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Abstract Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. Metformin, a first-line oral agent used in the treatment of type 2 diabetes, exhibits efficacy in metabolic reprogramming fueling changes in cell growth and proliferation for multiple cancer types, including HCC. However, the molecular mechanism by which metformin delays hepatocarcinogenesis in individuals with hepatic steatosis remains rare. Here, we investigate the preventive efficacy of metformin in a rapid AKT/c-Met-triggered HCC mouse model featuring excessive levels of steatosis. Hematoxylin and eosin staining, Oil Red O staining and immunoblotting were applied for mechanistic investigations. Pharmacological and biochemical strategies were employed to illuminate molecular evidence for HCC cell lines. The results show that metformin obstructs the malignant transformation of hepatocytes in AKT/c-Met mice. Mechanistically, metformin reduces the expression of phospho-ERK (Thr202/Tyr204) and two forms of proto-oncogenes, Cyclin D1 and c-Myc, in AKT/c-Met mice. Moreover, metformin ameliorates FASN-mediated aberrant lipogenesis and HK2/PKM2-driven ATP generation in vivo. Furthermore, metformin represses the expression of FASN and HK-2 by targeting c-Myc in an AMPK-dependent manner in vitro. In addition, metformin is effective at inhibiting PKM2 expression in the presence of an AMPK inhibitor compound C, suggesting that its functioning in PKM2 is AMPK-independent. Our study experimentally validates a novel molecular mechanism by which metformin alleviates enhanced lipogenesis and high energy metabolism during hepatocarcinogenesis, indicating that metformin may serve as an agent for the prevention of HCC in patients with nonalcoholic fatty liver diseases. Highlights • Metformin delays AKT/c-Met-driven hepatocarcinogenesis in mice. • Metformin attenuates lipogenesis and ATP generation in AKT/c-Met HCC mice. • Metformin suppresses the expression of FASN and HK-2 in an AMPK/c-Myc dependent manner. • Metformin AMPK-independently reduces the expression of PKM2. [ABSTRACT FROM AUTHOR]

Orlistat (Xenical™), a US Food and Drug Administration (FDA)-approved anti-obesity drug, shows efficacy against multiple tumor types, including hepatocellular carcinoma (HCC), due to its ability to inhibit fatty acid synthase (FASN) activity. However, whether orlistat affects hepatocellular malignant transformation during hepatocarcinogenesis in vivo is unknown. This study assessed the antisteatotic and antitumorigenic efficacy of orlistat in a rapid HCC FVB/N mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Human hepatoma cell lines were used for mechanical validation in vitro. Hematoxylin and eosin staining, immunohistochemistry, and immunoblotting were applied for the mechanistic investigation. The results revealed that when orlistat was administered in the early stage of AKT/c-Met-triggered hepatocarcinogenesis, it resulted in the elimination of hepatic tumor burden. Mechanistically, orlistat efficiently elevated PTEN expression and suppressed AKT/SREBP1/FASN signaling both in vivo and in vitro , impairing AKT/c-Met-driven de novo lipogenesis and aberrant proliferation. Altogether, this study demonstrates the antilipogenic and antiproliferative efficacy of orlistat in hepatocarcinogenesis, suggesting that orlistat may be beneficial for the treatment of HCC, especially in NAFLD-related HCCs featuring activated AKT/mTOR cascade and increased lipogenesis in livers. • FASN inhibitor orlistat delays AKT/c-Met-driven hepatocarcinogenesis in mice. • Orlistat attenuates hepatocellular malignant transformation in mice. • Orlistat elevates PTEN expression and inhibits AKT phosphorylation in the HCC mice. [ABSTRACT FROM AUTHOR]