Herein, we demonstrate that miR-21 deficiency can facilitate inflammation in cardiac tissue and inflammatory cytokine production in macrophages triggered by DAMPs, thus exacerbate cardiac dysfunction and increase infarct and scar sizes post MI, which is attributed to the enhanced activation of p38 and NF-κB signaling mediated by the interaction between KBTBD7 and MKK3/6. Here, KBTBD7 is linked to myocardial infarction.