Citation: Zunica, E.R.M.; Heintz, E.C.; Axelrod, C.L.; Kirwan, J.P. Obesity Management in the Primary Prevention of Hepatocellular Carcinoma. Cancers 2022, 14, 4051. https://doi.org/10.3390/ cancers14164051 Academic Editor: Antonio Grieco Received: 28 July 2022 Accepted: 20 August 2022 Published: 22 August 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Review Obesity Management in the Primary Prevention of Hepatocellular Carcinoma Elizabeth R. M. Zunica , Elizabeth C. Heintz , Christopher L. Axelrod * and John P. Kirwan * Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA * Correspondence: christopher.axelrod@pbrc.edu (C.L.A.); john.kirwan@pbrc.edu (J.P.K.); Tel.: +1-225-763-2513 (J.P.K.) Simple Summary: Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease driven in part by the rising obesity epidemic. Obesity causes HCC by initiating and progressing fatty liver disease. As such, weight reduction with the intention to treat fatty liver disease appears ideal for the primary prevention of HCC, but evidence is limited. This review covers recent advances in the treatment and management of obesity and fatty liver disease as it pertains to HCC risk and prevention. We conclude that combinatorial lifestyle, behavioral, medical, and surgical therapies that maximize whole body and liver fat reduction have the greatest potential to prevent HCC; however, prospective studies are required to demonstrate effectiveness. Abstract: Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presenta- tion, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associa- tions between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal. Keywords: obesity; weight loss; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; hepatocellular carcinoma; liver cancer; primary prevention 1. Introduction The primary established risk factors for the development of HCC are biological sex, race/ethnicity, chronic alcohol consumption, viral infection, pre-existing liver disease, obesity, and type 2 diabetes [1]. HCC is not known to be caused by specific genetic mu- tations, but increased susceptibility is observed in patients with specific germline DNA polymorphisms including EGF, IFNL3, MICA, TLL1, PNPLA3, TM6SF2, and MBOAT7 [2] as well as heritable conditions such as Wilson’s disease, tyrosinemia, alpha1-antitrypsin deficiency, and porphyria cutanea tarda [3]. The onset of HCC is frequently observed in patients with high alcohol intake and chronic viral hepatitis B or C infection, accounting for greater than 50% of cases [4]. Prevention of hepatitis-induced HCC occurs through preven- tion of exposure, inoculation with the hepatitis B vaccine (currently there is no hepatitis C vaccine), and/or treatment with targeted antiviral medications [5]. The expansion of vaccine inoculation in the United States, which was incorporated into the infant inoculation schedule in 1991, has greatly reduced the risk of hepatitis and cancer related mortality [6]. Cancers 2022, 14, 4051. https://doi.org/10.3390/cancers14164051 https://www.mdpi.com/journal/cancers