Role of Wnt/beta-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance Ahmed M Khalaf,1 David Fuentes,1 Ali I Morshid,2 Mata R Burke,3 Ahmed O Kaseb,4 Manal Hassan,4 John D Hazle,1 Khaled M Elsayes2 1Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; 4Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and one of the fastest-growing causes of cancer-related mortality in the United States. The molecular basis of HCC carcinogenesis has not been clearly identified. Among the molecular signaling pathways implicated in the pathogenesis of HCC, the Wnt/β-catenin signaling pathway is one of the most frequently activated. A great effort is under way to clearly understand the role of this pathway in the pathogenesis of HCC and its role in the transition from chronic liver diseases, including viral hepatitis, to hepatocellular adenomas (HCAs) and HCCs and its targetability in novel therapies. In this article, we review the role of the β-catenin pathway in hepatocarcinogenesis and progression from chronic inflammation to HCC, the novel potential treatments targeting the pathway and its prognostic role in HCC patients, as well as the imaging features of HCC and their association with aberrant activation of the pathway. Keywords: hepatocellular carcinoma, Wnt/β-catenin, gadoxetic acid-enhanced magnetic resonance imaging, molecular therapy