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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月16日

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  • Malvina Pizzuto,
  • Mercedes Monteleone,
  • Sabrina Sofia Burgener,
  • Jakub Began,
  • Melan Kurera,
  • Jing Rong Chia,
  • Emmanuelle Frampton,
  • Joanna Crawford,
  • Monalisa Oliveira,
  • Kirsten M Kenney,
  • Jared R Coombs,
  • Masahiro Yamamoto,
  • Si Ming Man,
  • Petr Broz,
  • Pablo Pelegrin,
  • Kate Schroder

摘要

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.