Isodunnianol alleviates doxorubicin-induced myocardial injury by activating protective autophagy

Abstract

Recurrent cardiotoxicity limits the clinical application of doxorubicin (DOX); however the detailed molecular mechanism of DOX cardiotoxicity remains unclear. In the current study, we found that a natural product extracted from Illicium verum, isodunnianol (IDN), mitigates DOX-induced cardiotoxicity by regulating autophagy and apoptosis both in vitro and in vivo. DOX suppressed protective autophagy and induced apoptosis in H9C2 cardiac myoblasts. Additionally, IDN demonstrated up-regulated autophagy and reduced apoptosis through the activation of the AMPK–ULK1 pathway. In addition, the beneficial effects of IDN on DOX which induced myocardial injury were dependent on AMPK and ULK1 phosphorylation. Similar results were also observed in a DOX-induced cardiotoxicity rat model. The combination of IDN and DOX resulted in decreased apoptosis and inflammatory myocardial fibrosis compared to the DOX mono-treatment group. In summary, our findings provide novel insights into the prevention of DOX-related toxicity by isodunnianol, a food source natural product, warranting further investigation.