In summary, our data in mice reveal negative correlations between Sirt1 and genes involved in hepatic lipid accumulation and inflammation, as well as a Sirt1 upregulation induced by treadmill exercise, especially when combined with DHA-rich diet, suggesting that Sirt1 could participate in the beneficial mechanisms of exercise to alleviate MASLD. This evidence concerns the gene SIRT1 and metabolic dysfunction-associated steatotic liver disease.