Background: Activated hepatocytes drive liver fibrosis, yet the specific pathways governing cell-cell interactions for hepatic inflammation and fibrosis are not fully understood. While Hippo-YAP signaling is implicated, identifying downstream components may offer targeted strategies to halt fibrosis progression.
Method: Hepatocyte-specific YAP knockout and hepatocyte-specific YAP overexpression mice fibrosis models were induced by carbon tetrachloride (CCl4) and bile duct ligation (BDL). The YAP-SOX9 axis in liver fibrosis was examined.
Results: We identified that the novel YAP-SOX9 axis in hepatocytes tracks with disease severity in patients with liver fibrosis/cirrhosis and CCl4- and BDL-induced mouse fibrosis models. Hepatocyte-specific YAP loss-of-function mouse models exhibited limited myofibroblast expansion, less macrophage infiltration, and decreased hepatic inflammation and fibrosis. Conversely, forced hepatocyte YAP activation provoked the opposite phenotype in CCl4- and BDL-treated mice. Intriguingly, we identified SOX9 as a downstream target of YAP in hepatocytes. Moreover, increasing SOX9 expression exacerbated hepatic inflammation and fibrosis in hepatocyte-specific YAP knockout mice. In vitro experiments further showed that YAP induced SOX9-dependent osteopontin (OPN) production from hepatocytes, thereby enhancing the activation of hepatic stellate cells and infiltration of macrophages.
Conclusion: Our findings demonstrate that the YAP-SOX9 axis in hepatocytes promotes hepatic inflammation and fibrosis by increasing OPN secretion, raising the possibility of targeting hepatocyte YAP-SOX9 signaling as a novel refined therapeutic strategy for liver fibrosis/cirrhosis.