatures.