Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis.

Covalent caspase inhibitors delivered via GSDMD pores effectively suppress pyroptosis and cytokine release, offering a targeted approach for inflammatory disease treatment.

• Why it matters: Current cell-permeable caspase inhibitors have failed in clinical trials, highlighting the need for alternative delivery methods to block pyroptosis without affecting other cell death pathways.
• What they did: Researchers developed covalent inhibitors that selectively enter cells through GSDMD pores during pyroptosis, preventing caspase activity and cytokine secretion in vitro and in a mouse model.
• The result: This strategy successfully reduced IL-1β and IL-18 levels in vivo, demonstrating the potential of exploiting GSDMD-mediated membrane permeabilization for targeted anti-inflammatory therapies.