Considering that Fndc5 is widely expressed and can be secreted into blood to form irisin by various tissues 51,52, we generated a global knockout mice of Fndc5 (Fndc5-/- mice, Figure 2A-C) to test the role of Fndc5/irisin in protection of NR in NAFLD. This evidence concerns the gene FNDC5 and metabolic dysfunction-associated steatotic liver disease.