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The role of RIPK1 mediated cell death in acute on chronic liver failure

Takayuki Kondo1,2, Stewart Macdonald1, Cornelius Engelmann1,3,4

  • 1Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.

Cell Death & Disease
|December 18, 2021
PubMed

Insights

This study reveals that RIPK1-mediated necroptosis is crucial in acute-on-chronic liver failure (ACLF). Inhibiting RIPK1 shows potential as a novel therapy to prevent ACLF progression and reduce organ damage.

Area of Science:

  • Hepatology
  • Cell Death Mechanisms
  • Immunology

Background:

  • Acute-on-chronic liver failure (ACLF) involves significant hepatocyte death, often non-apoptotic.
  • Necroptosis, a programmed lytic cell death pathway, is mediated by RIPK1, RIPK3, and pMLKL.

Purpose of the Study:

  • To investigate the role of RIPK1-mediated cell death in the pathogenesis of ACLF.
  • To evaluate RIPK1 inhibitors as a potential therapeutic strategy for ACLF.

Main Methods:

  • Measured RIPK3 plasma levels and hepatic expression of RIPK1, RIPK3, and pMLKL in human cohorts (healthy, cirrhosis, ACLF).
  • Utilized rodent models of ACLF (LPS in bile-duct ligated rats, CCL4/GalN in mice) to assess necroptosis.
  • Administered RIPK1 inhibitors (necrostatin-1, RIPA56) in animal models to evaluate therapeutic efficacy.

Main Results:

  • Plasma RIPK3 levels predicted mortality and ACLF progression in patients, validated in a second cohort.
  • ACLF rodent models showed suppressed caspase-8 activity, indicating a shift towards necroptosis.
  • RIPK1 inhibition (NEC-1, RIPA56) significantly reduced liver, kidney, and brain injury in ACLF models.

Conclusions:

  • RIPK1-mediated necroptosis plays a significant role in both human and rodent ACLF.
  • Inhibiting RIPK1 represents a promising therapeutic avenue for preventing ACLF development and progression.

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