Erianin alleviates doxorubicin-induced cardiotoxicity by activating the Keap1-Nrf2 signaling pathway

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-22 DOI:10.1016/j.phymed.2025.156684

Shiyao Kang , Huimin Li , Ming Li , Yuan Zhao , Jianyu Pang , Juhua Dan , Miaomiao Sheng

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Abstract

Background

Doxorubicin (DOX) has significant toxic side effects on cardiomyocytes, and existing preventive drug dexrazoxane has serious side effects. Therefore, in-depth research on drugs that can enhance the antitumor effect of DOX and simultaneously reduce its cardiotoxicity is of crucial significance. Our study explored the regulatory role of Erianin in DOX-induced cardiotoxicity and the specific molecular mechanism.

Methods

In this study, we constructed a myocardial injury model in mice with DOX. The toxic side effects of DOX on the organism were determined by recording the weight changes of the mice and calculating the spleen index and heart-tibia ratio of the mice. The degree of myocardial injury in mice was evaluated by methods such as echocardiography and Sirius red staining. Further in vivo experiments were conducted to verify whether the silencing of Nrf2 could block the protective effect of Erianin on myocardial cells.

Results

We found Erianin significantly alleviated DOX-induced cardiomyocyte injury (p < 0.0001), increased heart tissue pumping efficiency and contractility (p < 0.001), and reduced myocardial cell fibrosis. Mechanism study showed that Erianin can bind to Keap1, promote its ubiquitination and autophagic degradation, increase the acetylation of lysine 599 site in Nrf2 protein, and activate the antioxidant stress response.

Conclusions

Taken together, our study had for the first time elucidated the molecular mechanism by which Erianin alleviated DOX-induced myocardial injury by activating the Keap1-Nrf2 signaling pathway. It provides a theoretical basis for the development of Erianin as a potential protective drug for DOX-induced cardiotoxicity. It has very important clinical application and translational value.

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Erianin通过激活Keap1-Nrf2信号通路减轻阿霉素诱导的心脏毒性

背景多柔比星（Doxorubicin，DOX）对心肌细胞有明显的毒副作用，而现有的预防药物右雷佐生（dexrazoxane）也有严重的副作用。因此，深入研究既能增强 DOX 的抗肿瘤作用，又能降低其心脏毒性的药物具有重要意义。本研究探讨了 Erianin 在 DOX 诱导的心脏毒性中的调控作用及其具体的分子机制。通过记录小鼠体重变化、计算小鼠脾脏指数和心胫比来确定 DOX 对机体的毒副作用。通过超声心动图和天狼星红染色等方法评估了小鼠心肌损伤的程度。结果我们发现 Erianin 能显著减轻 DOX 诱导的心肌细胞损伤（p < 0.0001），提高心脏组织泵血效率和收缩力（p < 0.001），减少心肌细胞纤维化。机制研究表明，Erianin能与Keap1结合，促进其泛素化和自噬降解，增加Nrf2蛋白中赖氨酸599位点的乙酰化，激活抗氧化应激反应。这为开发 Erianin 作为一种潜在的保护性药物治疗 DOX 诱导的心脏毒性提供了理论依据。它具有非常重要的临床应用和转化价值。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.