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Background: Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib, a tyrosine kinase inhibitor. However, many patients with HCC are resistant to sorafenib and sensitivity to sorafenib differs according to the progression of liver cancer. SIRT3, a member of the mammalian sirtuin family, is localized to the mitochondria and regulates metabolic activity. To date, a few studies have investigated the effects of SIRT3 on prognosis and drug resistance in patients with HCC. Methods: A correlation study between SIRT3 and other genes was conducted through the TCGA online data portal site (http://cancergenome.nih.gov). To determine the protein expression of SIRT3, immunohistochemistry (IHC) was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2 and Hep3B cells) and conducted functional assays. Results: We identified that SIRT3 expression is downregulated in patients with HCC and high GLUT1 (glucose metabolism index) and Ki67 (proliferation index) expression. In addition, analysis of Cancer Imaging Archive data (TCGA) revealed a negative correlation between GLUT1 and SIRT3 mRNA expression and also HIF1a and SIRT3 mRNA expression. There was also a negative correlation between Ki67 and SIRT3 mRNA expression. After sorafenib treatment, SIRT3 protein expression was highly downregulated in various HCC cell lines (HepG2/Hep3B/SK-Hep1/Huh7). These cells altered their therapeutic resistance to sorafenib via SIRT3 modulation through a 2 dimensional (D)/3D cell culture system. Conclusions: Taken together, our results show that SIRT3 acts as a tumor suppressor and plays an important role in therapy resistance for HCC. Legal entity responsible for the study: Misu Lee. Funding: The National Research Foundation of Korea (Seoul, Korea; Grant Nos. NRF-2015R1D1A1A01057737, NRF-2018R1C1B6003894). Disclosure: All authors have declared no conflicts of interest.