Multi‐Omics Identifies CTSS as a Susceptibility Gene and Actionable Target That Regulates Melanocyte MHC ‐ II

ABSTRACT

Vitiligo is a common autoimmune disorder characterized by melanocyte loss, yet the molecular mechanisms linking genetic susceptibility to melanocyte dysfunction remain incompletely understood. In this study, we integrated multi‐tissue transcriptome‐wide association studies (TWAS), summary‐data‐based Mendelian randomization (SMR), and colocalization analyses to identify causal genes within vitiligo susceptibility loci. CTSS was prioritized as a candidate susceptibility gene at the 1q21 locus. Single‐cell and bulk RNA sequencing analyses revealed that CTSS was significantly upregulated in lesional melanocytes and associated with an MHC class II‐related transcriptional program. Mechanistically, CTSS expression was induced downstream of IFN‐γ/STAT1 signaling and positively associated with oxidative phosphorylation, suggesting potential metabolic regulation. Functional experiments demonstrated that CTSS overexpression was associated with increased HLA‐DRA expression, enhanced apoptosis, and reduced proliferation in melanocytes. Furthermore, the selective CTSS inhibitor RO5459072 attenuated HLA‐DRA induction in vitro. Clinically, serum CTSS levels were elevated in patients with active vitiligo, showed moderate diagnostic performance for disease activity (AUC = 0.787), and correlated with disease severity. Collectively, these findings suggest that CTSS may serve as a key mediator linking genetic susceptibility, inflammatory signaling, and metabolic status in vitiligo. Rather than establishing melanocytes as professional antigen‐presenting cells, our results indicate that melanocytes may acquire partial immunogenic features under inflammatory stress conditions. This study provides new insights into melanocyte‐intrinsic mechanisms underlying vitiligo pathogenesis and highlights CTSS as a potential therapeutic target for future investigation.