Nobiletin Alleviated Epithelial–Mesenchymal Transition of Hepatocytes in Liver Fibrosis Based on Autophagy—Hippo/YAP Pathway

Scope The current researches indicated that the epithelial–mesenchymal transition (EMT) of hepatocytes plays a crucial role in the development of liver fibrosis. To date, there is a paucity of literature regarding the impact of nobiletin (NOB) on liver fibrosis. This study investigates the inhibitory effect of NOB on EMT in hepatocytes during the progression of liver fibrosis and its underlying mechanism. Methods and results The findings demonstrated that NOB significantly suppresses liver fibrosis in carbon tetrachloride (CCl 4 )‐induced mice by reducing inflammation and fiber deposition in the liver. Moreover, NOB mitigates EMT in hepatocytes, concurrently alleviating inflammatory status and reducing the production of reactive oxygen species (ROS) generation. The comprehensive investigation reveals that the hepatoprotective effect of NOB in liver fibrosis is attributed to autophagy activation, as evidenced by a significant increase in LC3 II expression and p62 degradation upon NOB treatment. Additionally, NOB activates the Hippo/YAP pathway by downregulating YAP and its downstream targets in liver fibrosis, which is regulated by autophagy based on experiments with chloroquine (CQ), 3‐methyladenine (3‐MA), and siYAP intervention. Conclusion Therefore, this study provides evidences that NOB can protect hepatocytes from undergoing EMT during liver fibrosis by inducing autophagy and subsequently modulating the Hippo/YAP pathway.