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FXR: Big fish or small fry for drug-induced liver injury?

François Ballet1

  • 1Medicen Paris Region, 3-5, impasse Reille, 75014 Paris, France.

Clinics and Research in Hepatology and Gastroenterology
|January 23, 2016
PubMed

Insights

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause liver injury by inhibiting the Farnesoid X receptor (FXR). This study reveals FXR antagonism as a potential mechanism behind NSAID-induced liver damage, impacting bile acid homeostasis.

Area of Science:

  • Pharmacology
  • Hepatology
  • Molecular Biology

Background:

  • Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation.
  • NSAID-induced liver injury (ILI) is a significant clinical concern.
  • The precise molecular mechanisms underlying NSAID-induced liver injury are not fully understood.

Purpose of the Study:

  • To investigate the potential off-target effects of NSAIDs in liver injury.
  • To identify molecular targets involved in NSAID-induced liver injury.
  • To explore the role of the Farnesoid X receptor (FXR) in NSAID toxicity.

Main Methods:

  • Utilized a systems pharmacology approach integrating network analysis and molecular modeling.
  • Conducted in vitro assays to assess NSAID interactions with FXR.
  • Evaluated the impact of NSAID-FXR antagonism on FXR transcriptional activity.

Main Results:

  • Identified FXR as a potential off-target protein mediating NSAID-induced liver injury.
  • Demonstrated that NSAIDs act as potent FXR antagonists.
  • Showed that NSAIDs inhibit FXR transcriptional activity in vitro.

Conclusions:

  • FXR antagonism by NSAIDs is a potential mechanism contributing to NSAID-induced liver injury.
  • The findings highlight the role of FXR in maintaining liver health and bile acid homeostasis.
  • Further research is warranted to explore therapeutic strategies targeting FXR to mitigate NSAID hepatotoxicity.

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