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

  • EMBO J. 2025 Aug;44(16):4419-4442. doi: 10.1038/s44318-025-00507-z.
Malvina Pizzuto  1  2  3 ,  Mercedes Monteleone  #  4 ,  Sabrina Sofia Burgener  #  4 ,  Jakub Began  5 ,  Melan Kurera  6 ,  Jing Rong Chia  4 ,  Emmanuelle Frampton  4 ,  Joanna Crawford  4 ,  Monalisa Oliveira  4 ,  Kirsten M Kenney  4 ,  Jared R Coombs  4 ,  Masahiro Yamamoto  7  8 ,  Si Ming Man  6 ,  Petr Broz  5 ,  Pablo Pelegrin  #  9  10 ,  Kate Schroder  #  4
Affiliations
  • 1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia. [email protected].
  • 2. Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain. [email protected].
  • 3. Structure and Function of Biological Membranes Laboratory, Université Libre de Bruxelles, Brussels, Belgium. [email protected].
  • 4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
  • 5. Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
  • 6. Division of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • 7. Department of Immunoparasitology, Research Institute for Microbial Diseases Osaka University, Suita, Osaka, Japan.
  • 8. Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center Osaka University, Suita, Osaka, Japan.
  • 9. Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain.
  • 10. Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Murcia, Spain.
  • # Contributed equally.
PMID: 40670771 DOI: 10.1038/s44318-025-00507-z
Abstract

Caspase-4 and caspase-11 (CASP4/11) sense Bacterial lipopolysaccharide (LPS). Currently available inhibitors of CASP4/11 also block the activity of Caspase-1 (CASP1), which restricts their usefulness in the study of CASP4/11 functions, as well as their clinical potential for the treatment of LPS-linked diseases through CASP4/11 inhibition. Here, we identify mitochondrial cardiolipin as a selective inhibitor of CASP4/11-dependent cell death and inflammatory cytokine secretion, without affecting CASP1 function. Cardiolipin targets the CARD domain of CASP4/11, impeding its interaction with LPS to restrain CASP4/11 activation, thereby suppressing LPS-induced systemic inflammation in vivo. By identifying cardiolipin as a selective inhibitor of CASP4/11, we provide an urgently needed tool for studying caspase-4/11 and noncanonical inflammasome functions in inflammatory pathways and LPS-induced pathogenesis.

Keywords
Cardiolipin; Caspase-11; Caspase-4; LPS; Noncanonical Inflammasome.
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