With the hypothesis that the Lrp6 genetic polymorphism influences individual susceptibility to NAFLD, the present work was aimed to ascertain whether the functional changes of Lrp6 caused by genetic mutation or knockdown have any impact on NAFLD progress and the therapeutic response to silibinin by using human clinical data, MCD diet-induced NAFLD mouse model, and cell models. This evidence concerns the gene LRP6 and metabolic dysfunction-associated steatotic liver disease.