New insights into the noncanonical inflammasome point to caspase-4 as a druggable target

• Published in: Nature reviews. Immunology Vol. 25; no. 8; pp. 558 - 568
• Main Authors: Elkayam, Elad, Gervais, Francois G., Wu, Hao, Crackower, Michael A., Lieberman, Judy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2025; Nature Publishing Group
• Subjects: 631/250/2520; 631/250/256/2177; Allosteric properties; Animals; Bacteria; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Caspase-11; Caspase-4; Caspases, Initiator - chemistry; Caspases, Initiator - immunology; Caspases, Initiator - metabolism; Cells; Cytokines; Endothelial cells; Gasdermins; Gram-negative bacteria; Humans; Immunology; Inflammasomes; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammation - drug therapy; Inflammation - immunology; Inflammatory diseases; Interleukin 18; Interleukin-18 - metabolism; Leakage; Lipids; Lipopolysaccharides; Mice; Phosphate-Binding Proteins; Progress; Pyroptosis; Recruitment; Therapeutic targets
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/s41577-025-01142-9

Recent studies indicate that the human lipopolysaccharide sensor caspase-4, unlike its mouse homologue caspase-11, is constitutively expressed and activates pro-IL-18 as well as gasdermin D-mediated pyroptosis. Activation of human caspase-4 causes vascular leakage systemically and at the blood–brain barrier in mice and is implicated in the pathogenesis of a range of inflammatory diseases for which there are currently no effective therapies. These results suggest the therapeutic potential of modulating caspase-4 activity, and structural studies indicate that the caspase-4 exosite might be a promising inhibitory target. This Progress article describes recent studies showing that the human lipopolysaccharide sensor caspase-4 activates pro-IL-18 and causes vascular leakage by inducing pyroptosis in endothelial cells. Structural studies have uncovered allosteric sites of caspase-4 that might be effective drug targets to inhibit vascular leakage.