{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:56:29Z","timestamp":1788954989553,"version":"build-2803163510"},"reference-count":43,"publisher":"World Scientific Pub Co Pte Ltd","issue":"08","funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"crossref","award":["2020J01018"],"award-info":[{"award-number":["2020J01018"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Scientific Research Foundation of Guangdong Province","award":["A2019130"],"award-info":[{"award-number":["A2019130"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Am. J. Chin. Med."],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p> 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. <\/jats:p>","DOI":"10.1142\/s0192415x22500902","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T07:06:30Z","timestamp":1667113590000},"page":"2103-2123","source":"Crossref","is-referenced-by-count":55,"title":["Activation of p62-NRF2 Axis Protects against Doxorubicin-Induced Ferroptosis in Cardiomyocytes: A Novel Role and Molecular Mechanism of Resveratrol"],"prefix":"10.1142","volume":"50","author":[{"given":"Wei","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Xiang\u2019an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. 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