Backgroud: Hepatocellular carcinoma (HCC) is characterized by rapid early proliferation and distant metastasis and is extremely difficult to treat. Aerobic glycolysis is a hallmark of abnormal glucose metabolism in cancer cells as has been shown to be associated with tumor proliferation and metastasis; however, the mechanisms underlying aerobic glycolysis remain unclear.Methods: Immunohistochemistry (IHC) and qRT-PCR was performed to investigate the association between TMEM147 expression and the clinicopathological characteristics and prognosis of patients with HCC. Loss-and gain-of function assays were performed to investigate the role of TMEM147 in proliferation, metastasis and glycolysis in vitro and vivo. Bioinformatic analysis and rescue assay were used to demonstrated the TMEM147 interacted with EGFR and promoted its retromer-mediated recycling back to the plasma membrane.Results: we identified TMEM147 as a protein that was highly expressed and associated with poor survival in patients with HCC. Both gain-and loss-of-function studies revealed that TMEM147 acted as a key oncoprotein by promoting HCC growth, metastasis, and glycolysis via the EGFR/ MAPK signaling pathway. Mechanistically, TMEM147 interacted with EGFR and promoted its retromer-mediated recycling back to the plasma membrane, thus increasing the stability of EGFR and prolonging activation of the downstream MAPK pathway. Conclusion:Collectively, these results demonstrated the role and functional mechanism of TMEM147 in HCC, and indicated that TMEM147 may represent a prognostic biomarker and potential therapeutic target for HCC. BackgroundHepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death worldwide [1].Although improvements in many therapeutic strategies, including surgical resection, liver transplantation, and radiofrequency ablation, have improved the 5-year survival rate of HCC patients, its prognosis remains unsatisfactory [2]. Survival is associated with the use of targeted treatments, such as the tyrosine kinase inhibitor sorafenib, in patients with advanced stage cancer with vascular invasion and distant metastasis [3,4]. Clarifying the biological processes and molecular mechanisms