Suppressing pyroptosis by delivering caspase inhibitors via gasdermin D pores

Activation  gasdermin D (GSDMD) pores from Caspase-1, -4, -5 and -11 leads to  pyroptotic cell death. Due to toxicity and limited efficacy, caspase inhibitors however, have repeatedly failed in clinical trials.

 The authors in this study describe caspase inhibitors that selectively block pyroptosis and IL-1β secretion despite being excluded from healthy cells. 

The researchers show that gasdermin D pores admit otherwise membrane-impermeable inhibitors into pyroptotic cells, turning poor permeability into a mechanism of cell-state selectivity.

In a mouse model of endotoxic shock inhibiting caspase-1 and caspase-11 suppressed IL-1β and IL-18, underscoring the therapeutic potential of exploiting GSDMD pores for targeted caspase inhibition in inflammatory diseases.

https://www.nature.com/articles/s41586-026-10957-y

https://sciencemission.com/Gasdermin-D-mediated-delivery-of-caspase-inhibitors