In the present study, knockdown of AMPK suppressed AKT-NRF2 pathway and it mediated cardiomyocyte protection induced by FGF21, suggesting that AMPK mediated FGF21-induced cardiac protection against DCM partially through activation of AKT2–NRF2-induced antioxidative pathway (Fig. 8). Here, NFE2L2 is linked to familial dilated cardiomyopathy.