The traditional herb Sargentodoxa cuneata alleviates DSS-induced colitis by attenuating epithelial barrier damage via blocking necroptotic signaling

Ethnopharmacological relevance: The traditional Chinese herb, Sargentodoxa cuneata, is primarily utilized as a crucial herb for managing ulcerative colitis (UC), also known as "Da Xue Teng (DXT)" or "Hong Teng" in Chinese. Nevertheless, the chemical composition, prototype, and metabolite constituents of DXT and its pharmacological mechanism of treatment for UC remain unclear. Aim of the study: Necroptosis, a caspase-independent form of programmed cell death, plays a crucial role in the inflammatory pathogenesis of UC. The occurrence of necroptosis in intestinal epithelial cells triggers a robust inflammatory response and disrupts the integrity of both the mucinous barrier and tight junction construction. The objective of our study was to determine the chemical composition of DXT, identify its absorbed active ingredients and metabolites in rat serum, and investigate whether DXT possesses epithelial barrier protective effects by inhibiting necroptosis. Materials and methods: First, the UPLC-Q-TOF/MS was applied to identify the chemical composition of DXT, as well as the absorption components and metabolites of DXT in rat serum. Second, the network pharmacology analysis was further investigated to elucidate the potential targets for treating UC. Finally, the mechanism of action was validated by necroptosis-based experiment in vitro and an in vivo model of colitis. Results: A comprehensive analysis revealed the presence of 31 phytochemicals derived from DXT herb, as well as a total of 39 components in rat serum. Network pharmacology analysis indicated that TNF, EGFR, HSP90, etc. are the potential targets. Experimental in vitro and in vivo verified that the DXT could improve disease activity index, body weight, colon length and intestinal barrier permeability in mice with colitis by inhibiting necroptosis of intestinal epithelial cells. Conclusions: In this study, the phytochemicals derived from DXT herb and absorption active ingredients and metabolites of DXT in rat serum were analyzed. The biological mechanism of treatment for UC can be elucidated by combining network pharmacology investigation with experimental in vitro and in vivo studies. The findings offered a theoretical basis for comprehending the bioactive substances and the pharmacological process of DXT.