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

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, induce visible scars and require suturing, limiting their use in clinical and translational research. Here, we demonstrate that minimally invasive 1 mm punch biopsies yield adequate RNA for bulk transcriptomic profiling, enabling 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.