{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Physiological Chemistry Department, Genentech, South San Francisco, CA, USA",
    "Drug Metabolism and Pharmacokinetics Department, Genentech, South San Francisco, CA, USA",
    "Small Molecule Pharmaceutics Department, Genentech, South San Francisco, CA, USA",
    "Translational Immunology Department, Genentech, South San Francisco, CA, USA",
    "Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA",
    "Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland",
    "Centre for Chemical Biology, Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland",
    "Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland. marcin.poreba@pwr.edu.pl",
    "Physiological Chemistry Department, Genentech, South San Francisco, CA, USA. dixit@gene.com"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Katarzyna M. Groborz",
      "orcid": "0000-0002-1894-4881"
    },
    {
      "affs": [
        0
      ],
      "name": "Melissa E. Truong",
      "orcid": "0000-0003-1526-1521"
    },
    {
      "affs": [
        0
      ],
      "name": "Irma B. Stowe"
    },
    {
      "affs": [
        0
      ],
      "name": "Katherine E. Wickliffe"
    },
    {
      "affs": [
        0
      ],
      "name": "Bettina L. Lee"
    },
    {
      "affs": [
        0
      ],
      "name": "Stefan Bauernfried",
      "orcid": "0000-0003-1910-5032"
    },
    {
      "affs": [
        1
      ],
      "name": "Robert S. Jones",
      "orcid": "0000-0002-5283-8070"
    },
    {
      "affs": [
        1
      ],
      "name": "Emile G. Plise",
      "orcid": "0000-0001-7038-5127"
    },
    {
      "affs": [
        2
      ],
      "name": "Elizabeth S. Levy",
      "orcid": "0000-0001-6802-885X"
    },
    {
      "affs": [
        2
      ],
      "name": "Ponien Kou",
      "orcid": "0009-0008-2605-1398"
    },
    {
      "affs": [
        3
      ],
      "name": "Wyne P. Lee",
      "orcid": "0000-0002-3415-2710"
    },
    {
      "affs": [
        3
      ],
      "name": "Juan Zhang"
    },
    {
      "affs": [
        4
      ],
      "name": "Hanna Budayeva"
    },
    {
      "affs": [
        4
      ],
      "name": "Christopher M. Rose",
      "orcid": "0000-0002-7502-3368"
    },
    {
      "affs": [
        5
      ],
      "name": "Julia Nguyen",
      "orcid": "0009-0009-8518-2328"
    },
    {
      "affs": [
        5
      ],
      "name": "Małgorzata Kalinka"
    },
    {
      "affs": [
        6,
        5
      ],
      "name": "Marcin Drąg",
      "orcid": "0000-0001-8510-1967"
    },
    {
      "affs": [
        0
      ],
      "name": "Nobuhiko Kayagaki",
      "orcid": "0000-0001-8129-1740"
    },
    {
      "affs": [
        0
      ],
      "name": "Kim Newton",
      "orcid": "0000-0002-4197-0340"
    },
    {
      "affs": [
        7
      ],
      "name": "Marcin Poręba",
      "orcid": "0000-0002-0214-6252"
    },
    {
      "affs": [
        8
      ],
      "name": "Vishva M. Dixit",
      "orcid": "0000-0001-6983-0326"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5t2mratwxmbpr.bib",
  "cited_by": 9,
  "doi": "10.1038/s41586-026-10957-y",
  "fulltext_url": null,
  "id": "5t2mratwxmbpr",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10957-y",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Inflammasome and immune disorders"
    ]
  ],
  "openalex": "W7172297444",
  "pdf_url": null,
  "pmcid": "PMC13645671",
  "pmid": "42649286",
  "published": "2026-08-03",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/5t2mratwxmbpr.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T13:20:30Z",
      "native_id": "W7172297444",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10957-y"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Inflammasome and immune disorders",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis",
  "title_text": "Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:30Z",
  "url": "https://research.draconitic.com/paper/5t2mratwxmbpr",
  "venue": "Nature",
  "versions": []
}