Drug Repositioning of Inflammatory Bowel Disease Based on Co-Target Gene Expression Signature of Glucocorticoid Receptor and TET2

文献类型： 外文期刊

第一作者： Zhao, Xianglin

作者： Zhao, Xianglin;Hu, Chenghao;Chen, Xinyu;Ren, Shuqiang;Gao, Fei;Zhao, Xianglin;Zhao, Xianglin;Chen, Xinyu;Gao, Fei;Gao, Fei

作者机构： Chinese Acad Agr Sci, Agr Genom Inst Shenzhen, Minist Agr & Rural Affairs, Genome Anal Lab, Shenzhen 518000, Peoples R China;Henan Univ, Sch Life Sci, Kaifeng 475004, Peoples R China;Henan Univ, Shenzhen Res Inst, Shenzhen 518000, Peoples R China;Guangxi Univ, Coll Anim Sci & Technol, Nanning 530004, Peoples R China;Chinese Acad Sci, Zhejiang Canc Hosp, Hangzhou Inst Med HIM, HIM BGI Omics Ctr, Hangzhou 310022, Peoples R China;Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet & Anim Sci, Comparat Pediat & Nutr, DK-2100 Copenhagen, Denmark

关键词： IBD; GR; TET2; drug repositioning; in vitro inflammatory model

期刊名称：BIOLOGY-BASEL （ 2022影响因子：4.2； 五年影响因子：4.4 ）

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年卷期： 2024 年 13 卷 2 期

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收录情况： SCI

摘要： Simple Summary Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), impacts millions globally and is characterized by complex immune responses. This research aimed to unravel the collaborative roles of two critical protein factors in immune regulation within IBD. Through extensive analysis of public datasets, we identified specific gene signatures associated with these factors in IBD. Subsequent drug repositioning efforts and the utilization of cellular models led to the identification of BMS-536924 as a promising anti-inflammatory agent. This investigation has enriched our understanding of IBD's pathogenesis and suggests novel therapeutic approaches to enhance the quality of life for individuals affected by these inflammatory conditions.Abstract The glucocorticoid receptor (GR) and ten-eleven translocation 2 (TET2), respectively, play a crucial role in regulating immunity and inflammation, and GR interacts with TET2. However, their synergetic roles in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), remain unclear. This study aimed to investigate the co-target gene signatures of GR and TET2 in IBD and provide potential therapeutic interventions for IBD. By integrating public data, we identified 179 GR- and TET2-targeted differentially expressed genes (DEGs) in CD and 401 in UC. These genes were found to be closely associated with immunometabolism, inflammatory responses, and cell stress pathways. In vitro inflammatory cellular models were constructed using LPS-treated HT29 and HCT116 cells, respectively. Drug repositioning based on the co-target gene signatures of GR and TET2 derived from transcriptomic data of UC, CD, and the in vitro model was performed using the Connectivity Map (CMap). BMS-536924 emerged as a top therapeutic candidate, and its validation experiment within the in vitro inflammatory model confirmed its efficacy in mitigating the LPS-induced inflammatory response. This study sheds light on the pathogenesis of IBD from a new perspective and may accelerate the development of novel therapeutic agents for inflammatory diseases including IBD.

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