With MASLD increasing globally, together with the prevalence of obesity and the interaction between genetic predisposition and other factors partially explaining the large variability observed in MASLD patients' phenotype and natural history, there is a need to further increase our knowledge on the role and mechanisms of PNPLA3 (variants) in MASLD or MASH [106, 107, 108]. This evidence concerns the gene PNPLA3 and obesity due to melanocortin 4 receptor deficiency.