Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.

Abstract

Simple SummaryNon-alcoholic fatty liver disease (NAFLD) is a major health problem globally linked with the growing prevalence of metabolic syndrome. A subset of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH), which increases the risk of hepatocellular carcinoma (HCC). However, the mechanisms responsible for the progression to HCC are unclear, and no preventative modalities have been developed. To address this issue, the present study used the natural compound honokiol to clarify the mechanism of this process. The results illustrated that epidermal growth factor receptor (EGFR) was upregulated in mice with NASH, and treatment with honokiol inhibited EGFR and the progression to HCC. Further analysis illustrated that honokiol increased glucocorticoid receptor (GR) nuclear translocation and mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, thereby promoting EGFR degradation. These findings were confirmed in tissues from patients with NASH and HCC.Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study’s clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH–HCC treatment and prevention, and the GR–MIG6 axis is a newly defined target that can be activated by HNK and related compounds.