Using a cardiac disease mimicking mouse model developing a mutant protein aggregation cardiomyopathy (MPAC) caused by mutations in the protein alpha B-Crystallin, the authors demonstrate that normal Nrf2 expression in the MPAC model deteriorated the cardiac phenotype reflected by heart failure, whereas the MPAC model with Nrf2 deficiency did not develop heart failure. Here, NFE2L2 is linked to heart disorder.