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Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11

Malvina Pizzuto1,2,3, Mercedes Monteleone4, Sabrina Sofia Burgener4

  • 1Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia. m.pizzuto@uq.edu.au.

The EMBO Journal
|July 16, 2025
PubMed

Insights

Mitochondrial cardiolipin selectively inhibits caspase-4/11 (CASP4/11) to block lipopolysaccharide (LPS)-induced inflammation. This discovery offers a new tool for studying CASP4/11 and developing treatments for LPS-related diseases.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Caspase-4 and caspase-11 (CASP4/11) are key sensors of bacterial lipopolysaccharide (LPS).
  • Existing CASP4/11 inhibitors also affect caspase-1 (CASP1), limiting research and therapeutic applications for LPS-linked diseases.
  • There is a need for selective inhibitors to study CASP4/11 functions and develop targeted therapies.

Purpose of the Study:

  • To identify a selective inhibitor of CASP4/11 activity.
  • To investigate the mechanism of selective inhibition by cardiolipin.
  • To evaluate the therapeutic potential of cardiolipin in LPS-induced inflammation.

Main Methods:

  • Identification of mitochondrial cardiolipin as a selective inhibitor.
  • Biochemical assays to determine cardiolipin's interaction with the CARD domain of CASP4/11.
  • In vivo studies to assess the suppression of LPS-induced systemic inflammation.

Main Results:

  • Mitochondrial cardiolipin selectively inhibits CASP4/11-dependent cell death and inflammatory cytokine secretion.
  • Cardiolipin targets the CARD domain of CASP4/11, preventing LPS binding and activation.
  • Cardiolipin effectively suppresses LPS-induced systemic inflammation in vivo without affecting CASP1.

Conclusions:

  • Cardiolipin is a novel, selective inhibitor of CASP4/11.
  • Cardiolipin provides a valuable tool for studying noncanonical inflammasome pathways.
  • Cardiolipin holds potential for treating LPS-associated inflammatory diseases.

Keywords:
CardiolipinCaspase-11Caspase-4LPSNoncanonical Inflammasome

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