期刊
AMERICAN JOURNAL OF CHINESE MEDICINE
卷 50, 期 8, 页码 2103-2123出版社
WORLD SCIENTIFIC PUBL CO PTE LTD
DOI: 10.1142/S0192415X22500902
关键词
Resveratrol; Polyphenolic Compound; Ferroptosis; p62-NRF2 Axis; Doxorubicin; Cardiotoxicity
资金
- Natural Science Foundation of Fujian Province [2020J01018]
- Medical Scientific Research Foundation of Guangdong Province [A2019130]
Doxorubicin, a common chemotherapeutic agent, has limited clinical efficacy due to its severe cardiotoxicity. Resveratrol, known for its antioxidative and anti-inflammatory properties, protects cardiomyocytes by inhibiting ferroptosis induced by doxorubicin. This study reveals that resveratrol activates the p62-NRF2/HO-1 pathway and suppresses mitochondrial reactive oxygen species, thereby preventing ferroptosis in cardiomyocytes.
Doxorubicin (DOX) is a most common anthracycline chemotherapeutic agent; however, its clinical efficacy is limited due to its severe and irreversible cardiotoxicity. Ferroptosis, characterized by iron overload and lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. Resveratrol (RSV) displays cardioprotective and anticancer effects, owing to its antioxidative and anti-inflammatory properties. However, the role and mechanism of RSV in DOX-mediated ferroptosis in cardiomyocytes is unclear. This study showed that DOX decreased cell viability, increased iron accumulation and lipid peroxidation in H9c2 cells; however, these effects were reversed by RSV and ferroptosis inhibitor ferrostatin-1 (Fer-1) pre-treatment. Additionally, RSV significantly increased the cell viability of H9c2 cells treated with ferroptosis inducers Erastin (Era) and RSL3. Mechanistically, RSV inhibited mitochondrial reactive oxygen species (mtROS) overproduction and upregulated the p62-NRF2/HO-1 pathway. RSV-induced NRF2 activation was partially dependent on p62, and the selective inhibition of p62 (using p62-siRNA interference) or NRF2 (using NRF2 specific inhibitor, ML385) significantly abolished the anti-ferroptosis function of RSV. Furthermore, RSV treatment protected mice against DOX-induced cardiotoxicity, including significantly improving left ventricular function, ameliorating myocardial fibrosis and suppressing ferroptosis. Consistent with in vitro results, RSV also upregulated the p62-NRF2/HO-1 expression, which was inhibited by DOX, in the myocardium. Notably, the protective effect of RSV in DOX-mediated ferroptosis was similar to that of Fer-1 in vitro and in vivo. Thus, the p62-NRF2 axis plays a critical role in regulating DOX-induced ferroptosis in cardiomyocytes. RSV as a potent p62 activator has potential as a therapeutic target in preventing DOX-induced cardiotoxicity via ferroptosis modulation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据