Fisetin attenuates doxorubicin‐induced cardiotoxicity by inhibiting the insulin‐like growth factor II receptor apoptotic pathway through estrogen receptor‐α/‐β activation

Abstract Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX‐induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX‐induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX‐induced cell death in a dose‐dependent manner. Moreover, western blotting and TUNEL‐DAPI staining showed that fisetin significantly attenuated DOX‐induced cardiotoxicity in vitro and in vivo by inhibiting the insulin‐like growth factor II receptor (IGF‐IIR) apoptotic pathway through estrogen receptor (ER)‐α/‐β activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX‐induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX‐induced cardiotoxicity.