Quzhou Fructus Aurantii extract alleviates non-alcoholic steatohepatitis by activating PPARa signaling pathway

Ethnopharmacological relevance: NASH was a chronic metabolic disease that seriously affects people's health. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE) was a natural flavonoid extracted from Quzhou Fructus Aurantii, which exhibited multiple pharmacological properties, demonstrating significant anti-inflammatory and antioxidant activities. However, the anti-NASH effects and underlying mechanisms of QFAEE remained undetermined.Aim of the study: To investigate the role and mechanisms of QFAEE in the treatment of NASH.Materials and methods: QFAEE was administered orally to mice with HFHC diet-induced metabolic dysfunction. Network pharmacology and RNA sequencing were used to analyze the mechanism of action of QFAEE in the treatment of NASH. Furthermore, the therapeutic effects and mechanistic insights were validated through RT-qPCR, western blotting, immunofluorescence staining and flow cytometry analyses.Results: The therapeutic efficacy of QFAEE against hepatic steatosis, inflammatory responses, oxidative stress and apoptotic activity was systematically evaluated in both in vivo and in vitro models of metabolic stress. QFAEE administration significantly reduced hepatic lipid accumulation, inflammatory cell infiltration and liver injury in HFHC diet-fed mice. Combined RNA sequencing and network pharmacology analyses revealed that QFAEE exerted its anti-NASH effects through modulation of the PPAR signaling pathway. QFAEE ameliorated NASH through PPARa activation and subsequent CPT1A upregulation, which enhanced mitochondrial and peroxisomal b-oxidation. Notably, PPARa inhibition promoted hepatic lipid accumulation, inflammation and oxidative stress in hepatocytes, all of which were significantly attenuated by QFAEE treatment.