Drug-induced liver injury (DILI) poses a complex and heterogeneous clinical challenge, which often resembles non-drug related acute or chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). Furthermore, certain drugs can induce hepatic steatosis, which is considered a rare variant of hepatotoxicity. Additionally, the detection and diagnosis of DILI in patients with non-alcoholic liver disease present additional challenges that require attention. The importance of achieving an accurate diagnosis is highlighted by the different therapeutic approaches needed for each of these diseases. Nonetheless, as definitive diagnostic tests and distinct biomarkers often remain elusive, the differential diagnosis must rely on a combination of clinical, biochemical, histological, and immunophenotypic profiling. The diagnosis of hepatotoxicity is predicated upon the temporal nexus between the administration of a potentially hepatotoxic drug and the onset of hepatic injury, concomitantly excluding alternative hepatic pathologies. More frequently, this condition presents an acute course, with a more pronounced elevation of cytolytic and cholestatic parameters as compared to fatty liver disease. Advances in elucidating the underlying mechanisms hold promise for bolstering the diagnosis and management of these conditions. This article aims to thoroughly examine and emphasize the currently available scientific evidence to provide valuable insights into the diagnostic strategies for DILI, metabolic-associated liver disease, and drug-induced steatosis (DIS).

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.