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Minimally invasive 1 mm skin biopsies capture regional transcriptomic heterogeneity in vitiligo

ABSTRACT: Vitiligo is an autoimmune depigmentation disorder characterized by melanocyte loss and complex immune dysregulation. Despite therapeutic advances, variable efficacy and frequent relapse highlight the need for deeper insight into its pathophysiology. Conventional 3–5 mm skin biopsies are invasive and require suturing, limiting their use in clinical and translational research. Here, we demonstrate that minimally invasive 1 mm punch biopsies yield adequate RNA compatible with bulk transcriptomic profiling and enable comprehensive molecular characterization of vitiligo skin. RNA sequencing of 105 biopsies spanning lesional, perilesional, non-lesional, and control skin revealed distinct region-specific transcriptional signatures involving interferon signaling, immune activation, and metabolic reprogramming. Beyond canonical melanocyte and immune pathways, we identify underexplored dysregulation of cellular clearance and structural regulatory mechanisms, implicating ferroptosis, peroxisome, and efferocytosis pathways in lesion persistence. Connectivity Map analysis further predicted candidate compounds capable of reversing the lesional transcriptional signature, pointing to epigenetic regulators, tyrosine kinase inhibitors, and metabolic modulators. These findings establish 1 mm skin biopsies as a feasible and biologically informative tool for minimally invasive molecular profiling and highlight new therapeutic axes in vitiligo pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311770 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Background: Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being FDA-approved. Although vitiligo is primarily regarded as a Th1/IFN-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. Objective: To obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. Results: Robust inflammatory dysregulation was captured not only in lesional, but also nonlesional vitiligo skin relative to healthy controls. Lesional samples demonstrated upregulation of Th1 (OASL, CXCL9, CXCL10), Th2 (IL4, IL4R, CCL13, CCL17, CCL22, CCL26), and Th17/22 (IL20, S100A7, S100A8, S100A9, PI3) related markers. Similarly, nonlesional samples demonstrated activation of Th1 (CXCL9, OASL), Th2 (IL4R, IL10, CCL13, CCL17, CCL22), and Th17/22 (PI3, DEFB4A) associated markers. Clinical severity scores (VASI and/or VIDA) significantly and positively correlated with multiple inflammatory mediators (i.e., CXCL14, IL25, IL17RC) in lesional and/or nonlesional vitiligo skin. On a single-cell level, IL13 and IFNG expression were primarily found in nonlesional helper T cells and in lesional proliferating T cells, respectively. Conclusions: Our findings show that immune dysregulation in vitiligo involves immune axes beyond Th1/Tc1, with upregulation of particularly type 2 markers already in nonlesional skin, suggesting a role during early lesion formation. Capsule Summary: We suggest that the inflammatory dysregulation of vitiligo is more complex than previously appreciated, involving not only Th1, but also Th2 and some components of Th17/22 immune axes, even in clinically normal appearing skin. Clinical implications: The dysregulation of multiple inflammatory mediators in nonlesional vitiligo skin might have major implications for future targeted treatment approaches.

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Minimally invasive 1 mm skin biopsies capture regional transcriptomic heterogeneity in vitiligo

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