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Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis

Nature作者：Katarzyna M. Groborz2026年8月3日正文已收录本站
  • Article
  • Published:
  • Melissa E. Truong  ORCID: orcid.org/0000-0003-1526-15211 na1,
  • Irma Stowe1,
  • Katherine E. Wickliffe1,
  • Bettina Lee1,
  • Stefan Bauernfried1,
  • Robert S. Jones  ORCID: orcid.org/0000-0002-5283-80702,
  • Emile Plise2,
  • Elizabeth S. Levy3,
  • Ponien Kou  ORCID: orcid.org/0009-0008-2605-13983,
  • Wyne P. Lee  ORCID: orcid.org/0000-0002-3415-27104,
  • Juan Zhang4,
  • Hanna Budayeva5,
  • Christopher M. Rose5,
  • Julia Nguyen  ORCID: orcid.org/0009-0009-8518-23286,
  • Malgorzata Kalinka6,
  • Marcin Drag6,7,
  • Nobuhiko Kayagaki  ORCID: orcid.org/0000-0001-8129-17401,
  • Kim Newton  ORCID: orcid.org/0000-0002-4197-03401,
  • Marcin Poreba  ORCID: orcid.org/0000-0002-0214-62526 &
  • …
  • Vishva M. Dixit  ORCID: orcid.org/0000-0001-6983-03261 

Nature (2026) Cite this article

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Abstract

Caspase-1, -4, -5, and -11 activate Gasdermin D (GSDMD) pores, causing pyroptotic cell death and the release of interleukin (IL)-1β and IL-18 1. Blocking this pathway holds therapeutic promise for the treatment of inflammatory disorders, but cell permeable caspase inhibitors have not been successful in clinical trials 2. Here, we describe covalent caspase inhibitors that selectively block pyroptosis and IL-1β secretion despite being excluded from healthy cells. These inhibitors did not prevent caspase-driven apoptosis, implying that GSDMD pores facilitated their uptake. Membrane-impermeable dyes entered the cells rescued from pyroptosis, consistent with transient membrane permeabilization by GSDMD pores. Caspase inhibition prevented rather than delayed cell death, consistent with membrane repair mechanisms neutralizing the initial GSDMD pores. Inhibiting caspase-1 and -11 suppressed IL-1β and IL-18 production in a mouse model of endotoxic shock, underscoring the therapeutic potential of exploiting GSDMD pores for targeted caspase inhibition in inflammatory diseases.

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Author notes

  1. These authors contributed equally: Katarzyna M. Groborz, Melissa E. Truong

Authors and Affiliations

  1. Physiological Chemistry Department, Genentech, South San Francisco, CA, USA

    Katarzyna M. Groborz, Melissa E. Truong, Irma Stowe, Katherine E. Wickliffe, Bettina Lee, Stefan Bauernfried, Nobuhiko Kayagaki, Kim Newton & Vishva M. Dixit

  2. Drug Metabolism and Pharmacokinetics Department, Genentech, South San Francisco, CA, USA

    Robert S. Jones & Emile Plise

  3. Small Molecule Pharmaceutics Department, Genentech, South San Francisco, CA, USA

    Elizabeth S. Levy & Ponien Kou

  4. Translational Immunology Department, Genentech, South San Francisco, CA, USA

    Wyne P. Lee & Juan Zhang

  5. Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA

    Hanna Budayeva & Christopher M. Rose

  6. Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland

    Julia Nguyen, Malgorzata Kalinka, Marcin Drag & Marcin Poreba

  7. Centre for Chemical Biology, Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland

    Marcin Drag

Authors

  1. Katarzyna M. Groborz
  2. Melissa E. Truong
  3. Irma Stowe
  4. Katherine E. Wickliffe
  5. Bettina Lee
  6. Stefan Bauernfried
  7. Robert S. Jones
  8. Emile Plise
  9. Elizabeth S. Levy
  10. Ponien Kou
  11. Wyne P. Lee
  12. Juan Zhang
  13. Hanna Budayeva
  14. Christopher M. Rose
  15. Julia Nguyen
  16. Malgorzata Kalinka
  17. Marcin Drag
  18. Nobuhiko Kayagaki
  19. Kim Newton
  20. Marcin Poreba
  21. Vishva M. Dixit

Corresponding authors

Correspondence to Marcin Poreba or Vishva M. Dixit.

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Groborz, K.M., Truong, M.E., Stowe, I. et al. Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis. Nature (2026). https://doi.org/10.1038/s41586-026-10957-y

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  • DOI: https://doi.org/10.1038/s41586-026-10957-y