Tectorigenin attenuates myocardial damage by doxorubicin-induced ferroptosis by activating the p62-Keap1-Nrf2/HO-1/GPX4 axis

IF 3 3区医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE

Journal of Traditional and Complementary Medicine Pub Date : 2025-09-01 DOI:10.1016/j.jtcme.2025.02.006

Like Xie , Sujun Xiao , Qinyi Zhou , Wang Chen , Zhihao Hu , Yunhui Li , Yizhou Liu , Xiaofeng Ma , Yuan Li

{"title":"Tectorigenin attenuates myocardial damage by doxorubicin-induced ferroptosis by activating the p62-Keap1-Nrf2/HO-1/GPX4 axis","authors":"Like Xie , Sujun Xiao , Qinyi Zhou , Wang Chen , Zhihao Hu , Yunhui Li , Yizhou Liu , Xiaofeng Ma , Yuan Li","doi":"10.1016/j.jtcme.2025.02.006","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Anticancer agent doxorubicin is essential for cancer treatment but often causes cardiotoxicity. Tectorigenin has shown potential cardioprotective effects, but underlying mechanisms remain unclear. We aimed to investigate whether Tectorigenin attenuates doxorubicin-induced myocardial injury.</div></div><div><h3>Methods</h3><div>Doxorubicin (DOX) was utilized in C57BL/6J mice and cardiomyocytes H9c2, to establish <em>in vivo</em> and <em>in vitro</em> cardiotoxicity models, then treated with Tectorigenin. The levels of ferroptosis-related factors were measured using specific assay kits. The Liperfluo and DHE stainings were used to detect levels of lipid ROS. Cardiac function in rats was assessed using echocardiography. Immunofluorescence staining was used to detect Nrf2 nuclear translocation. ELISA assay was employed to check serum CK-MB, BNP and Tn-T levels. Cardiac injury and fibrosis were evaluated through HE and Masson stainings. Furthermore, TEM was employed to observe mitochondrial ultrastructure. Western blot and immunofluorescence staining were utilized to detect protein levels.</div></div><div><h3>Results</h3><div>DOX induced ferroptosis in H9c2 cells concentration-dependently and time-dependently, which was alleviated by Tectorigenin treatment. ML385 or K67 abolished Tectorigenin's inhibition on DOX-induced H9c2 cell ferroptosis. Mechanistically, Tectorigenin promoted the expressions of p62 and p-p62, leading to decreased Keap1 expression. This cascade facilitated Nrf2 nuclear translocation and subsequently elevated HO-1 and GPX4 expressions. Moreover, Tectorigenin treatment improved cardiac function, myocardial injury, fibrosis and mitochondrial function in C57BL/6J mice induced by DOX, as well as ferroptosis.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that Tectorigenin attenuates DOX-induced ferroptosis and myocardial damage by activating the p62-Keap1-Nrf2/HO-1/GPX4 axis, this may provide a therapeutic strategy for mitigating cardiotoxicity associated with chemotherapeutic agents.</div></div>","PeriodicalId":17449,"journal":{"name":"Journal of Traditional and Complementary Medicine","volume":"15 5","pages":"Pages 573-581"},"PeriodicalIF":3.0000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Traditional and Complementary Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2225411025000161","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INTEGRATIVE & COMPLEMENTARY MEDICINE","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Anticancer agent doxorubicin is essential for cancer treatment but often causes cardiotoxicity. Tectorigenin has shown potential cardioprotective effects, but underlying mechanisms remain unclear. We aimed to investigate whether Tectorigenin attenuates doxorubicin-induced myocardial injury.

