Mitofusin 2 Alleviates Liver Fibrogenesis by Suppressing β-Catenin Nuclear Translocation

Abstract

Objective

To investigate the inhibitory effects of mitofusin 2 (MFN2) on hepatic stellate cell (HSC) activation and liver fibrosis progression in nonalcoholic fatty liver disease (NAFLD) through the inhibition of β-catenin nuclear translocation.

Methods

In vitro, primary mouse HSCs were treated with palmitic acid (PA), and MFN2 expression was modulated using lentiviral overexpression or knockdown. Fibrotic markers and β-catenin localization were analyzed via Western blot, cellular fractionation, and immunofluorescence. In vivo, liver fibrosis was induced in C57BL/6 J mice using a high-fat diet (HFD) combined with CCl₄ injections. MFN2 was systemically overexpressed or silenced via AAV2 vectors delivered through tail vein injection. Liver tissues were examined histologically and biochemically for fibrosis progression.

Results

PA treatment markedly downregulated MFN2 and upregulated fibrotic markers in HSCs. Overexpression of MFN2 strongly suppressed HSC activation, reduced α-SMA and N-cadherin levels, and significantly inhibited β-catenin nuclear accumulation. Conversely, MFN2 knockdown exacerbated fibrotic responses and promoted β-catenin translocation. In mice, MFN2 overexpression substantially attenuated collagen deposition and improved liver histology, while MFN2 silencing significantly aggravated fibrosis and enhanced β-catenin signaling.

Conclusion

MFN2 inhibits HSC activation and liver fibrosis by suppressing β-catenin nuclear translocation, making it a promising therapeutic target for NAFLD-related fibrosis and associated complications, such as hepatocellular carcinoma.

Keywords

Hepatic stellate cells / Nonalcoholic steatohepatitis (NASH) / Metabolic dysfunction-associated steatotic liver disease (MASLD) / Lipotoxicity / Wnt/β-catenin signaling / Liver fibrosis / Mitofusin 2

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Funding

Startup Fund for Scientific Research, Fujian Medical University(2019QH1146)

The Natural Science Foundation of Fujian Province(general program)(2020J011063)

the Joint Funds for the Innovation of Science and Technology, Fujian province(2024Y9028)

Guided Project of Social Development in Fujian Province(2025Y0006)

Zhejiang Provincial Traditional Chinese Medicine Science and Technology Program Project(2025ZL118)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology