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GPX1和RCN1作为多发性硬化症脑组织中与内质网应激相关的新生物标志物及其在APP-CD74途径中的作用：一项结合机器学习和多组学的综合研究

GPX1 and RCN1 as New Endoplasmic Reticulum Stress-Related Biomarkers in Multiple Sclerosis Brain Tissue and Their Involvement in the APP-CD74 Pathway: An Integrated Study Combining Machine Learning and Multi-Omics.

作者信息

Qiao Zhixin, Wang Yanping, Ma Xiaoru, Zhang Xiyu, Wu Junfeng, Li Anqi, Wang Chao, Xiu Xin, Zhang Sifan, Lang Xiujuan, Liu Xijun, Sun Bo, Li Hulun, Liu Yumei

机构信息

Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China.

The Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin 150081, China.

出版信息

Int J Mol Sci. 2025 Jun 29;26(13):6286. doi: 10.3390/ijms26136286.

DOI:10.3390/ijms26136286
PMID:40650067
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12249644/
Abstract

This study identified 13 endoplasmic reticulum stress (ERS)-related biomarkers associated with multiple sclerosis (MS) through integrated bioinformatics analysis (including weighted gene co-expression network analysis and machine learning algorithms) and single-cell sequencing, combined with validation in an experimental autoimmune encephalomyelitis (EAE) mouse model. Among them, , , and exhibited high diagnostic value (AUC > 0.7, < 0.05), and the diagnostic potential of and was confirmed in the animal model. The study found that memory B cells, plasma cells, neutrophils, and M1 macrophages were significantly increased in MS patients, while naive B cells and activated NK cells decreased. Consensus clustering based on key ERS-related genes divided MS patients into two subtypes. Single-cell sequencing showed that microglia and pericytes were the cell types with the highest expression of key ERS-related genes, and the APP-CD74 pathway was enhanced in the brain tissue of MS patients. Mendelian randomization analysis suggested that plays a protective role in MS. These findings reveal the mechanisms of ERS-related biomarkers in MS and provide potential targets for diagnosis and treatment.

摘要

本研究通过综合生物信息学分析（包括加权基因共表达网络分析和机器学习算法）和单细胞测序，并结合实验性自身免疫性脑脊髓炎（EAE）小鼠模型进行验证，鉴定出13种与多发性硬化症（MS）相关的内质网应激（ERS）生物标志物。其中， 、 和 表现出较高的诊断价值（AUC>0.7， <0.05），并且 和 在动物模型中得到了诊断潜力的证实。研究发现，MS患者的记忆B细胞、浆细胞、中性粒细胞和M1巨噬细胞显著增加，而幼稚B细胞和活化NK细胞减少。基于关键ERS相关基因的一致性聚类将MS患者分为两个亚型。单细胞测序表明，小胶质细胞和周细胞是关键ERS相关基因表达最高的细胞类型，并且APP-CD74途径在MS患者的脑组织中增强。孟德尔随机化分析表明， 在MS中起保护作用。这些发现揭示了ERS相关生物标志物在MS中的机制，并为诊断和治疗提供了潜在靶点。

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