There is ample evidence that type 2 diabetes is an independent risk factor for the development of various cancers including hepatocellular carcinoma (HCC). Metformin, a widely used antidiabetic agent, has been shown to have chemopreventive properties that may reduce the risk of cancer in diabetes. Here we summarize clinical and experimental data concerning the role of metformin in diabetes-associated hepatocarcinogenesis and review the key molecular mechanisms implicated in this action. By modulating mitochondrial function, metformin activates adenosine monophosphateactivated protein kinase (AMPK), a master regulator of energy metabolism that corrects most diabetes-associated derangements and mitigates the impact of insulin resistance on tumor growth. Moreover, metformin acts through additional AMPK targets in various pathways of oncogenesis and tumor suppression. Finally, metformin may also hinder hepatocarcinogenesis through AMPK-independent mechanisms. Controversies about the use of metformin as a chemopreventive agent include an efficacy bias related to duration and severity of diabetes, a lack of convincing impact on nonalcoholic fatty liver disease (NAFLD) representing the liver manifestation of diabetes, and a disputed role in lactic acidosis as a major adverse event. Future research may help develop randomized clinical trials on the impact of HCC by metformin, explore its utility in the non-diabetic and noncirrhotic population, elucidate its precise mechanisms of action to identify new molecular targets, and evaluate safer and more efficient derivatives of this intriguing compound
