Abstract

Deoxynivalenol (DON) is a prevalent mycotoxin that compromises intestinal barrier integrity, yet the mechanisms underlying DON-induced chronic inflammation remain unclear. This study investigated these mechanisms using a 28-day piglet model and porcine intestinal epithelial cells (IPEC-J2). In vivo, DON exposure caused intestinal morphological damage and inflammation, accompanied by caspase-3/Gasdermin E (GSDME)-mediated pyroptosis. In vitro experiments confirmed that DON triggers pyroptosis via the caspase-3/GSDME pathway. Mechanistically, activated GSDME permeabilized mitochondrial membranes, promoting cytosolic mitochondrial DNA (mtDNA) release and subsequent activation of the cGAS-STING innate immune pathway, which amplified the inflammatory response. Notably, GSDME knockdown preserved mitochondrial integrity, prevented mtDNA leakage, and blocked cGAS-STING activation, thereby attenuating intestinal injury. These findings identify a sequential mechanism where the caspase-3/GSDME axis triggers mitochondrial dysfunction and cGAS-STING-mediated signaling, offering novel therapeutic targets for mycotoxin-associated enteropathy.