Transcriptomic Subtyping of Atopic Dermatitis Reveals Distinct Drug Response Signatures

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by marked clinical heterogeneity and variable responses to systemic therapies. Although transcriptomic studies have revealed substantial molecular diversity within AD lesions, how this heterogeneity relates to therapeutic responsiveness remains incompletely understood. Here, we performed integrative transcriptomic analyses of lesional and non-lesional skin from patients with AD to define molecular subtypes and examine their biological and therapeutic relevance. Unsupervised clustering of lesional skin transcriptomes identified two distinct lesional subtypes with divergent molecular features. These subtypes differed markedly in immune activation, cell-cycle–associated programs, and immune cell composition. We next assessed subtype-specific drug responsiveness by comparing lesional gene expression signatures with transcriptomic changes induced by dupilumab and cyclosporine treatment. The major lesional subtype exhibited strong inverse transcriptional concordance with drug-induced expression changes, whereas the minor lesional subtype showed attenuated responses, particularly to cyclosporine. Analysis of an independent cyclosporine-treated cohort further demonstrated that clinical non-responders displayed transcriptomic features resembling the minor lesional subtype, including enrichment of cell-cycle–associated programs. Together, these findings demonstrate that AD lesions comprise biologically distinct transcriptomic subtypes with differential immune composition and systemic drug responsiveness, providing a molecular framework for understanding heterogeneity in AD and supporting transcriptome-based stratification for precision treatment strategies.