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Intestinal barrier injury has been reported to play a vital role in the pathogenesis of endotoxemia. This study aimed to investigate the protective effect of GYY4137, a newly synthesized H2S donor, on the intestinal barrier function in the context of endotoxemia both in vitro and in vivo. Caco-2 (a widely used human colon cancer cell line in the study of intestinal epithelial barrier function) monolayers incubated with lipopolysaccharide (LPS) or TNF-α/IFN-γ and a mouse model of endotoxemia were used in this study.The results suggested that GYY4137 significantly attenuated LPS or TNF-α/IFN-γ induced increased Caco-2 monolayer permeability. The decreased expression of TJ (tight junction) proteins induced by LPS and the altered localization of TJs induced by TNF-α/IFN-γ was significantly inhibited by GYY4137; similar results were obtained in vivo. Besides, GYY4137 promoted the clinical score and histological score of mice with endotoxemia. Increased level of TNF-α/IFN-γ in the plasma and increased apoptosis in colon epithelial cells was also attenuated by GYY4137 in mice with endotoxemia. This study indicates that GYY4137 preserves the intestinal barrier function in the context of endotoxemia via multipathways and throws light on the development of potential therapeutic approaches for endotoxemia.