Shen Yu, Pang Lijun, Wang Han, Han Qili, Wan Wang, Luo Si, Song Ziwei, Fang Yaofeng, Chen Hao, Qiu Yusen, Tan Dandan, Zhou Meihong, Hong Daojun
Department of Neurology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
College of Pharmacy, Guangxi Medical University, Nanning, China.
CNS Neurosci Ther. 2025 Mar;31(3):e70361. doi: 10.1111/cns.70361.
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.
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.
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.
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.
先前的研究表明，氧化应激可显著损害乙酰胆碱受体（AChR），而乙酰胆碱受体与重症肌无力（MG）的发病机制有关。尿酸（UA）作为过氧亚硝酸盐的清除剂和天然抗氧化剂，在清除血液中的自由基方面起着关键作用。然而，UA与MG之间的关系及其潜在机制仍未得到充分探索。
进行一项荟萃分析以评估UA与MG之间的临床相关性。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。利用诸如TCGA和GEO等公共数据集以及我们临床中心的患者数据，对MG患者中IGF1R与UA之间的关系进行全面分析。此外，进行虚拟筛选和分子对接以鉴定靶向IGF1R的小分子作为MG的潜在治疗药物。
荟萃分析显示低UA水平与MG之间存在显著关联（比值比-48.46 [95%置信区间-63.26，-33.65]，p < 0.00001）。两样本MR分析表明UA与MG之间存在遗传关系（p = 0.024；p = 0.036）。FUMA分析和富集分析确定IGF1R是可能参与这种关系的关键蛋白。使用来自TCGA数据库的胸腺瘤数据集，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）。来自GEO数据库的单细胞RNA测序数据进一步支持了低IGF1R表达与MG以及危象发生之间的关联（p < 0.05）。此外，我们中心治疗的MG患者的数据表明，IGF1R表达与UA水平相关，且较高的IGF1R表达与较轻的临床表型（眼肌型表型）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，我们鉴定出几种可能靶向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、严重程度及预后不良相关。我们还探讨了IGF1R在MG中发挥保护作用的分子机制，并鉴定出治疗MG的潜在药物。