Methods

Doxorubicin (DOX) was utilized in C57BL/6J mice and cardiomyocytes H9c2, to establish in vivo and in vitro cardiotoxicity models, then treated with Tectorigenin. The levels of ferroptosis-related factors were measured using specific assay kits. The Liperfluo and DHE stainings were used to detect levels of lipid ROS. Cardiac function in rats was assessed using echocardiography. Immunofluorescence staining was used to detect Nrf2 nuclear translocation. ELISA assay was employed to check serum CK-MB, BNP and Tn-T levels. Cardiac injury and fibrosis were evaluated through HE and Masson stainings. Furthermore, TEM was employed to observe mitochondrial ultrastructure. Western blot and immunofluorescence staining were utilized to detect protein levels.

Results

DOX induced ferroptosis in H9c2 cells concentration-dependently and time-dependently, which was alleviated by Tectorigenin treatment. ML385 or K67 abolished Tectorigenin's inhibition on DOX-induced H9c2 cell ferroptosis. Mechanistically, Tectorigenin promoted the expressions of p62 and p-p62, leading to decreased Keap1 expression. This cascade facilitated Nrf2 nuclear translocation and subsequently elevated HO-1 and GPX4 expressions. Moreover, Tectorigenin treatment improved cardiac function, myocardial injury, fibrosis and mitochondrial function in C57BL/6J mice induced by DOX, as well as ferroptosis.

Conclusion

Our findings reveal that Tectorigenin attenuates DOX-induced ferroptosis and myocardial damage by activating the p62-Keap1-Nrf2/HO-1/GPX4 axis, this may provide a therapeutic strategy for mitigating cardiotoxicity associated with chemotherapeutic agents.

Abstract Image

查看原文本刊更多论文

鸢尾黄素通过激活p62-Keap1-Nrf2/HO-1/GPX4轴，减轻阿霉素诱导的铁凋亡对心肌的损害

多柔比星是治疗癌症必不可少的抗癌药物，但常引起心脏毒性。鸢尾黄素已显示出潜在的心脏保护作用，但其潜在机制尚不清楚。我们的目的是研究鸢尾黄素是否能减轻阿霉素引起的心肌损伤。方法采用多柔比星（DOX）对C57BL/6J小鼠和心肌细胞H9c2建立体内、体外心脏毒性模型，并用鸢尾黄素处理。采用特异的检测试剂盒检测嗜铁相关因子的水平。Liperfluo和DHE染色用于检测脂质ROS水平。采用超声心动图评价大鼠心功能。免疫荧光染色检测Nrf2核易位。ELISA法检测血清CK-MB、BNP、Tn-T水平。HE、Masson染色评价心脏损伤及纤维化情况。透射电镜观察线粒体超微结构。Western blot和免疫荧光染色检测蛋白水平。结果dox诱导H9c2细胞铁下垂呈浓度依赖性和时间依赖性，鸢尾黄素可减轻其作用。ML385或K67均可消除Tectorigenin对dox诱导的H9c2细胞铁下垂的抑制作用。从机制上讲，丁香黄素促进p62和p-p62的表达，导致Keap1表达降低。这个级联促进了Nrf2核易位，随后提高了HO-1和GPX4的表达。此外，鸢尾黄素治疗可改善DOX诱导的C57BL/6J小鼠的心功能、心肌损伤、纤维化和线粒体功能以及铁吊。结论鸢尾黄素可通过激活p62-Keap1-Nrf2/HO-1/GPX4轴，减轻dox诱导的铁下沉和心肌损伤，这可能为减轻化疗药物相关的心脏毒性提供了一种治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Traditional and Complementary Medicine Medicine-Complementary and Alternative Medicine

CiteScore

9.30

自引率

6.70%

发文量

审稿时长

66 days

期刊介绍： eJTCM is committed to publish research providing the biological and clinical grounds for using Traditional and Complementary Medical treatments as well as studies that demonstrate the pathophysiological and molecular/biochemical bases supporting the effectiveness of such treatments. Review articles are by invitation only. eJTCM is receiving an increasing amount of submission, and we need to adopt more stringent criteria to select the articles that can be considered for peer review. Note that eJTCM is striving to increase the quality and medical relevance of the publications.