NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

SIMPLE SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), which can progress to fibrosis and cirrhosis and ultimately lead to hepatocarcinoma (HCC). Due to its increasing prevalence, NAFLD has become a major public health problem. Given the partial understanding of the complex pathological mechanisms of NAFLD-induced human HCC and the lack of effective treatment, relevant pre-clinical models are still urgently needed to better recapitulate and investigate the process and mechanism of human NAFLD/HCC. This review discusses a selection of the most relevant mouse models in the study of NAFLD/HCC, with their specific advantages and disadvantages, and also the emergence of new ex vivo technologies, which will greatly accelerate the transition from basic science to clinical discoveries. ABSTRACT: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world’s population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease’s development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC.