PNPLA3 I148M and Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. With the widespread implementation of HBV vaccination and the availability of highly effective antiviral therapies, the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC has proportionally increased. Notably, up to 20%-30% of MASLD-related HCC cases develop in the absence of overt cirrhosis. Several genetic variants, primarily in genes related to lipid metabolism, play a key role in HCC development in individuals with MASLD and alcohol-related liver disease. Among these, the rs738409 C>G polymorphism (I148M) in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is the strongest genetic factor predisposing to the entire spectrum of MASLD conditions, including cirrhosis and HCC. Importantly, combining PNPLA3 I148M with multiple genetic variants robustly associated with progressive liver disease (i.e., polygenic risk scores) improves risk stratification and prediction of HCC in at-risk individuals compared to the single variant alone. In this review, we will discuss the latest evidence on the epidemiology of HCC and the contribution of PNPLA3 and PNPLA3-based polygenic risk scores to the development of HCC in at-risk individuals.