Integrating Multiomic Mendelian Randomization, Microarray, Single-Cell RNA Sequencing, and Spatial RNA Sequencing to Identify Potential Therapeutic Targets for Vitiligo.

Vitiligo is a chronic skin disorder characterized by the selective destruction of melanocytes. Current treatments, such as topical steroids, tacrolimus, systemic steroids, and phototherapy, often yield suboptimal efficacy, underscoring the urgent need for more effective therapeutic targets. To identify potential drug targets, we conducted multiomics Mendelian randomization analyses using quantitative trait loci data for 4479 druggable genes in combination with vitiligo GWAS data from the GWAS Catalog and the FinnGen consortium. Among these candidates, CTSS demonstrated the highest therapeutic potential after comprehensive validation. Clinical samples and bioinformatics analyses revealed that CTSS was upregulated in melanocytes from vitiligo lesions and halo nevi. Single-cell and spatial transcriptomic sequencing further indicated that elevated CTSS expression was associated with increased infiltration of antigen-presenting cells and CD8+ T cells and strongly correlated with immunogenic cell death. In vitro experiments confirmed that oxidative stress promotes CTSS expression through IRF1, leading to the release of damage-associated molecular patterns. In conclusion, oxidative stress-mediated CTSS upregulation through IRF1 may drive autoantigen exposure, damage-associated molecular pattern release, enhanced antigen presentation, and antigen-presenting cell activation, thereby triggering autoimmune responses and immunogenic cell death, ultimately contributing to vitiligo pathogenesis. Inhibiting CTSS could offer a potential therapeutic approach for vitiligo.