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Review
. 2025 Aug;25(8):558-568.
doi: 10.1038/s41577-025-01142-9. Epub 2025 Mar 5.

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

Elad Elkayam  1 , Francois G Gervais  1 , Hao Wu  2   3 , Michael A Crackower  4 , Judy Lieberman  5   6
Affiliations
Review

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

Elad Elkayam et al. Nat Rev Immunol. 2025 Aug.

Abstract

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.

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Conflict of interest statement

Competing interests: All the authors are associated with Ventus Therapeutics (E.E., F.G.G. and M.A.C. as employees; H.W. and J.L. as cofounders and advisers) and have stock options.

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