Phenotypes of MASLD-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) typically develops as consequence of liver cirrhosis, but HCC epidemiology has evolved drastically in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), has emerged as the most common chronic liver disease worldwide and a leading cause of HCC. A substantial proportion of MASLD-associated HCC (MASLD-HCC) can also develop in patients without cirrhosis. The specific pathways that trigger carcinogenesis in this context are not completely elucidated, and recommendations for HCC surveillance in MASLD patients are challenging. In the era of precision medicine, it is critical to understand the processes that define the profiles of patients at increased risk of HCC in the MASLD setting, including cardio-metabolic risk factors, and the molecular targets that could be effectively tackled. Ideally, defining categories that encompass key pathophysiological features, associated with tailored diagnostic and treatment strategies, should facilitate the identification of specific MASLD-HCC phenotypes. In this review, we discuss MASLD-HCC, including its epidemiology and healthcare burden, the mechanistic data promoting MASLD, MASH, and MASLD-HCC. Its natural history, prognosis and treatment are specifically addressed, as the role of metabolic phenotypes of MASLD-HCC as a potential strategy for risk stratification. The challenges in identifying high-risk patients and screening strategies are also discussed, as well as the potential approaches for MASLD-HCC prevention and treatment.