microRNA-203 (miR203) plays an important role in the formation and development of multiple types of cancers. However, its role in hepatic carcinogenesis has not been well studied. Mitogen-activated protein kinase signaling is known to be activated in hepatocellular carcinoma (HCC), but there is a lack of effective drugs targeting this pathway for HCC treatment. In this study, we investigated the role of miR203 in HCC and the underlying mechanism. We found that miR203 was significantly downregulated in HCC cell lines and patient tissues compared with a hepatocyte cell line (L02) or normal liver tissues. Restoration of miR203 inhibited HCC cell growth and induced cell cycle arrest and apoptosis. In primary and xenograft HCC mouse models, miR203 also significantly blocked HCC growth. Bioinformatic analysis indicated that miR203 directly binds to the 3'UTR of NRas mRNA, resulting in decreased expression of NRas and inactivation of mitogen-activated protein kinase (MAPK) signaling. Activation of MAPK signaling by ectopic NRas expression rescued the cell proliferation blocked by miR203. Together, our findings illustrate the fundamental role of miR203 as a natural inhibitor of RAS/MAPK signaling in hepatic carcinogenesis in vitro and in vivo. In light of the critical and universal activation of the MAPK pathway in HCC, miR203 has the potential to serve as a nucleotide drug for the treatment of HCC with activated MAPK signaling.AJCR Copyright © 2023.