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Yingcai Yan,1,* Minjie Xie,1,* Linshi Zhang,1 Xiaohu Zhou,1 Haiyang Xie,1 Lin Zhou,1 Shusen Zheng,2,3 Weilin Wang2,31Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University, 2Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, 3Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The first Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide and is a prominent source of mortality. Ras-related associated with diabetes (RRAD), one of the first members of the 35–39kDa class of novel Ras-related GTPases, is linked to several types of cancer, although its function in HCC remains unclear. In this study, we observed that RRAD was downregulated in HCC compared with adjacent normal tissues. This change was associated with a poor prognosis. Furthermore, knockdown of RRAD in SK-Hep-1 cells facilitated cell proliferation, accelerated the G1/S transition during the cell cycle, induced cell migration, and reduced apoptosis. In contrast, overexpression of RRAD in Huh7 cells had the opposite effects. Moreover, we demonstrated that RRAD induced cell proliferation through regulation of the cell cycle by downregulating cyclins and cyclin-dependent kinases. RRAD induced tumor cell apoptosis through the mitochondrial apoptosis pathway. In addition, we confirmed that knockdown of RRAD promoted aerobic glycolysis by upregulating glucose transporter 1, whereas overexpression of RRAD inhibited aerobic glycolysis. In conclusion, RRAD plays a pivotal role as a potential tumor suppressor in HCC. An improved understanding of the roles of RRAD in tumor metabolism may provide insights into its potential as a novel molecular target in HCC therapy. Keywords: hepatocellular carcinoma, Ras-related associated with diabetes, aerobic glycolysis, tumorigenicity, glucose transporter 1