RNA binding protein is a highly conserved protein family with the RNA binding domain to bind RNA and alter RNA metabolism and function.1 Abnormal expression of RNA binding protein is common in malignant tumors and connected to migration, invasion, death, and proliferation.2 RBM43, a member of the RNA binding protein family, was verified to be considerably down-regulated in hepatocellular carcinoma (HCC), indicating poor prognosis in HCC patients. RBM43 acted as a tumor suppressor that modulated CCNB1 expression to regulate the cell cycle, providing sufficient evidence for the significance of RBM43 in HCC.3 However, it is unknown if RBM43 has an impact on the process of HCC metastasis. Here, we discovered that Rbm43-deficient mice treated with diethylnitrosamine and carbon tetrachloride developed more intrahepatic and lung metastasis tumors. Consistently, the ability of migration and invasion was dramatically promoted in RBM43-deficient HCC cells. In terms of mechanisms, RBM43 suppressed HCC cell migration through the regulation of Slug mRNA stability. Additionally, in contrast to primary HCC and non-tumorous tissues, RBM43 expression was markedly decreased in metastatic HCC. In summary, our findings implied that RBM43 played a pivotal role in regulating the metastatic process of HCC, and highlighted the RBM43-Slug axis as a prospective HCC therapeutic target.