Wang Yingwei, Yao Tao, Lin Yunlu, Wu Jianming
Department of Dermatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China.
Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China.
Clin Cosmet Investig Dermatol. 2025 May 27;18:1281-1295. doi: 10.2147/CCID.S523231. eCollection 2025.
Vitiligo is an autoimmune, hypopigmented dermatological disease for which the pathogenesis remains unclear. With limited therapeutic options, it has a significant treatment burden and adverse psychological effects for patients.
The core method employed was Mendelian randomization (MR), which was used to assess the impact of over 2,000 plasma proteins on generalized vitiligo. To further enhance the reliability of the MR conclusions, we conducted a series of comprehensive analyses, including reverse MR, the Steiger test, colocalization analysis, and phenotype scanning. Subsequently, we employed Phenome-wide MR (PheW-MR) analysis to exclude targets associated with adverse effects and evaluated the druggability of these targets through drug gene list mapping and molecular docking. Additionally, we employed protein-protein interaction (PPI) analysis to elucidate the interactions between the target proteins and existing vitiligo treatments. Finally, pathway enrichment analysis and transcriptome-proteome correlation analysis provided further biological insight into the target proteins.
Following a series of comprehensive analyses, we identified three potential drug targets for the treatment of vitiligo: GZMB, FCRL3, and ULK3, each of which is associated with an increased risk of the disease. Validation across different cohorts confirmed the significance of GZMB and FCRL3. Colocalization analysis indicated that these targets share common variants with vitiligo, while PheW-MR analysis suggested that targeting these proteins would not result in significant side effects. Furthermore, molecular docking demonstrated stable binding between the target proteins and predicted drugs. The PPI network revealed that GZMB, FCRL3, and ULK3 interact with the target proteins of existing vitiligo treatments.
Our study has identified three promising drug target proteins for the treatment of vitiligo, which merit prioritization in drug development efforts. These targets warrant further investigation to elucidate their underlying mechanisms.
白癜风是一种自身免疫性色素减退性皮肤病，其发病机制尚不清楚。由于治疗选择有限，它给患者带来了巨大的治疗负担和不良心理影响。
采用的核心方法是孟德尔随机化（MR），用于评估2000多种血浆蛋白对泛发性白癜风的影响。为进一步提高MR结论的可靠性，我们进行了一系列综合分析，包括反向MR、斯泰格检验、共定位分析和表型扫描。随后，我们采用全表型组孟德尔随机化（PheW-MR）分析来排除与不良反应相关的靶点，并通过药物基因列表映射和分子对接评估这些靶点的可成药性。此外，我们采用蛋白质-蛋白质相互作用（PPI）分析来阐明目标蛋白与现有白癜风治疗方法之间的相互作用。最后，通路富集分析和转录组-蛋白质组相关性分析为目标蛋白提供了进一步的生物学见解。
经过一系列综合分析，我们确定了三种治疗白癜风的潜在药物靶点：颗粒酶B（GZMB）、FCRL3和ULK3，每一种都与疾病风险增加相关。在不同队列中的验证证实了GZMB和FCRL3的重要性。共定位分析表明，这些靶点与白癜风共享常见变异，而PheW-MR分析表明，针对这些蛋白质不会导致明显的副作用。此外，分子对接证明了目标蛋白与预测药物之间的稳定结合。PPI网络显示，GZMB、FCRL3和ULK3与现有白癜风治疗方法的目标蛋白相互作用。
我们的研究确定了三种有前景的治疗白癜风的药物靶点蛋白，值得在药物开发工作中优先考虑。这些靶点值得进一步研究以阐明其潜在机制。
