MEK inhibitor induces cardiac complications by preventing ZMYND8-mediated ubiquitination and proteasomal degradation of HMGB1

The cardiac complications caused by drugs, including cardiac dysfunction and heart failure, significantly limit the wide clinical application of drugs and lead to morbidity and mortality. High mobility group box 1 (HMGB1) plays an extensive role in drug-induced cardiotoxicity. However, the cardiotoxic mechanisms for most small-molecule kinase inhibitors (SMKIs) remains unknown. Here, we identify that accumulated HMGB1 is associated with the cardiac complications caused by a series of FDA-approved SMKIs, among which trametinib-induced cardiomyocyte death was most significantly reversed by HMGB1 knockout. Moreover, cardiomyocyte-specific Hmgb1 deletion in mice could improve cardiac muscle contraction, calcium regulation and cardiomyocyte Apoptosis in autophagy- or inflammation-independent manner. We further show that trametinib leads to the aberrant accumulation of HMGB1 by increasing its stability via inhibiting Zinc Finger Protein Zinc Finger MYND-Type Containing 8 (ZMYND8)-mediated ubiquitination and proteasomal degradation of HMGB1, identifying ZMYND8 as a novel negative regulator of HMGB1 stability in cardiomyocyte and a potential novel regulator of cardiac function. Glycyrrhizic acid, an HMGB1 inhibitor used in clinic, prevents trametinib-induced cardiac complications. These findings reveal the mechanism and propose an effective intervention strategy for trametinib-induced cardiac complications, which would contribute to the safe application of trametinib, cardiac safety evaluation of drugs or candidate compounds and novel drug development.