Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11
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.
Authors
- Pablo Pelegrı́n (ORCID: https://orcid.org/0000-0002-9688-1804)
- Sabrina Sofia Burgener (ORCID: https://orcid.org/0000-0002-9332-7998)
- Kate Schroder (ORCID: https://orcid.org/0000-0001-9261-3805)
- Si Ming Man (ORCID: https://orcid.org/0000-0002-5079-2857)
- Mercedes Monteleone (ORCID: https://orcid.org/0000-0003-0777-3965)
- Petr Brož (ORCID: https://orcid.org/0000-0002-2334-7790)
- Emmanuelle Frampton
- Jakub Began (ORCID: https://orcid.org/0000-0003-3934-3767)
- Masahiro Yamamoto (ORCID: https://orcid.org/0000-0002-6821-2785)
- Malvina Pizzuto (ORCID: https://orcid.org/0000-0001-6330-6937)
- Joanna Crawford (ORCID: https://orcid.org/0000-0003-0786-6889)
- J. Coombs (ORCID: https://orcid.org/0000-0002-1703-1247)
- Melan Kurera (ORCID: https://orcid.org/0009-0004-6901-8505)
- Kirsten Myra Kenney (ORCID: https://orcid.org/0000-0002-0626-0538)
- M. L. Oliveira
- J. K. S. Chia
Institutions
- Australian National University (AU)
- Université Libre de Bruxelles (BE)
- The University of Queensland (AU)
- Instituto Murciano de Investigación Biosanitaria (ES)
- Osaka International University (JP)
- Universidad de Murcia (ES)
- University of Lausanne (CH)
- The University of Osaka (JP)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s44318-025-00507-z
- Citations
- 9
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- National Science Foundation
- Barth Syndrome Foundation
- Novartis Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Curtin University of Technology
- Ministerio de Ciencia e Innovación
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- Agencia Estatal de Investigación