Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver diseases. Over time, there has been a significant increase in the prevalence of MASLD. It has become one of the leading causes of hepatocellular carcinoma (HCC) in the United States, France, and the United Kingdom. Globally, the incidence of HCC related to MASLD may further increase with the growing prevalence of obesity. Non-alcoholic steatohepatitis (NASH) is an important stage of MASLD, which is more likely to cause cirrhosis and even HCC. And patients with NASH cirrhosis have a much higher incidence of hepatocellular cancer than patients with non-cirrhotic MASLD. As a result, it is critical to investigate the targets of MASLD therapy in HCC. This article reviews therapeutic targets of MASLD, such as farnesoid X receptor (FXR), peroxisome proliferator activated receptor (PPAR), fibroblast growth factor-21 (FGF-21), etc., and introduces the drugs related to these targets and their mechanisms of action in HCC. In addition, the developmental process and pathogenesis of MASLD, as well as risk factors for HCC development, are discussed. These are of great significance for the prevention and treatment of HCC.

Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. Metabolites, such as short-chain fatty acids, impact the function, inflammation, and death of hepatocytes, the primary parenchymal cells in the liver tissue. Cholangiocytes, the epithelial cells that line the bile ducts, can differentiate into proliferative hepatocytes in chronic liver injury. In addition, hepatic non-parenchymal cells, including liver sinusoidal endothelial cells, hepatic stellate cells, and innate and adaptive immune cells, are involved in liver inflammation. Proteins such as fibroblast growth factors, acetyl-coenzyme A carboxylases, and nuclear factor erythroid 2-related factor 2 are involved in liver metabolism and inflammation, which are potential targets for NASH treatment. This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments.