α-Tocopherol Ameliorates Liver Fibrosis by Inhibiting Hepatic Stellate Cell Activation by Promoting Nrf2 Nuclear Translocation

<b><i>Aims:</i></b> α-Tocopherol is a potent natural antioxidant with a variety of biological functions and is widely used in clinical practice. However, the effect and mechanism of α-tocopherol on liver fibrosis remain unknown. The core of liver fibrosis is the activation of hepatic stellate cell (HSC). Inhibiting HSC activation may be the underlying mechanism by which α-tocopherol alleviates liver fibrosis. <b><i>Results:</i></b> Our study revealed that α-tocopherol improved liver injury and fibrosis in both CCl₄ and bile duct ligation induced liver fibrosis model mice. α-Tocopherol inhibited HSC activation by promoting nuclear erythroid 2-related factor 2 (Nrf2) translocation into the nucleus. α-Tocopherol directly promoted Nrf2 nuclear translocation by reducing its degradation, additionally, α-tocopherol suppressed autophagy by inhibiting endoplasmic reticulum stress, resulting in increased SQSTM1 competition to bind KEAP1 and indirectly promoting Nrf2 translocation into the nucleus. The increased Nrf2 nuclear translocation upregulated the expression of antioxidant genes, thereby reducing ROS and subsequently inhibiting HSC activation. Moreover, the antifibrotic and hepatoprotective effects of α-tocopherol were verified by the addition of the Nrf2 activator-curcumin, the autophagy inhibitor-3-methyladenine and the endoplasmic reticulum stress inhibitor-sodium 4-phenylbutyrate. <b><i>Innovation and Conclusion:</i></b> Our study is the first to identify the mechanism by which α-tocopherol alleviates liver fibrosis. Broadly speaking, this study demonstrated that α-tocopherol promotes Nrf2 nuclear translocation by reducing Nrf2 degradation and inhibiting endoplasmic reticulum stress, which then inhibits HSC activation and ultimately ameliorates liver injury and fibrosis. Therefore, α-tocopherol may become a novel therapeutic strategy for liver fibrosis. <i>Antioxid. Redox Signal.</i> 43, 833-848.