Schaftoside ameliorates MCD diet-induced nonalcoholic steatohepatitis via modulating immune microenvironment

BACKGROUND: Schaftoside (SS), a bioactive natural flavonoid di-C-glycoside derived from some famous Chinese herbs including Scutellaria baicalensis, Glycyrrhiza uralensis and Abrus mollis, has been reported to mitigate hepatic lipid accumulation and enhance liver health. PURPOSE: This study aimed to assess the effects of SS on non-alcoholic steatohepatitis (NASH) and to investigate the potential mechanisms. METHODS: A methionine-choline deficiency (MCD)-induced model of NASH was established. The efficacy of SS in intervening NASH was evaluated through assessments of blood lipids, liver function, and pathological conditions. Transcriptomic analysis was conducted to predict potential pathways of SS intervention in NASH, and the prediction results were validated by testing biochemical parameters, real-time quantitative PCR (qPCR), ELISA assays, and immunohistochemistry. RESULTS: Our results revealed that SS markedly ameliorated liver dysfunction and lipid metabolism disorders, as indicated by decreased serum concentrations of ALT and AST, along with lower liver levels of TG and TC. Based on RNA-sequencing results, we found that the expression of genes associated with inflammatory processes and fibrotic responses, including Ccl2, Cxcl2, Col1a1, Col3a1, Mmp13, Itgax, Itgam, and Acta2, were reduced following intervention with SS. In conjunction with the immune cell infiltration analysis and qPCR, we determined that SS significantly restored the disrupted immune microenvironment via regulating the functional properties of various immunocyte, particularly the modulation of genes expression related to macrophages (Cd80, Cd86, Cd204, MCP-1, Cd206, Il10, Arg1 and Tgfb1) and dendritic cells (Itgax/Cd11c, Itgam/Cd11b, MMP8, MMP9, MMP13, and TNF-α). CONCLUSION: In summary, our study provides the first evidence that SS exerts anti-NASH effects by orchestrating immune cell functions, particularly through macrophage polarization and dendritic cell modulation, thereby rectifying the dysregulated immune microenvironment. These findings position SS as a promising candidate for novel NASH therapies.