Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Geriatric, Renmin Hospital of Wuhan University, Wuhan, China.
Front Immunol. 2023 May 23;14:1158648. doi: 10.3389/fimmu.2023.1158648. eCollection 2023.
Endoplasmic reticulum stress (ERS) is a critical factor in the development of ulcerative colitis (UC); however, the underlying molecular mechanisms remain unclear. This study aims to identify pivotal molecular mechanisms related to ERS in UC pathogenesis and provide novel therapeutic targets for UC.
Colon tissue gene expression profiles and clinical information of UC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database, and the ERS-related gene set was downloaded from GeneCards for analysis. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal modules and genes associated with UC. A consensus clustering algorithm was used to classify UC patients. The CIBERSORT algorithm was employed to evaluate the immune cell infiltration. Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. The external sets were used to validate and identify the relationship of ERS-related genes with biologics. Small molecule compounds were predicted using the Connectivity Map (CMap) database. Molecular docking was performed to simulate the binding conformation of small molecule compounds and key targets.
The study identified 915 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) from the colonic mucosa of UC patients and healthy controls, and these genes had good diagnostic value and were highly correlated. Five potential small-molecule drugs sharing tubulin inhibitors were identified, including albendazole, fenbendazole, flubendazole, griseofulvin, and noscapine, among which noscapine exhibited the highest correlation with a high binding affinity to the targets. Active UC and 10 ERSRGs were associated with a large number of immune cells, and ERS was also associated with colon mucosal invasion of active UC. Significant differences in gene expression patterns and immune cell infiltration abundance were observed among ERS-related subtypes.
The results suggest that ERS plays a vital role in UC pathogenesis, and noscapine may be a promising therapeutic agent for UC by affecting ERS.
内质网应激（ERS）是溃疡性结肠炎（UC）发病的关键因素，但其中的分子机制尚不清楚。本研究旨在确定与 UC 发病机制中 ERS 相关的关键分子机制，并为 UC 提供新的治疗靶点。
从基因表达综合数据库（GEO）中获取 UC 患者和健康对照的结肠组织基因表达谱和临床信息，并从 GeneCards 下载 ERS 相关基因集进行分析。采用加权基因共表达网络分析（WGCNA）和差异表达分析鉴定与 UC 相关的关键模块和基因。采用共识聚类算法对 UC 患者进行分类。采用 CIBERSORT 算法评估免疫细胞浸润。采用基因集变异分析（GSVA）、基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析探讨潜在的生物学机制。采用外部数据集验证和鉴定 ERS 相关基因与生物制剂的关系。利用 Connectivity Map（CMap）数据库预测小分子化合物。采用分子对接模拟小分子化合物与关键靶标的结合构象。
本研究从 UC 患者和健康对照的结肠黏膜中鉴定出 915 个差异表达基因（DEGs）和 11 个 ERS 相关基因（ERSRGs），这些基因具有良好的诊断价值且相关性高。鉴定出 5 种潜在的具有相似微管蛋白抑制剂作用的小分子药物，包括阿苯达唑、芬苯达唑、氟苯达唑、灰黄霉素和罂粟碱，其中罂粟碱与靶标具有最高的相关性且结合亲和力高。活跃性 UC 和 10 个 ERSRGs 与大量免疫细胞相关，ERS 也与活跃性 UC 的结肠黏膜浸润有关。ERS 相关亚型之间的基因表达模式和免疫细胞浸润丰度存在显著差异。
研究结果表明，ERS 在 UC 发病机制中起重要作用，罂粟碱可能通过影响 ERS 成为治疗 UC 的有前途的药物。
