GEOTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328048GEOGSEfalseSingle-cell transcriptome reveals keratinocyte subclusters that contribute to altered differentiation and inflammatory responses in atopic dermatitisAtopic dermatitis (AD) is a common chronic inflammatory skin disease with complex, poorly understood pathogenesis due to its mechanistic heterogeneity. To investigate underlying mechanisms, we performed single-cell RNA sequencing (scRNA-seq) on lesional (LAD) and non-lesional (NAD) skin from 42 AD patients and skin from 23 healthy controls (HC). Keratinocytes (KCs) were the most abundant cell type identified. In healthy skin, KC differentiation followed a linear trajectory from basal KCs (BKs) through seven differentiated stages (DK1–DK7) to terminal keratinized cells (KK1 and KK2). In LAD, this process was disrupted, showing a reversed transition from KK2 to KK1, mainly driven by DK7. APOD and LYZ were identified as LAD-specific regulators of this aberrant keratinization, linked to IL-13- and IL-22-driven responses involving endoplasmic reticulum (ER) stress and oxidative damage. Mitochondrial and ER dysfunction were specifically enriched in LAD DK6 cells, suggesting this subcluster as a key pathogenic compartment associated with cytokine activation. Further, cell-cell interaction analysis (validated through Xenium spatial transcriptomics and immunohistochemistry) highlighted TWEAK, derived from IL13+ Th2 and cycling T cells acting on FN14+ basal and differentiated KCs, as a key contributor to AD-associated epidermal responses. These findings reveal how disrupted KC differentiation and specific immune pathways contribute to AD pathogenesis, identifying distinct cellular compartments and inflammatory circuits as potential therapeutic targets.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 sapiens