Comprehensive Analysis of Uric Acid and Myasthenia Gravis: IGF1R as a Protective Factor and Potential Therapeutic Target

IF 5 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2025-03-28 DOI:10.1111/cns.70361

Yu Shen, Lijun Pang, Han Wang, Qili Han, Wang Wan, Si Luo, Ziwei Song, Yaofeng Fang, Hao Chen, Yusen Qiu, Dandan Tan, Meihong Zhou, Daojun Hong

{"title":"Comprehensive Analysis of Uric Acid and Myasthenia Gravis: IGF1R as a Protective Factor and Potential Therapeutic Target","authors":"Yu Shen, Lijun Pang, Han Wang, Qili Han, Wang Wan, Si Luo, Ziwei Song, Yaofeng Fang, Hao Chen, Yusen Qiu, Dandan Tan, Meihong Zhou, Daojun Hong","doi":"10.1111/cns.70361","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Previous studies have suggested that oxidative stress can significantly damage acetylcholine receptors (AChRs), which are implicated in the pathogenesis of myasthenia gravis (MG). Uric acid (UA), a scavenger of peroxynitrite and a natural antioxidant, plays a crucial role in eliminating free radicals in the bloodstream. However, the relationship between UA and MG, as well as the underlying mechanisms, remains insufficiently explored.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>A meta-analysis was conducted to evaluate the clinical correlation between UA and MG. Subsequently, Mendelian randomization (MR) and bioinformatics analyses were employed to identify the key protein IGF1R. Public datasets, such as TCGA and GEO, along with patient data from our clinical center, were used for a comprehensive analysis of the relationship between IGF1R and UA in MG patients. Additionally, virtual screening and molecular docking were performed to identify small molecules that target IGF1R as potential therapeutic agents for MG.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The meta-analysis revealed a significant association between low UA levels and MG (OR −48.46 [95% CI −63.26, −33.65], <i>p</i> < 0.00001). The two-sample MR analysis indicated a genetic relationship between UA and MG (<i>p</i> = 0.024; <i>p</i> = 0.036). The FUMA analysis and enrichment analysis identified IGF1R as a key protein likely involved in this relationship. Using the thymoma dataset from the TCGA database, we analyzed IGF1R expression in the MG and non-MG groups and found that IGF1R expression was lower in MG patients and was associated with a poor prognosis (<i>p</i> < 0.05). Single-cell RNA-seq data from the GEO database further supported the association between low IGF1R expression and MG, as well as the occurrence of crisis (<i>p</i> < 0.05). Additionally, data from MG patients treated at our center showed that IGF1R expression correlated with UA levels and that higher IGF1R expression was associated with milder clinical phenotypes (ocular phenotypes). Through a virtual screen and molecular docking of small molecules in the DrugBank database, we identified several potential small-molecule drugs that may target IGF1R to treat MG.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our study revealed an association between low UA levels and MG and subsequently showed that low IGF1R expression is associated with the onset, severity, and poor prognosis of MG. We also explored the molecular mechanisms underlying the protective role of IGF1R in MG and identified potential drugs for treating MG.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":5.0000,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70361","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70361","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Previous studies have suggested that oxidative stress can significantly damage acetylcholine receptors (AChRs), which are implicated in the pathogenesis of myasthenia gravis (MG). Uric acid (UA), a scavenger of peroxynitrite and a natural antioxidant, plays a crucial role in eliminating free radicals in the bloodstream. However, the relationship between UA and MG, as well as the underlying mechanisms, remains insufficiently explored.

Methods

A meta-analysis was conducted to evaluate the clinical correlation between UA and MG. Subsequently, Mendelian randomization (MR) and bioinformatics analyses were employed to identify the key protein IGF1R. Public datasets, such as TCGA and GEO, along with patient data from our clinical center, were used for a comprehensive analysis of the relationship between IGF1R and UA in MG patients. Additionally, virtual screening and molecular docking were performed to identify small molecules that target IGF1R as potential therapeutic agents for MG.

Results

The meta-analysis revealed a significant association between low UA levels and MG (OR −48.46 [95% CI −63.26, −33.65], p < 0.00001). The two-sample MR analysis indicated a genetic relationship between UA and MG (p = 0.024; p = 0.036). The FUMA analysis and enrichment analysis identified IGF1R as a key protein likely involved in this relationship. Using the thymoma dataset from the TCGA database, we analyzed IGF1R expression in the MG and non-MG groups and found that IGF1R expression was lower in MG patients and was associated with a poor prognosis (p < 0.05). Single-cell RNA-seq data from the GEO database further supported the association between low IGF1R expression and MG, as well as the occurrence of crisis (p < 0.05). Additionally, data from MG patients treated at our center showed that IGF1R expression correlated with UA levels and that higher IGF1R expression was associated with milder clinical phenotypes (ocular phenotypes). Through a virtual screen and molecular docking of small molecules in the DrugBank database, we identified several potential small-molecule drugs that may target IGF1R to treat MG.

Conclusions

Our study revealed an association between low UA levels and MG and subsequently showed that low IGF1R expression is associated with the onset, severity, and poor prognosis of MG. We also explored the molecular mechanisms underlying the protective role of IGF1R in MG and identified potential drugs for treating MG.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

尿酸与重症肌无力的综合分析：IGF1R作为保护因子和潜在的治疗靶点

背景已有研究表明氧化应激可显著损伤乙酰胆碱受体（achr），其与重症肌无力（MG）的发病机制有关。尿酸（UA）是一种过氧亚硝酸盐的清除剂和天然抗氧化剂，在消除血液中的自由基方面起着至关重要的作用。然而，UA和MG之间的关系以及潜在的机制仍然没有得到充分的探讨。方法采用meta分析评价UA与MG的临床相关性。随后，采用孟德尔随机化（MR）和生物信息学分析来鉴定关键蛋白IGF1R。公共数据集，如TCGA和GEO，以及我们临床中心的患者数据，被用于全面分析MG患者中IGF1R和UA之间的关系。此外，还进行了虚拟筛选和分子对接，以确定靶向IGF1R的小分子作为MG的潜在治疗剂。结果荟萃分析显示，低UA水平与MG之间存在显著相关性（OR = 48.46 [95% CI = 63.26, - 33.65], p < 0.00001）。双样本MR分析显示UA和MG之间存在遗传关系(p = 0.024；p = 0.036)。fua分析和富集分析确定IGF1R是可能参与这种关系的关键蛋白。利用TCGA数据库中的胸腺瘤数据，我们分析了MG组和非MG组中IGF1R的表达，发现MG患者中IGF1R表达较低，且与预后不良相关（p < 0.05）。GEO数据库的单细胞RNA-seq数据进一步支持IGF1R低表达与MG以及危机发生之间的关联（p < 0.05）。此外，我们中心治疗的MG患者的数据显示，IGF1R表达与UA水平相关，较高的IGF1R表达与较轻的临床表型（眼部表型）相关。通过对DrugBank数据库中的小分子进行虚拟筛选和分子对接，我们发现了几种可能靶向IGF1R治疗MG的潜在小分子药物。我们的研究揭示了低UA水平与MG之间的关联，随后表明低IGF1R表达与MG的发病、严重程度和不良预后相关。我们还探索了IGF1R在MG中保护作用的分子机制，并确定了治疗MG的潜在药物。

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分钟内获得全文去求助

来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.