文献类型：期刊文献

英文题名：FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach

作者：Lu, Weiqiang[1,2,3];Cheng, Feixiong[3];Jiang, Jing[3];Zhang, Chen[3];Deng, Xiaokang[3];Xu, Zhongyu[3];Zou, Shien[4];Shen, Xu[3,5];Tang, Yun[3];Huang, Jin[3]

机构：[1]E China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China;[2]E China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China;[3]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[4]Fudan Univ, Obstet & Gynecol Hosp, Dept Gynecol, Shanghai 200011, Peoples R China;[5]Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

年份：2015

卷号：5

外文期刊名：SCIENTIFIC REPORTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000348501100005)】；

基金：This work was supported by the National Natural Science Foundation of China (Grants 81102420, 81200415, 81373329 and 81402482), the Shanghai Committee of Science and Technology (Grant 11DZ2260600 and 14ZR1411100), China Postdoctoral Science Foundation grant (2014M551361), the Shanghai Municipal Commission of Health and Family Planning (No. 20124468) and Fudan University (No. 20520133421) and the Fundamental Research Funds for the Central Universities (Grant WY1113007).

语种：英文

摘要：Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics.