Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis
9 affiliations
- 1Physiological Chemistry Department, Genentech, South San Francisco, CA, USA
- 2Drug Metabolism and Pharmacokinetics Department, Genentech, South San Francisco, CA, USA
- 3Small Molecule Pharmaceutics Department, Genentech, South San Francisco, CA, USA
- 4Translational Immunology Department, Genentech, South San Francisco, CA, USA
- 5Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA
- 6Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland
- 7Centre for Chemical Biology, Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland
- 8Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland. [email protected]
- 9Physiological Chemistry Department, Genentech, South San Francisco, CA, USA. [email protected]
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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BibTeX
@article{groborz2026gasdermin,
title = {{Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis}},
author = {Katarzyna M. Groborz and Melissa E. Truong and Irma B. Stowe and Katherine E. Wickliffe and Bettina L. Lee and Stefan Bauernfried and Robert S. Jones and Emile G. Plise and Elizabeth S. Levy and Ponien Kou and Wyne P. Lee and Juan Zhang and Hanna Budayeva and Christopher M. Rose and Julia Nguyen and Małgorzata Kalinka and Marcin Drąg and Nobuhiko Kayagaki and Kim Newton and Marcin Poręba and Vishva M. Dixit},
journal = {Nature},
year = {2026},
month = aug,
doi = {10.1038/s41586-026-10957-y},
url = {https://doi.org/10.1038/s41586-026-10957-y},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis
AU - Katarzyna M. Groborz
AU - Melissa E. Truong
AU - Irma B. Stowe
AU - Katherine E. Wickliffe
AU - Bettina L. Lee
AU - Stefan Bauernfried
AU - Robert S. Jones
AU - Emile G. Plise
AU - Elizabeth S. Levy
AU - Ponien Kou
AU - Wyne P. Lee
AU - Juan Zhang
AU - Hanna Budayeva
AU - Christopher M. Rose
AU - Julia Nguyen
AU - Małgorzata Kalinka
AU - Marcin Drąg
AU - Nobuhiko Kayagaki
AU - Kim Newton
AU - Marcin Poręba
AU - Vishva M. Dixit
PY - 2026
DA - 2026/08/03
JO - Nature
DO - 10.1038/s41586-026-10957-y
UR - https://doi.org/10.1038/s41586-026-10957-y
AB - 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.
SN - 0028-0836
SN - 1476-4687
ER -