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SpvC, a critical virulence determinant of salmonella, facilitates bacterial dissemination. Gasdermin D (GSDMD) is the only gasdermin known to protect mice against acute Salmonella enteritis. Our preliminary findings indicated that SpvC counteracts GSDMD-mediated antibacterial effects to enhance bacterial dissemination, although its functional relevance to epithelial-derived GSDMD and the underlying mechanisms remain unclear. To address this, Gsdmd\u2212\/\u2212 C57BL\/6J and wild-type mice were infected with Salmonella Typhimurium (S. Typhimurium) wild-type strain and spvC deletion mutant. Our results demonstrate that SpvC compromises intestinal epithelial barrier integrity, overcoming GSDMD-mediated protection against systemic infection. Specifically, through bioinformatics analysis, LC-MS\/MS, and in vivo experiments with Caco-2 cell monolayers and site-directed spvC mutants, we identified SEC23B as a novel target of SpvC. This interaction disrupts the intestinal epithelial barrier through the autophagy\u2013pyroptosis pathway. This study identifies SEC23B as a unique cellular target of SpvC involved in GSDMD activation during S. Typhimurium systemic infection. It also reveals a novel mechanism by which Salmonella evades host defense mechanisms.<\/jats:p>","DOI":"10.3390\/microorganisms14051148","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:53:10Z","timestamp":1779191590000},"page":"1148","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Salmonella Effector SpvC Targets SEC23B of Intestinal Epithelial Cells to Resist Gasdermin D-Mediated Protection Against Systemic Infection"],"prefix":"10.3390","volume":"14","author":[{"given":"Liting","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Basic Medical Science, Suzhou Medical College of Soochow University, Suzhou 215123, China"},{"name":"Center of Clinical Laboratory, The Fourth Affiliated Hospital of Soochow University, Suzhou 215123, China"},{"name":"MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and 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