〔Abstract〕 Objective To investigate the impact of dexmedetomidine on the oncological behavior of hepatocellular carcinoma and explore the role of NF-E2-related factor 2(Nrf2) at bothin vitroandin vivolevels. Methods In vivoexperiment, Male C57BL/6J mice were randomly divided into a control group(Ctrl group), a hepatocellular carcinoma group(HCC group), and a hepatocellular carcinoma+dexmedetomidine group(HCC+Dex group). Hepatocellular carcinoma was induced in mice by combining N-Nitrosodiethylamine(DEN)/carbon tetrachloride(CCl4), followed by daily intraperitoneal injection of 10% dexmedetomidine for two weeks. After feeding the mice for one month, the mice were assessed for the quantity and size of liver tumors. The proliferation ability of liver cancer was evaluated using Ki67 immunohistochemistry. Additionally, the expression level of Nrf2 protein in tumor tissue was measured through immunofluorescence.In vitroexperiment, Hepa1-6 cells were incubated with different concentrations of dexmedetomidine(0.1, 1, 5 nmol/L) for 48 hours to examine their effects. The proliferation, migration and invasion abilities of Hepa1-6 cells were evaluated using the MTT and Transwell methods. The expression level of Nrf2 protein in the Hepa1-6 cells was measured using Western blot and immunofluorescence. Additionally, the proliferation, migration and invasion abilities of cells were assessed after Nrf2 knockdownviasi-RNA transfection, in combination with incubation with 1 nmol/L dexmedetomidine for 48 hours. Results Compared to the HCC group, the anatomical examination results revealed an increase in the number of liver tumors and the longest diameter in the HCC+Dex group(P<0.05). Ki67 immunohistochemistry results indicated the number of Ki67 positive cells in liver cancer tissue increased in the HCC+Dex group(P<0.01). The immunofluorescence assay demonstrated an upregulation of Nrf2 expression level in the HCC+Dex group(P<0.05). MTT results showed that 1 nmol/L of dexmedetomidine increased the cell viability of Hepa1-6 cells(P<0.05). Transwell results indicated that 0.1, 1, and 5 nmol/L of dexmedetomidine enhanced the invasive ability of Hepa1-6 cells, while 0.1 and 1 nmol/L of dexmedetomidine enhanced the migration ability(P<0.05). Western blot and immunofluorescence results showed an upregulation of Nrf2 expression level in cells after treatment with 1 nmol/L dexmedetomidine(P<0.01). The Nrf2 expression level of cells was reduced using si-RNA, followed by treatment with 1 nmol/L dexmedetomidine. The results from MTT and Transwell assays revealed a decrease in the viability, invasion and migration ability of Hepa1-6 cells(P<0.01). Conclusion Dexmedetomidine may enhance the proliferation, invasion and migration capacity of hepatocellular carcinoma by upregulating the expression of Nrf2.