〔Abstract〕 Objective To investigate the effect of N-myc downstream regulatory gene 1(NDRG1) on Hepatocellular carcinoma(HCC) and whether NDRG1 affects the sensitivity of HCC to Sorafenib. Methods The expression level of NDRG1 in HCC was predicted by TCGA database, and verified by Western blot(WB) and Immunohistochemistry(IHC). NDRG1 knockout cell lines were constructed, followed by cell counting kit-8(CCK-8), EdU, cell scratches and Transwell experiment to investigate the effects of NDRG1 and its combination with Sorafenib on the proliferation, migration and invasion of HCC cells. In addition, flow cytometry was used to detect the apoptosis of HCC cells. The effect of NDRG1 and Sorafenib on HCC tumor formation was studiedin vivoby subcutaneous tumor bearing in nude mice. WB and IHC were used to determine the pathway regulating the sensitivity of HCC to Sorafenib. Results WB and IHC confirmed that NDRG1 is highly expressed in HCC, consistent with the results of TCGA data. Tumor functional experiments showed that NDRG1 knockout or Sorafenib stimulation weakened the proliferation, migration, and invasion ability of HCC cells, and increased tumor cell apoptosis. However, NDRG1 knockout combined with Sorafenib further weakened the proliferation, migration and invasion ability of HCC cells, and further increased tumor cell apoptosis(P<0.000 1). Mouse subcutaneous tumor model showed that NDRG1 knockout or Sorafenib stimulation reduced the tumor volume and quality, while NDRG1 knockout combined with Sorafenib further reduced the tumor volume and quality(P<0.000 1). The WB and IHC results indicated that NDRG1 knockout combined with Sorafenib could reduce the phosphorylation level of Erk1/2. Conclusion NDRG1 is highly expressed in HCC, which promotes the proliferation, migration and invasion of HCC cells, and restricts apoptosis. NDRG1 knockout enhances HCC sensitivity to Sorafenib by reducing ERK signaling pathway phosphorylation.