JAK Activation Drives MED15-Associated Melanocyte Dysfunction in Vitiligo Beyond Immune Cells

Background: Vitiligo is an autoimmune disorder characterized by selective melanocyte loss, largely driven by interferon-gamma (IFN-γ)-induced Janus kinase/signal transducers and activators of transcription (JAK–STAT) activation. While the immune aspects of JAK–STAT signaling are well-documented, its downstream transcriptional mediators within melanocytes remain incompletely understood. Methods: We integrated multi-omics analyses, including cross-tissue and single-tissue transcriptome-wide association studies (TWAS), conditional and joint analysis (COJO), and summary data-based Mendelian randomization (SMR), using genome-wide association study (GWAS) data comprising 391 vitiligo cases and 465,673 controls. These were combined with single-cell RNA sequencing (scRNA-seq) data from 15 samples (10 vitiligo lesions and 5 healthy controls) and in vitro functional assays to identify causal JAK-responsive genes associated with vitiligo. Results: Mediator complex subunit 15 (MED15) emerged as a robust gene associated with increased vitiligo risk (significance thresholds were set at P < 0.05, with False Discovery Rate [FDR] corrections detailed in Supplementary Data ). Single-cell transcriptomic data revealed significant upregulation of MED15 in melanocytes from lesional skin, positively correlated with STAT1 expression and enrichment of the JAK–STAT pathway. Functional assays confirmed that MED15 overexpression profoundly inhibited melanocyte proliferation and suppressed intrinsic melanin synthesis, both of which were significantly reversed by JAK inhibition with Ruxolitinib. Furthermore, dual-luciferase reporter assays confirmed that MED15 is a direct transcriptional target of STAT1, governed by upstream JAK signaling. Conclusion: MED15 functions as a JAK-responsive transcriptional cofactor contributing to melanocyte proliferation and melanogenesis dysfunction in vitiligo. These findings establish a direct STAT1–MED15 transcriptional axis driving melanocyte injury, offering new insights into transcriptional mechanisms and potential therapeutic targets. MED15 may represent a complementary therapeutic target alongside JAK inhibition.