This observation seems to suggest a possible way to counteract the harmful effect due to the PNPLA3 genetic predisposition to NAFLD, recommending a low caloric, well-balanced diet regimen and physical exercise, even if the effect of these therapeutic approaches needs to be assessed in depth with other large population clinical trials, also considering the possibility of a different outcome in the case of concomitant multiple gene mutations. Here, PNPLA3 is linked to metabolic dysfunction-associated steatotic liver disease.