The Transcription Factor ZHX2 Alleviates Nonalcoholic Steatohepatitis by Transcriptional Activation of PTEN.

Background & aims Nonalcoholic steatohepatitis (NASH) has become a worldwide epidemic, which is a common clinical condition predisposing to advanced liver diseases. A large and growing unmet therapeutic need for this condition reflects incomplete understanding of its pathogenesis. In current study, we identified a transcription factor Zinc Fingers and Homeoboxes 2 (ZHX2) in hepatocytes as a protective factor against steatohepatitis. Approach & results We found that hepatic ZHX2 was significantly suppressed in NASH models and steatotic hepatic cells. Hepatocyte-specific ablation of ZHX2 exacerbated NASH-related phenotypes in mice, including lipid accumulation, enhanced inflammation, and hepatic fibrosis. Conversely, hepatocyte-specific overexpression of ZHX2 significantly alleviated the progression of NASH in an experimental setting. Integrated analysis of transcriptomic profiling and chromatin immunoprecipitation sequencing data demonstrated that the Phosphatase and Tensin Homologue (PTEN) was a target gene of ZHX2 in hepatocyte. ZHX2 bound to the promoter of PTEN gene and subsequently promoted the transcription of PTEN, which mediated the beneficial role of ZHX2 against NASH. Conclusion In conclusion, current findings unfolded a protective role of ZHX2 against NASH progression by transcriptionally activating PTEN. These findings shed light on the therapeutic potential of targeting ZHX2 for treating NASH and related metabolic disorders.