Quzhou Fructus Aurantii extract alleviates metabolic dysfunction-associated steatohepatitis by activating the PPARα signaling pathway

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic metabolic disease that severely affects human health. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE) is a mixture rich in diverse natural flavonoids that exhibits multiple pharmacological properties, including significant anti-inflammatory and antioxidant activities. However, the anti-MASH effects of QFAEE and the underlying mechanisms remain unknown. This study aimed to investigate the therapeutic effects of QFAEE on MASH and the related mechanisms. The therapeutic effects of QFAEE on hepatic steatosis, inflammatory responses, oxidative stress and apoptotic activity were 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-MASH effects through modulation of the PPAR signaling pathway. QFAEE ameliorated MASH by activating PPARα and subsequently upregulating CPT1A, which promoted mitochondrial and peroxisomal β-oxidation. Notably, PPARα inhibition promoted hepatic lipid accumulation, inflammation and oxidative stress in hepatocytes, all of which were significantly attenuated by QFAEE treatment. These findings suggest that QFAEE prevents metabolic stress-induced MASH progression by activating PPARα signaling.

Keywords

Quzhou Fructus Aurantii ethyl acetate extract (QFAEE) / Metabolic dysfunction-associated steatohepatitis (MASH) / PPAR signaling pathway / Peroxisome proliferator-activated receptor alpha (PPARα)

Funding

This work was suported by the National Natural Science Foundation of China (N. 82174050), Zhejiang Province’s Key Scientific and Technological Program for New Crop Varieties Development (No. 2021C02072), and Zhejiang’s High-Level Health Innovation Talent Development Initiative.

Supporting information

The primary data supporting the findings of this study are openly available in the NCBI Sequence Read Archive (SRA) under accession number PRJNA1288433. And the supporting information of this paper can be requested by sending E-mail to the corresponding author.

Declaration of competing interest

These authors have no conflict of interest to declare.

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