A novel cardioprotective mechanism of rosuvastatin: restoring PINK1/parkin-mediated mitophagy via SIRT1/FOXO1 activation in doxorubicin-induced cardiotoxicity.
Yomna S Momen, Mohamed A Kandeil, Mohamed O Mahmoud
{"title":"A novel cardioprotective mechanism of rosuvastatin: restoring PINK1/parkin-mediated mitophagy via SIRT1/FOXO1 activation in doxorubicin-induced cardiotoxicity.","authors":"Yomna S Momen, Mohamed A Kandeil, Mohamed O Mahmoud","doi":"10.1007/s00280-025-04805-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy remains a key cancer treatment despite advancements in cancer therapy, with doxorubicin (DOX) widely used for solid and hematological tumors. However, its clinical use is limited by severe acute and chronic cardiotoxicity, primarily driven by oxidative stress and mitophagic dysregulation. Rosuvastatin (RSV), a lipid-lowering drug, has shown cardioprotective effects. This study aimed to investigate the molecular mechanism underlying RSV's protection against DOX-induced cardiotoxicity.</p><p><strong>Methods: </strong>Adult male Wistar rats were assigned to eight groups: control, RSV-only (20 mg/kg, orally, for 3 weeks), DOX-only (18 mg/kg, intraperitoneally, over 2 weeks), RSV + DOX, CQ + RSV + DOX (chloroquine 25 mg/kg, intraperitoneally, for 2 weeks), CQ-only, RSV + CQ, and CQ + DOX. 48 h after the last DOX injection, serum myocardial injury markers, oxidative stress markers, and autophagic flux biomarkers (LC3II & P62) were assessed. RT-PCR evaluated lncRNA APF gene expression, while western blotting quantified p-SIRT1, FOXO1, p-PINK1, and p-Parkin protein levels.</p><p><strong>Results: </strong>RSV mitigated DOX-induced myocardial injury and oxidative stress while restoring autophagic flux, as evidenced by P62 and LC3II reversal. RSV enhanced lncRNA APF gene expression, p-SIRT1, p-PINK1, and p-Parkin levels while downregulating FOXO1. The autophagy inhibitor CQ blunted RSV's cardioprotective effects.</p><p><strong>Conclusion: </strong>RSV protects against DOX-induced cardiotoxicity, at least in part, by restoring autophagic flux and rescuing PINK1/Parkin-mediated mitophagy via upregulation of the SIRT1/FOXO1 pathway. Thus, combining RSV with DOX may enable patients to complete chemotherapy with a reduced risk of cardiotoxicity. However, further studies are warranted to confirm its translational potential.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"84"},"PeriodicalIF":2.3000,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Chemotherapy and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00280-025-04805-5","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Chemotherapy remains a key cancer treatment despite advancements in cancer therapy, with doxorubicin (DOX) widely used for solid and hematological tumors. However, its clinical use is limited by severe acute and chronic cardiotoxicity, primarily driven by oxidative stress and mitophagic dysregulation. Rosuvastatin (RSV), a lipid-lowering drug, has shown cardioprotective effects. This study aimed to investigate the molecular mechanism underlying RSV's protection against DOX-induced cardiotoxicity.
Methods: Adult male Wistar rats were assigned to eight groups: control, RSV-only (20 mg/kg, orally, for 3 weeks), DOX-only (18 mg/kg, intraperitoneally, over 2 weeks), RSV + DOX, CQ + RSV + DOX (chloroquine 25 mg/kg, intraperitoneally, for 2 weeks), CQ-only, RSV + CQ, and CQ + DOX. 48 h after the last DOX injection, serum myocardial injury markers, oxidative stress markers, and autophagic flux biomarkers (LC3II & P62) were assessed. RT-PCR evaluated lncRNA APF gene expression, while western blotting quantified p-SIRT1, FOXO1, p-PINK1, and p-Parkin protein levels.
Results: RSV mitigated DOX-induced myocardial injury and oxidative stress while restoring autophagic flux, as evidenced by P62 and LC3II reversal. RSV enhanced lncRNA APF gene expression, p-SIRT1, p-PINK1, and p-Parkin levels while downregulating FOXO1. The autophagy inhibitor CQ blunted RSV's cardioprotective effects.
Conclusion: RSV protects against DOX-induced cardiotoxicity, at least in part, by restoring autophagic flux and rescuing PINK1/Parkin-mediated mitophagy via upregulation of the SIRT1/FOXO1 pathway. Thus, combining RSV with DOX may enable patients to complete chemotherapy with a reduced risk of cardiotoxicity. However, further studies are warranted to confirm its translational potential.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
