The tumor suppressor NDRG2 promotes ACC1 proteasomal degradation and inhibits de novo lipogenesis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor characterized by high metabolic dependence. In particular, it relies on dysregulated lipid synthesis. N-myc downstream regulated gene 2 (NDRG2) acts as a tumor suppressor in HCC, yet its underlying mechanisms remain unclear. This study aimed to elucidate the role of NDRG2 in HCC progression through the regulation of lipid metabolism. We established NDRG2-overexpressing and knockout HCC cell lines, and a hepatocellular-specific Ndrg2(-/-) mouse model of induced HCC. Metabolomics, Co-IP, and bioinformatics prediction were used to investigate the regulatory mechanisms and biological functions of NDRG2 on lipogenesis and the activity of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1). Interestingly, compared with wild-type mice, Ndrg2 knockout mice exhibited significantly enhanced hepatic lipogenesis and hepatocarcinogenesis. Mechanistically, NDRG2 functions as a scaffold protein that specifically recruits the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1), forming an NDRG2-COP1-ACC1 ternary complex, and thereby promoting ACC1 degradation via the ubiquitin-proteasome pathway. Furthermore, the accelerated degradation of ACC1 leads to decreases in de novo lipogenesis (DNL) and lipid droplet formation, thereby reducing the proliferation and progression of HCC cells. Notably, NDRG2-mediated ACC1 degradation significantly synergized with sorafenib to suppress tumor growth and angiogenesis. Our study revealed that NDRG2 mediates the ubiquitination and degradation of ACC1 through recruiting COP1. Thus, targeting the NDRG2-ACC1 axis or its combination with sorafenib may be a novel potential strategy for HCC therapy.