Integrative Proteomics and Genomics Identify Novel Biomarkers and Therapeutic Targets in Vitiligo via Mendelian Randomization.

IF 3.5 3区医学 Q1 DERMATOLOGY

Dermatology and Therapy Pub Date : 2025-08-01 Epub Date: 2025-06-19 DOI:10.1007/s13555-025-01448-5

Chenjue Yan, Ling Jiang, Yibo Hu, Ting You, Jing Chen, Songjiang Wu

{"title":"Integrative Proteomics and Genomics Identify Novel Biomarkers and Therapeutic Targets in Vitiligo via Mendelian Randomization.","authors":"Chenjue Yan, Ling Jiang, Yibo Hu, Ting You, Jing Chen, Songjiang Wu","doi":"10.1007/s13555-025-01448-5","DOIUrl":null,"url":null,"abstract":"Introduction: Given that the proteome is a major source of therapeutic targets, we conducted a proteome-wide Mendelian randomization (MR) combined with transcriptome sequencing analysis to identify candidate protein markers and therapeutic targets for vitiligo.Methods: Based on protein quantitative trait loci (pQTLs) and genetic associations with vitiligo obtained from the European Bioinformatics Institute (EBI) database (60 vitiligo cases and 402,672 controls), and the UK Biobank (95 vitiligo cases and 337,064 controls), bidirectional MR and colocalization analyses identified genetically predicted levels of nine proteins collectively linked to vitiligo risk. Based on the RNA-seq data and single-cell RNA-seq data of vitiligo, bioinformatics analysis and model prediction of genes associated with vitiligo progression evaluated the relationship between candidate core proteins and the development of vitiligo.Results: Four proteins (KLF4, MYL4, TNFRSF13C, TNFSF13B) were associated with lower vitiligo risk, while five proteins (ALPI, CDH1, ITGB1, SERPINH1, TNFSF10) were linked to higher risk. Of these, three proteins (KLF4, TNFRSF13C, and TNFSF10) were high priority with the most convincing evidence. Bioinformatics analysis and model prediction of genes associated with vitiligo progression showed these three protein-coding genes were significantly associated with vitiligo occurrence, and their functions were related to cell cycle, apoptosis, oxidative stress, inflammatory response, and immune infiltration. Mechanistically, the expression of these key candidate molecules was regulated by various miRNAs and transcription factors. The druggability assessment and molecular docking identified some drugs targeting these proteins, such as APTO-2535 and butyric acid.Conclusion: KLF4, TNFRSF13C, and TNFSF10 may be involved in regulating the occurrence and development of vitiligo, providing potential targets for improving the diagnosis and treatment of vitiligo.","PeriodicalId":11186,"journal":{"name":"Dermatology and Therapy","volume":" ","pages":"2159-2177"},"PeriodicalIF":3.5000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256375/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Dermatology and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13555-025-01448-5","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"DERMATOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Introduction: Given that the proteome is a major source of therapeutic targets, we conducted a proteome-wide Mendelian randomization (MR) combined with transcriptome sequencing analysis to identify candidate protein markers and therapeutic targets for vitiligo.

Methods: Based on protein quantitative trait loci (pQTLs) and genetic associations with vitiligo obtained from the European Bioinformatics Institute (EBI) database (60 vitiligo cases and 402,672 controls), and the UK Biobank (95 vitiligo cases and 337,064 controls), bidirectional MR and colocalization analyses identified genetically predicted levels of nine proteins collectively linked to vitiligo risk. Based on the RNA-seq data and single-cell RNA-seq data of vitiligo, bioinformatics analysis and model prediction of genes associated with vitiligo progression evaluated the relationship between candidate core proteins and the development of vitiligo.

Results: Four proteins (KLF4, MYL4, TNFRSF13C, TNFSF13B) were associated with lower vitiligo risk, while five proteins (ALPI, CDH1, ITGB1, SERPINH1, TNFSF10) were linked to higher risk. Of these, three proteins (KLF4, TNFRSF13C, and TNFSF10) were high priority with the most convincing evidence. Bioinformatics analysis and model prediction of genes associated with vitiligo progression showed these three protein-coding genes were significantly associated with vitiligo occurrence, and their functions were related to cell cycle, apoptosis, oxidative stress, inflammatory response, and immune infiltration. Mechanistically, the expression of these key candidate molecules was regulated by various miRNAs and transcription factors. The druggability assessment and molecular docking identified some drugs targeting these proteins, such as APTO-2535 and butyric acid.

Conclusion: KLF4, TNFRSF13C, and TNFSF10 may be involved in regulating the occurrence and development of vitiligo, providing potential targets for improving the diagnosis and treatment of vitiligo.

查看原文本刊更多论文

综合蛋白质组学和基因组学通过孟德尔随机化鉴定白癜风的新生物标志物和治疗靶点。

鉴于蛋白质组是白癜风治疗靶点的主要来源，我们进行了蛋白质组范围的孟德尔随机化（MR）结合转录组测序分析，以确定白癜风的候选蛋白质标记和治疗靶点。方法：基于从欧洲生物信息学研究所（EBI）数据库（60例白癜风病例和402,672例对照）和英国生物银行（95例白癜风病例和337,064例对照）中获得的蛋白质数量性状位点（pqtl）和白癜风遗传关联，双向MR和共定位分析确定了与白癜风风险相关的9种蛋白质的遗传预测水平。基于白癜风的RNA-seq数据和单细胞RNA-seq数据，对白癜风进展相关基因进行生物信息学分析和模型预测，评估候选核心蛋白与白癜风发展的关系。结果：4种蛋白（KLF4、MYL4、TNFRSF13C、TNFSF13B）与白癜风风险较低相关，5种蛋白（ALPI、CDH1、ITGB1、SERPINH1、TNFSF10）与白癜风风险较高相关。其中，三种蛋白（KLF4， TNFRSF13C和TNFSF10）具有最令人信服的证据。白癜风进展相关基因的生物信息学分析和模型预测表明，这3个蛋白编码基因与白癜风的发生有显著相关性，其功能与细胞周期、细胞凋亡、氧化应激、炎症反应、免疫浸润等相关。在机制上，这些关键候选分子的表达受到各种mirna和转录因子的调节。通过对APTO-2535和丁酸等靶向蛋白的药物进行了药理评价和分子对接。结论：KLF4、TNFRSF13C和TNFSF10可能参与白癜风的发生发展调控，为改善白癜风的诊断和治疗提供了潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Dermatology and Therapy Medicine-Dermatology

CiteScore

6.00

自引率

8.80%

发文量

187

审稿时长

6 weeks

期刊介绍： Dermatology and Therapy is an international, open access, peer-reviewed, rapid publication journal (peer review in 2 weeks, published 3–4 weeks from acceptance). The journal is dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of dermatological therapies. Studies relating to diagnosis, pharmacoeconomics, public health and epidemiology, quality of life, and patient care, management, and education are also encouraged. Areas of focus include, but are not limited to all clinical aspects of dermatology, such as skin pharmacology; skin development and aging; prevention, diagnosis, and management of skin disorders and melanomas; research into dermal structures and pathology; and all areas of aesthetic dermatology, including skin maintenance, dermatological surgery, and lasers. The journal is of interest to a broad audience of pharmaceutical and healthcare professionals and publishes original research, reviews, case reports/case series, trial protocols, and short communications. Dermatology and Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an International and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of quality research, which may be considered of insufficient interest by other journals. The journal appeals to a global audience and receives submissions from all over the world.