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Background Sepsis-induced intestinal barrier dysfunction drives systemic inflammation and multi-organ failure. While epithelial pyroptosis is a central mechanism underlying this barrier disruption, the pathways by which metabolic signals regulate GSDMD activation remain poorly understood. Succinate accumulates significantly during sepsis, but its role in controlling GSDMD membrane translocation and subsequent barrier failure has not been elucidated. This study investigated whether succinate promotes epithelial pyroptosis and barrier breakdown via SUCNR1-dependent regulation of GSDMD palmitoylation.Methods Plasma succinate levels and markers of intestinal injury were measured in a clinical sepsis cohort. In septic mice, intestinal tissues were analyzed by single-cell RNA sequencing (scRNA-seq) . Mechanistic studies used intestinal organoids and genetic mouse models, including epithelial-specific Sucnr1 or Zdhhc9 knockdown and Gsdmd knockout. GSDMD palmitoylation, membrane localisation, and barrier integrity were assessed, and SUCNR1 inhibition was used to evaluate its regulatory role.Results Plasma succinate levels were significantly elevated in septic patients and mice, correlating with clinical markers of intestinal barrier injury. In septic mice, intestinal ZDHHC9 and GSDMD expression were increased, accompanied by loss of tight junction proteins ( Tjp1, Ocln) and elevated mucosal permeability. scRNA-seq identified enterocyte and crypt epithelial subpopulations with high Zdhhc9, Caspase-11, and Gsdmd expression, exhibiting downregulation of barrier-related genes.In intestinal organoids, succinate induced ZDHHC9-dependent GSDMD palmitoylation and pyroptosis, resulting in organoid disintegration. Mechanistically, succinate sensing via SUCNR1 upregulated ZDHHC9, which directly catalyzed GSDMD palmitoylation at Cys191. This modification enhanced GSDMD-N membrane localisation and pore formation. Genetic deletion or pharmacological inhibition of SUCNR1 or ZDHHC9 reduced GSDMD membrane targeting, attenuated epithelial pyroptosis, and preserved tight junction integrity and barrier function.Conclusions Succinate promotes epithelial pyroptosis via SUCNR1-dependent upregulation of ZDHHC9 and GSDMD palmitoylation at Cys191, enhancing membrane localisation and pore formation. Inhibition of the SUCNR1–ZDHHC9–GSDMD pathway reduced pyroptosis and preserved intestinal barrier integrity in septic mice, suggesting a potential therapeutic approach to protect barrier function in sepsis.