Inhibition of gasdermin D attenuates neutrophil extracellular trap formation induced by platelet-derived exosome in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a critical gastrointestinal disorder observed in neonates, defined by intestinal inflammation and tissue necrosis. This research examines the involvement of gasdermin D (GSDMD) in platelet pyroptosis and its effect on the formation of neutrophil extracellular traps (NETs) in the context of NEC. Clinical data from preterm infants diagnosed with NEC revealed increased inflammatory markers along with signs of platelet pyroptosis. Furthermore, platelet-derived exosomes, identified through transmission electron microscopy and Western blot analysis, were found to facilitate NET formation. In experimental models, the depletion of platelets resulted in decreased levels of NETs and exosome release, while pharmacological inhibition of GSDMD using disulfiram alleviated intestinal injury and enhanced survival rates. Our mechanistic investigations identified mitochondrial reactive oxygen species (ROS) and oxidized mitochondrial DNA (ox-mtDNA) as crucial mediators connecting platelet pyroptosis to NET formation. These findings indicate that targeting GSDMD may offer a promising therapeutic approach for NEC by diminishing excessive NET formation and the resultant inflammatory response.