Transcriptomic Profiling of Lesional and Perilesional Skin in Atopic Dermatitis Suggests Barrier Dysfunction, Inflammatory Activation, and Alterations to Vitamin D Metabolism

Atopic dermatitis (AD) is a chronic inflammatory skin disease marked by impaired barrier func-tion and immune dysregulation. This study explores transcriptomic differences between lesional (IL) and perilesional (PL) skin in patient with AD, focusing on barrier-related and vitamin D–associated pathways. RNA sequencing was performed on matched IL and PL biopsies from 21 adults with moderate-to-severe AD. Differential gene expression, pathway enrichment, and cor-relation analysis with clinical variables were assessed. A total of 8,817 genes were differentially expressed in IL versus PL skin (padj<0.05). Among genes with highest level of dysregulation, strong upregulation was observed for inflammatory mediators (IL-19, IL-8, CXCL6), and epi-dermal remodeling and barrier-disrupting proteins (MMP1, GJB2). Vitamin D pathway enzymes CYP27B1 and CYP24A1 were also significantly upregulated. In contrast, key barrier-related genes such as FLG2 and CGNL1 were markedly downregulated. While some patterns in gene expression showed subgroup-specific trends, no independent clinical predictors emerged in multivariate models. Reactome pathway analysis revealed enrichment of pathways involved in keratinization, cornified envelope formation, IL-4/IL-13 signaling, chemokine activity, and antimicrobial re-sponses, highlighting coordinated structural and immunologic dysregulation in lesional skin. Lesional skin in AD displays a distinct transcriptomic profile marked by barrier impairment, heightened inflammatory signaling, and activation of vitamin D–related pathways. These findings enhance our understanding of the molecular mechanisms underlying inflammation in AD.