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Repurposing TAK875 as a novel STAT3 inhibitor for treating inflammatory bowel disease

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机构： [1]Department of Gastroenterology and Hepatology, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2]State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.

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关键词： TAK875 Anti-inflammatory ROS STAT3 Inflammatory bowel disease

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Inflammatory bowel disease (IBD) is a chronic immune-mediated disease associated with a high recurrence rate and an elevated risk of colon cancer. In this study, we screened a bioactive compound library using a luciferase reporter assay and identified the compound TAK875 as a novel inhibitor of signal transducer and activator of transcription 3 (STAT3). Surface plasmon resonance analysis, differential scanning fluorimetry, and isothermal titration calorimetry demonstrated that TAK875 directly bound to recombinant STAT3. TAK875 suppressed the lipopolysaccharide (LPS)-induced release of nitric oxide, inducible nitric oxide synthase, and inflammatory factors in RAW264.7 cells, likely by inhibiting STAT3 phosphorylation. In addition, TAK875 inhibited the differentiation of CD4+ T cells into T-helper 17 cells, which may partially account for its anti-inflammatory effect. TAK875 also alleviated the LPS-induced accumulation of intracellular reactive oxygen species, thus displaying its antioxidant effects. Finally, we demonstrated its satisfactory anti-inflammatory effect in a dextran sulfate sodium-induced mouse model of ulcerative colitis. In conclusion, this study presented TAK875 as a novel STAT3 inhibitor and demonstrated its anti-inflammatory and antioxidant effects both in vitro and in vivo.Copyright © 2023 Elsevier Inc. All rights reserved.

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出版当年[2023]版：

大类 | 2 区医学

小类 | 2 区药学

最新[2023]版：

大类 | 2 区医学

小类 | 2 区药学

第一作者：

第一作者机构： [1]Department of Gastroenterology and Hepatology, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2]State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.

通讯作者：

通讯机构： [1]Department of Gastroenterology and Hepatology, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2]State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.

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Repurposing TAK875 as a novel STAT3 inhibitor for treating inflammatory bowel disease

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