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

Sci Rep. 2015 Jan 29:5:8114. doi: 10.1038/srep08114.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / pathology*
  • Genetic Predisposition to Disease
  • Hep G2 Cells
  • Humans
  • Ibuprofen / adverse effects
  • Indomethacin / adverse effects
  • Luciferases / metabolism
  • Phosphorylation / drug effects
  • Protein Interaction Maps / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • STAT3 Transcription Factor / metabolism
  • Systems Biology*
  • Transcription, Genetic / drug effects
  • Transcriptional Activation / genetics
  • Two-Hybrid System Techniques


  • Anti-Inflammatory Agents, Non-Steroidal
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • STAT3 Transcription Factor
  • farnesoid X-activated receptor
  • Luciferases
  • Ibuprofen
  • Indomethacin