基于Foxm1/NF-κB轴探讨七味脂肝方改善饮食诱导小鼠代谢相关脂肪性肝炎的机制OA

Objective To investigate the mechanism of Qiwei Zhigan Formula(QWZG)in ameliorating diet-induced metabolic dysfunction-associated steatohepatitis(MASH)in mice.Methods A MASH model was established in male C57BL/6J mice by feeding a Western diet.After successful modeling at week 18,mice were randomly divided into a model group and QWZG low-,medium-,and high-dose intervention groups(n=8 per group),with a normal control group(n=8).Mice in the intervention groups received corresponding doses of QWZG by gavage for 6 weeks,while the model and control groups received an equal volume of 0.9%sodium chloride solution.After 6 weeks of treatment,body weight,liver weight,and liver-to-body weight ratio were measured;serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),total cholesterol(TC),and triglyceride(TG)were detected.Hepatic histopathological changes were assessed by hematoxylin-eosin(HE)staining and Oil Red O staining,and hepatic macrophage infiltration was evaluated by immunohistochemistry.Transcriptome sequencing(RNA-seq)was used to identify genes and pathways modulated by QWZG,and Western blot and reverse transcription quantitative real-time polymerase chain reaction(RT-qPCR)were applied to validate the key mechanism.Results Compared with the model group,QWZG intervention significantly reduced body weight,liver weight,and serum levels of ALT,AST,TC,and TG in MASH mice(P<0.05),and alleviated hepatic steatosis,ballooning degeneration,and macrophage infiltration.RNA-seq results showed that QWZG intervention significantly downregulated the expression of forkhead box protein M1(Foxm1)in mouse liver.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis revealed that inflammatory-related pathways such as the nuclear factor-κB(NF-κB)signaling pathway and cytokine-cytokine receptor interaction were significantly inhibited.Validation experiments confirmed that QWZG intervention markedly decreased Foxm1 protein expression and p65 phosphorylation levels in MASH mice.Conclusion The mechanism by which QWZG ameliorates MASH in mice may be associated with downregulating Foxm1 and inhibiting the activation of the NF-κB signaling pathway.