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Single-cell transcriptome reveals keratinocyte subclusters that contribute to altered differentiation and inflammatory responses in atopic dermatitis

GSE328048 Homo sapiens Expression profiling by high throughput sequencing 116 samples Submitted 2026/06/01 Platform GPL24676
Summary
Atopic 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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Direct links to NCBI, no account and no request form: the whole study as GSE328048_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 116 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1453562 and SRA study SRP691918. Searching any of these in the dataset finder brings you back here.

Study design
13 conditions, mostly in duplicate
6138-AB ×4 6726-JF ×3 6788-JF ×3 6178-AB ×2 6359-AB ×2 6372-AB ×2 6458-JF ×2 6636-JF ×2 +15 more

Supports a between-group comparison across 30 samples.

13 replicated groups read from the first 40 of 116 sample titles; they account for 30 of them. Check it against the sample list below before relying on it.

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