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

Nature Reviews Immunology volume 25, pages 558–568 (2025)Cite this article

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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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Fig. 1: Sequence and domain structure of the noncanonical inflammasome caspases.
Fig. 2: The noncanonical inflammasome pathway.
Fig. 3: Caspase-4 structure and substrate recognition.

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Acknowledgements

This work was supported in part by National Institutes of Health (NIH) grants CA240955 (to J.L.), and AI182369 and CA287076 (to H.W. and J.L.).

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  1. Ventus Therapeutics, Waltham, MA, USA

    Elad Elkayam, Francois G. Gervais & Michael A. Crackower

  2. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, USA

    Hao Wu & Judy Lieberman

  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Hao Wu

  4. Department of Paediatrics, Harvard Medical School, Boston, MA, USA

    Judy Lieberman

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Correspondence to Michael A. Crackower or Judy Lieberman.

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Elkayam, E., Gervais, F.G., Wu, H. et al. New insights into the noncanonical inflammasome point to caspase-4 as a druggable target. Nat Rev Immunol 25, 558–568 (2025). https://doi.org/10.1038/s41577-025-01142-9

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