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

Xinlian He; Xupeng Gou; Dongmei Fan; Jiaxing Yang; Xinyuan Fu; Youfu Luo; Tao Yang

doi:10.1016/j.bcp.2023.115957

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

Biochem Pharmacol. 2024 Jan:219:115957. doi: 10.1016/j.bcp.2023.115957. Epub 2023 Dec 2.

Authors

Xinlian He¹, Xupeng Gou², Dongmei Fan³, Jiaxing Yang², Xinyuan Fu³, Youfu Luo⁴, Tao Yang⁵

Affiliations

¹ Department of Gastroenterology and Hepatology, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, 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 Department of Gastroenterology and Hepatology, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
⁴ State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: luo_youfu@scu.edu.cn.
⁵ Department of Gastroenterology and Hepatology, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangtao@wchscu.cn.

PMID: 38049007
DOI: 10.1016/j.bcp.2023.115957

Abstract

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.

Keywords: Anti-inflammatory; Inflammatory bowel disease; ROS; STAT3; TAK875.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology
Antioxidants / pharmacology
Inflammatory Bowel Diseases* / drug therapy
Lipopolysaccharides
Mice
NF-kappa B / metabolism
STAT3 Transcription Factor* / antagonists & inhibitors
Signal Transduction*

Substances

Anti-Inflammatory Agents
Antioxidants
Lipopolysaccharides
NF-kappa B
STAT3 Transcription Factor
TAK-875