Clinical, cosmetic and investigational dermatology · 2026
JAK Activation Drives MED15-Associated Melanocyte Dysfunction in Vitiligo Beyond Immune Cells.
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Wu Jize, Ren Yijia, Cui Jiahao, He Mingjie, Zhang Xiaoyu, Li Dingding, Zhang Na
Аннотация
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.
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.