Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function

Background and Aims Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9 + hepatocytes in response to the acute liver injury and repair are poorly understood. Methods In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl 4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H 2 O 2 ) in order to induce cellular damage in an in vitro setting. Results We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H 2 O 2 -treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. Conclusions Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future. Graphical Abstract