Several important new findings also came from the present study: (a) after ZBTB20 overexpressing for four weeks post‐MI, survival rate was increased and cardiac dysfunction was ameliorated, accompanied by decreased LV dilatation, cardiac hypertrophy, apoptosis, inflammation, oxidative stress and interstitial fibrosis; (b) ZBTB20‐overexpressed cardiomyocytes exposed to hypoxia showed decreased cell apoptosis; (c) ZBTB20 suppressed TNFα/ASK1/JNK1/2 axis; (d) treatment with a JNK1/2 agonist abolished anti‐apoptotic effect of ZBTB20 in vitro. Here, MAP3K5 is linked to cardiac hypertrophy.