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

Elad Elkayam; Francois G Gervais; Hao Wu; Michael A Crackower; Judy Lieberman

doi:10.1038/s41577-025-01142-9

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

Nat Rev Immunol. 2025 Mar 5. doi: 10.1038/s41577-025-01142-9. Online ahead of print.

Authors

Elad Elkayam¹, Francois G Gervais¹, Hao Wu^{2

3}, Michael A Crackower⁴, Judy Lieberman^{5

6}

Affiliations

¹ Ventus Therapeutics, Waltham, MA, USA.
² Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
⁴ Ventus Therapeutics, Waltham, MA, USA. mcrackower@ventustx.com.
⁵ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. Judy.Lieberman@childrens.harvard.edu.
⁶ Department of Paediatrics, Harvard Medical School, Boston, MA, USA. Judy.Lieberman@childrens.harvard.edu.

PMID: 40044809
DOI: 10.1038/s41577-025-01142-9

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.

Publication types

Review