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. Epub 2025 Jul 16.

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.

MeSH terms

  • Animals
  • Cardiolipins* / metabolism
  • Cardiolipins* / pharmacology
  • Caspases* / genetics
  • Caspases* / metabolism
  • Caspases, Initiator* / genetics
  • Caspases, Initiator* / metabolism
  • Humans
  • Inflammasomes* / metabolism
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Lipopolysaccharides* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding

Substances

  • Lipopolysaccharides
  • Inflammasomes
  • Cardiolipins
  • Caspases, Initiator
  • Casp4 protein, mouse
  • Caspases