Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Due to the insidious onset of HCC, early diagnosis is relatively difficult. HCC also exhibit strong resistance to first-line therapeutic drugs. Therefore, novel precise diagnostic and prognostic biomarkers for HCC are urgently needed. We employed a combination methods of bioinformatic analysis, cell functional experiments in vitro and a xenograft tumour model in vivo to systematically investigate the role of solute carrier family 37 member 3 (SLC37A3) in HCC progression. First, bioinformatic analysis demonstrated that SLC37A3 expression was significantly increased in HCC tissues compared with normal tissues. SLC37A3 expression was also associated with tumour stages and various clinical and pathological features. Similar trends in SLC37A3 expression levels were verified in HCC cells and by using IHC experiments. Next, survival analysis showed that the overall, 1-year, 3-year and 5-year survival rates were decreased in HCC patients with high SLC37A3 expression compared with HCC patients low SLC37A3 expression. Xenograft tumour experiments also suggested that SLC37A3 knockdown significantly inhibited HCC tumourigenesis in vivo. Cell functional experiments suggested that SLC37A3 knockdown inhibited HCC cell proliferation and metastasis, but promoted apoptosis. Furthermore, RNA-seq analysis of SLC37A3-knockdown HCC cells indicated that the type 1 diabetes mellitus (T1DM)-related signalling pathway was significantly altered. The expression levels of insulin secretion-related and glycolysis/gluconeogenesis-related genes were also altered, suggesting that SLC37A3 might be involved in the regulation of glucose homeostasis. In summary, SLC37A3 represents a prospective diagnostic and prognostic biomarker for HCC that functions in glucose metabolism regulation.Copyright © 2023 Elsevier B.V. All rights reserved.