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Arctiin attenuated NASH by inhibiting glycolysis and inflammation via FGFR2/CSF1R signaling
Yeliu Fu1, Xiaolin Li1, Yuanyuan Zeng1
1The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China, 322000.
Abstract:
The present work was conducted to evaluate the pharmacological effect of Arctiin(ARC) on high fat diet(HFD)-induced Non-alcoholic steatohepatitis(NASH) and investigate its potential mechanism. The network pharmacology and bioinformatic analyses predicted that FGFR2 might be the potential target of ARC. Palmitic acid(PA)-induced AML12 cell was employed as the in vitro model. ARC reduced the levels of ALT, AST, TC, TG, and attenuated histopathological alteration. ARC inhibited inflammatory cytokines, inflammatory molecules, downregulated the expressions of FGFR2/CSF1R, inhibited glycolysis and promoted oxidative phosphorylation both in vivo and in vitro. ARC enhanced mitochondrial membrane potential and reduced oxidative stress. The application of FGFR2-OE plasmid, CSF1R-OE plasmid, CSF1R inhibitor PLX indicated that ARC attenuated glycolysis and inflammation in PA-induced AML12 cells via FGFR2/CSF1R signaling. HIF1A was proved to be involved in this process using HIF1A agonist DEF and HIF1A inhibitor PX478. Molecular docking and molecular dynamic suggested that ARC might combine with FGFR2. In conclusion, the present study demonstrated that ARC ameliorated NASH by inhibiting glycolysis and inflammation via FGFR2/CSF1R signaling.
Insights
Arctiin (ARC) effectively treats Non-alcoholic steatohepatitis (NASH) by reducing inflammation and improving metabolic function. This study reveals ARC
Area of Science:
- Pharmacology
- Hepatology
- Molecular Biology
Background:
- Non-alcoholic steatohepatitis (NASH) is a growing health concern linked to high-fat diets (HFD).
- Current treatments for NASH are limited, necessitating the exploration of novel therapeutic agents.
- Arctiin (ARC) is a natural compound with potential pharmacological benefits.
Purpose of the Study:
- To evaluate the therapeutic effects of Arctiin (ARC) on high-fat diet (HFD)-induced Non-alcoholic steatohepatitis (NASH).
- To elucidate the underlying molecular mechanisms of ARC's action in NASH.
- To identify potential molecular targets of ARC using network pharmacology and bioinformatics.
Main Methods:
- In vivo studies using HFD-induced NASH models and in vitro studies with palmitic acid (PA)-induced AML12 cells.
- Network pharmacology and bioinformatics analyses to predict ARC targets.
- Molecular experiments including gene/protein expression analysis, mitochondrial function assays, and signaling pathway investigations (FGFR2/CSF1R, HIF1A).
- Molecular docking and dynamic simulations to assess ARC-target binding.
Main Results:
- ARC treatment significantly reduced liver enzymes (ALT, AST), lipids (TC, TG), and improved liver histopathology in NASH models.
- ARC inhibited inflammatory cytokines and molecules, downregulated FGFR2/CSF1R expression, and modulated cellular metabolism by inhibiting glycolysis and promoting oxidative phosphorylation.
- ARC enhanced mitochondrial membrane potential, reduced oxidative stress, and its effects were confirmed to be mediated through the FGFR2/CSF1R signaling pathway involving HIF1A.
Conclusions:
- Arctiin (ARC) demonstrates significant therapeutic potential for ameliorating Non-alcoholic steatohepatitis (NASH).
- ARC exerts its protective effects by inhibiting inflammation and glycolysis via the FGFR2/CSF1R signaling pathway.
- ARC represents a promising therapeutic candidate for NASH treatment, warranting further clinical investigation.
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