Ramandi_2025_Liver.Int_45_e70091

Patatin-like phospholipase domain-containing 3 (PNPLA3) was the first gene identified through genome-wide association studies to be linked to hepatic fat accumulation. A missense variant, encoding the PNPLA3-148M allele, has since been shown to increase the risk for the full spectrum of steatotic liver disease (SLD), from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Despite extensive validation of this association and ongoing research into its pathogenic role, the precise mechanisms by which PNPLA3-148M contributes to the progression of SLD remain poorly understood. In this review, we evaluate preclinical in vitro and in vivo models used to investigate PNPLA3 and its involvement in SLD, with particular emphasis on metabolic dysfunction-associated steatotic liver disease. We assess the strengths and limitations of these models, as well as the challenges arising from species differences in PNPLA3 expression and function between human and murine systems.