Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42649286.
- Also identified by DOI 10.1038/s41586-026-10957-y.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
Caspase-1, -4, -5 and -11 activate gasdermin D (GSDMD) pores, causing pyroptotic cell death and the release of the interleukins IL-1β and IL-18 (ref. <sup>1</sup>). Blocking this pathway holds therapeutic promise for the treatment of inflammatory disorders, but cell-permeable caspase inhibitors have not proved successful in clinical trials<sup>2</sup>. 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 caspase-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.