Doxorubicin (DOX) is an
anthracycline antibiotic that is used extensively for the management of
carcinoma; however, its clinical application is limited due to its serious cardiotoxic side effects. Ferroptosis represents
iron-dependent and
reactive oxygen species (ROS)-related cell death and has been proven to contribute to the progression of DOX-induced
cardiomyopathy.
Fisetin is a natural
flavonoid that is abundantly present in fruits and vegetables. It has been reported to exert cardioprotective effects against DOX-induced
cardiotoxicity in experimental rats. However, the underlying mechanisms remain unknown. The present study investigated the cardioprotective role of
fisetin and the underlying molecular mechanism through experiments in the DOX-induced
cardiomyopathy rat and H9c2 cell models. The results revealed that
fisetin treatment could markedly abate DOX-induced
cardiotoxicity by alleviating cardiac dysfunction, ameliorating myocardial
fibrosis, mitigating
cardiac hypertrophy in rats, and attenuating ferroptosis of cardiomyocytes by reversing the decline in the GPX4 level. Mechanistically,
fisetin exerted its
antioxidant effect by reducing the MDA and
lipid ROS levels and increasing the
glutathione (GSH) level. Moreover,
fisetin exerted its protective effect by increasing the
SIRT1 expression and the Nrf2
mRNA and
protein levels and its nuclear translocation, which resulted in the activation of its downstream genes such as HO-1 and FTH1. Selective inhibition of
SIRT1 attenuated the protective effects of
fisetin in the H9c2 cells, which in turn decreased the GSH and GPX4 levels, as well as Nrf2, HO-1, and FTH1 expressions. In conclusion,
fisetin exerts its
therapeutic effects against DOX-induced
cardiomyopathy by inhibiting ferroptosis via
SIRT1/Nrf2 signaling pathway activation.