Honokiol prevents non-alcoholic steatohepatitis-induced liver cancer via EGFR degradation through the glucocorticoid receptor-MIG6 axis

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. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH. 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. 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. We analyzed more than 30 mice to examine NASH and NASH-induced liver cancer development with or without honokiol treatment. We chose 6 mice (3 with treatment, 3 without treatment) to perform RNA array analysis. Since EGFR expression was different between the two groups, EGFR signaling was further investigated.