ROS‐Dependent GSDMD Activation Drives Intestinal Pyroptosis in Neonatal Necrotizing Enterocolitis (NEC)

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This study investigates the role of Gasdermin D (GSDMD)-mediated pyroptosis in the pathogenesis of necrotizing enterocolitis (NEC) and reveals the mechanism by which reactive oxygen species (ROS) promote intestinal inflammation and injury through NLRP3/GSDMD pathway activation. Analysis of human NEC tissue samples showed significant oxidative stress (elevated MDA, decreased SOD activity, reduced GSH/GSSG ratio) and activation of the NLRP3/GSDMD/IL-1β pathway in the intestines of NEC patients. In an experimental NEC mouse model, GSDMD knockout (GSDMD-/-) significantly delayed NEC onset, reduced incidence, attenuated intestinal damage, and improved survival. GSDMD deficiency also decreased macrophage pyroptosis, systemic inflammation, and bacterial translocation, while improving intestinal barrier function. Pharmacological inhibition of GSDMD (using disulfiram) similarly mitigated pyroptosis and enhanced the bactericidal capacity of macrophages. Further mechanistic studies indicated that ROS drive pyroptosis by activating GSDMD, and the antioxidant N-acetyl-l-cysteine (NAC) could reverse this effect. The findings suggest that GSDMD is a potential therapeutic target for NEC, and strategies targeting GSDMD inhibition (genetic or pharmacological), combined with antioxidant therapy, may offer novel treatment approaches for NEC.

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