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
{"title":"Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11.","authors":"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","doi":"10.1038/s44318-025-00507-z","DOIUrl":null,"url":null,"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.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"3 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The EMBO Journal","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s44318-025-00507-z","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.
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