Dihydromyricetin regulates the miR-155-5p/SIRT1/VDAC1 pathway to promote liver regeneration and improve alcohol-induced liver injury

Abstract

Background

Alcohol-related liver disease (ALD) has become an increasingly serious global health issue. In recent years, growing evidence has highlighted the restoration of liver regenerative capacity as an effective therapeutic strategy for improving ALD. Previous studies have demonstrated the protective effect of dihydromyricetin (DMY) in alcohol-induced liver injury, but its pharmacological role in ALD-related liver regeneration impairment remains poorly understood.

Objective

This study aims to explore the therapeutic potential and molecular mechanisms of DMY in the context of liver regeneration impairment in ALD.

Methods

The classic Lieber-DeCarli alcohol liquid diet was used to establish an ALD model in vivo. DMY (75 and 150 mg/kg/day) and silybin (200 mg/kg) were administered for 7 weeks to assess the hepatoprotective effects of DMY. First, biochemical markers and liver histopathology were used to evaluate liver inflammation and steatosis in ALD mice. Second, we explored the potential molecular mechanisms by which DMY improves ALD through serum untargeted metabolomics, hepatic transcriptomics, and single-cell sequencing data. Furthermore, in vivo and in vitro experiments, combined with Western blotting, dual-luciferase reporter assays, and immunofluorescence, were conducted to elucidate the protective mechanisms underlying DMY's effects on ALD.

Results

In vivo studies showed that DMY significantly ameliorated ALT/AST abnormalities, liver inflammation, and steatosis in ALD mice. Multi-omics and bioinformatics analyses revealed that DMY may exert its anti-ALD effects by regulating the miR-155–5p/SIRT1/VDAC1 pathway, thereby mitigating cellular senescence. Notably, knockdown of miR-155 provided partial protection against ethanol-induced liver damage. Additionally, clinical ALD samples and in vivo and in vitro experiments further confirmed that excessive alcohol exposure induces the production of miR-155–5p in liver Kupffer cells. miR-155–5p targets and inhibits SIRT1, promoting the expression of mitochondrial VDAC1, leading to mitochondrial DNA leakage, thereby accelerating hepatocyte senescence and inflammation. However, DMY improved the disruption of the miR-155–5p/SIRT1/VDAC1 pathway and hepatocyte senescence, thereby restoring liver regenerative function and exerting anti-ALD effects.

Conclusion

In this study, we provide the first evidence that DMY improves liver inflammation and cellular senescence by regulating the miR-155–5p/SIRT1/VDAC1 positive feedback loop, promoting liver regeneration to improve ALD. In summary, our work provides important research evidence and theoretical support for DMY as a promising candidate drug for the prevention and treatment of ALD.