Higenamine protects against doxorubicin-induced heart failure by attenuating ferroptosis via modulating the Nrf2/GPX4 signaling pathway

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-24 DOI:10.1016/j.phymed.2025.156670

Jianxia Wen , Lu Li , Dinglin Ou , Jianling Li , Yi Yang , Liting Duan , Xinghai Zhang , Yichan Zhu , Junjie Hao , Yuling Tong

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Abstract

Background

Higenamine (HG), a benzylisoquinoline alkaloid in Aconiti Lateralis Radix Praeparata (ALRP), has cardioprotective effects. Prior research indicated its potential anti-heart failure (HF) function, yet the molecular mechanism remained elusive.

Purpose

This study aimed to explore the underlying mechanism of HG against doxorubicin (DOX)-induced HF via an integrated approach involving gut microbiota, untargeted metabolomics, network pharmacology, and molecular biology.

Methods

DOX was employed to induce HF in rats and H9c2 cardiomyocytes injury models. Cardiac injury was assessed using hemodynamic indices, cardiac injury biomarkers, and oxidative stress markers. Cell counting kit-8 (CCK-8) method and high-content analysis were used to investigate the effects of HG on the cell proliferation, morphology and mitochondrial function of H9c2 cardiomyocytes. 16S rDNA sequencing analysis, untargeted metabolomics, and network pharmacology were performed to identify the multi-target and multi-pathway mechanisms of HG in treating HF. Furthermore, reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, and Western Blotting was used to investigate its intervention on the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) ferroptosis pathway.

Results

HG alleviated DOX-mediated myocardial injury by enhancing cardiac and mitochondrial function, reducing oxidative stress levels, and promoting cell proliferation. Effects of HG on changes in the gut microbiota of rats is characterized by a low abundance of Firmicutes and Proteobacteria, along with a high abundance of Bacteroidetes and Actinobacteria, indicating an improvement in DOX-induced dysbiosis. Untargeted metabolomics combined with network pharmacology showed that HG exerted anti-HF effects by regulating eight metabolites, eight pathways, and interacting with ferroptosis-related targets. Molecular biology studies revealed its cardioprotective effects via regulating the Nrf2/GPX4 ferroptosis pathway.

Conclusion

HG could inhibit ferroptosis and protect against HF by regulating the Nrf2/GPX4-mediated "mitochondrial-ferroptosis" pathway, offering a potential treatment strategy for HF.

Abstract Image

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Higenamine通过调节Nrf2/GPX4信号通路减轻铁凋亡，从而预防阿霉素诱导的心力衰竭

背景Higenamine（HG）是Aconiti Lateralis Radix Praeparata（ALRP）中的一种苄基异喹啉生物碱，具有保护心脏的作用。本研究旨在通过一种涉及肠道微生物群、非靶向代谢组学、网络药理学和分子生物学的综合方法，探索 HG 抗多柔比星（DOX）诱导的 HF 的潜在机制。使用血流动力学指标、心脏损伤生物标志物和氧化应激标志物评估心脏损伤。采用细胞计数试剂盒-8（CCK-8）法和高含量分析法研究 HG 对 H9c2 心肌细胞增殖、形态和线粒体功能的影响。通过16S rDNA测序分析、非靶向代谢组学和网络药理学，确定了HG治疗HF的多靶点、多途径机制。此外，研究人员还利用逆转录定量聚合酶链反应（RT-qPCR）、免疫组织化学和 Western 印迹法研究了 HG 对核因子红细胞 2 相关因子 2（Nrf2）/谷胱甘肽过氧化物酶 4（GPX4）铁氧化通路的干预作用。HG 对大鼠肠道微生物群变化的影响表现为固缩菌和蛋白菌的低丰度以及类杆菌和放线菌的高丰度，这表明 DOX 诱导的菌群失调得到了改善。非靶向代谢组学结合网络药理学研究表明，HG 通过调节八种代谢物、八条通路以及与铁变态反应相关靶点的相互作用来发挥抗高血脂作用。结论HG可通过调节Nrf2/GPX4介导的 "线粒体-铁凋亡 "途径抑制铁凋亡并预防HF，为HF提供了一种潜在的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.