Novel Caspase Inhibitors Exploit Gasdermin D Pores to Halt Pyroptosis
Researchers have created covalent caspase inhibitors that enter cells through Gasdermin D pores, selectively blocking pyroptotic death and IL-1β release while sparing apoptosis.
A team of scientists reported covalent inhibitors that bind caspases and specifically prevent pyroptosis without affecting apoptosis, thanks to their entry via Gasdermin D-formed pores. In healthy cells the compounds remain outside, but during pyroptotic membrane disruption they are taken up, as evidenced by the uptake of otherwise impermeable dyes in rescued cells. This selective delivery stops the release of IL-1β and IL-18, key inflammatory mediators.
In mouse models of endotoxic shock, inhibition of caspase-1 and -11 reduced cytokine levels, highlighting potential clinical applications. The findings suggest that exploiting Gasdermin D pores could provide a new strategy for treating a range of inflammatory disorders.
Why it matters
Targeted caspase inhibition via Gasdermin D pores could yield safer therapies for inflammatory diseases.
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