AZD3759 is a tyrosine kinase inhibitor and has an encouraging future in treating brain metastases of non small cell lung cancer. Here, we determined that AZD3759 suppressed the viability of HepG2 cells, a hepatoma cell line, and induced their apoptosis, suggesting a new therapeutic potential of AZD3759 in hepatocellular carcinoma (HCC) treatment. Furthermore, we found that the activation of p53-SMAD family member 4 (SMAD4) positive feedback loop was involved in the induction of bulks of apoptosis in HepG2 cells in response to AZD3759 treatment. In this positive feedback loop, p53 induced the expression of SMAD4 by directly promoting its transcription as shown by p53 could bind to SMAD4 promoter; SMAD4, in turn, promoted the nuclear translocation of p53, which increased the transcription of pro-apoptotic genes, including PUMA and BAX (two p53 target genes) and finally resulted in apoptosis. To the. best of our knowledge, p53-induced SMAD4 transcription and SMAD4-determined the sub location of p53 have not been reported. Taken together, our results demonstrated that AZD3759 might be an alternative strategy for HCC treatment and activating p53-SMAD4 positive feedback loop might enhance its therapeutic effects on HCC. (C) 2018 Elsevier Inc. All rights reserved.