Related Experiment Video

Updated: Jun 12, 2026

Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor
09:21

Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor

Published on: January 4, 2016

A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

Yi Zang1,2, Jingjing Shi1,3, Guanguan Zhao1,3,4

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Nature
|June 10, 2026
PubMed

Insights

A new drug, linafexor, targets the farnesoid X receptor (FXR) with pulsatile activation, improving efficacy and reducing toxicity for liver diseases like NASH and PBC.

Area of Science:

  • Pharmacology
  • Hepatology
  • Drug Discovery

Background:

  • Nuclear receptors, including the farnesoid X receptor (FXR), are key regulators of metabolism.
  • Continuous activation of therapeutic targets can lead to diminished efficacy and significant toxicity.
  • Existing FXR agonists often cause adverse effects due to prolonged receptor engagement.

Purpose of the Study:

  • To develop a novel therapeutic strategy for liver diseases by aligning drug pharmacokinetics with physiological signaling cycles.
  • To engineer a non-bile acid FXR agonist with rapid clearance for pulsatile receptor activation.
  • To evaluate the efficacy and safety of this new approach in preclinical and clinical settings.

Main Methods:

  • Designed linafexor, a potent FXR agonist with rapid systemic clearance.
  • Tested linafexor in preclinical models of metabolic dysfunction-associated steatohepatitis, liver fibrosis, and cholangiopathies.
  • Conducted Phase 1 clinical studies to assess transient FXR pathway engagement and safety.
  • Utilized transcriptomic analyses to compare linafexor's effects with long-acting FXR agonists.

Main Results:

  • Linafexor demonstrated robust efficacy in multiple preclinical liver disease models.
  • Pulsatile FXR activation with linafexor preserved cyclic signaling, avoided receptor downregulation, and prevented transcriptional dysregulation.
  • Phase 1 studies showed transient FXR pathway engagement (FGF19 induction, C4 suppression) with no adverse events.
  • Sustained FXR activation, regardless of compound, was linked to severe toxicity.

Conclusions:

  • Pulsatile FXR activation is a mechanistically sound and clinically viable strategy for treating liver diseases.
  • Linafexor represents a first-in-class therapeutic agent for bile acid-related liver conditions.
  • Drug design focused on pharmacokinetic control can enhance therapeutic index by mimicking natural signaling patterns.

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