The present study showed that: (1) Ang II-induced cardiomyopathy could be related to the downregulation of Nrf2 and MHRT, (2) overexpression of MHRT activated Nrf2 to inhibit Ang II-induced ROS accumulation and oxidative damage in AC16 cells, and (3) MHRT inhibited Ang II-induced activation of the NLRP3 inflammasome, probably by decreasing cellular ROS deposition to suppress the binding of TXNIP with NLRP3 in AC16 cells. Here, NFE2L2 is linked to cardiomyopathy.