The novel combination of astragaloside IV and formononetin protects from doxorubicin-induced cardiomyopathy by enhancing fatty acid metabolism.
10.1016/S1875-5364(25)60868-5
- Author:
Xinyue YU
1
;
Zhaodi HAN
2
;
Linling GUO
3
;
Shaoqian DENG
2
;
Jing WU
3
;
Qingqing PAN
3
;
Liuyi ZHONG
4
;
Jie ZHAO
4
;
Hui HUI
5
;
Fengguo XU
6
;
Zunjian ZHANG
7
;
Yin HUANG
8
Author Information
1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
3. Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
4. Pharmaceutical Animal Experimental Center, China Pharmaceutical University, Nanjing 210009, China.
5. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
6. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
7. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zunjianzhangcpu@hotmail.com.
8. Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: huangyin@cpu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Anthracyclines;
Astragali Radix;
Cardio-oncology;
Combination therapy;
Lipidomics
- MeSH:
Animals;
Doxorubicin/adverse effects*;
Saponins/administration & dosage*;
Isoflavones/pharmacology*;
Rats;
Cardiomyopathies/prevention & control*;
Mice;
Fatty Acids/metabolism*;
Myocytes, Cardiac/metabolism*;
Triterpenes/administration & dosage*;
Male;
Drugs, Chinese Herbal/administration & dosage*;
Humans;
Cardiotonic Agents/administration & dosage*;
Mice, Inbred C57BL;
Cell Line;
Astragalus Plant/chemistry*;
Astragalus propinquus
- From:
Chinese Journal of Natural Medicines (English Ed.)
2025;23(10):1171-1182
- CountryChina
- Language:English
-
Abstract:
Astragali Radix (AR), a traditional Chinese medicine (TCM), has demonstrated therapeutic efficacy against various diseases, including cardiovascular conditions, over centuries of use. While doxorubicin serves as an effective chemotherapeutic agent against multiple cancers, its clinical application remains constrained by significant cardiotoxicity. Research has indicated that AR exhibits protective properties against doxorubicin-induced cardiomyopathy (DIC); however, the specific bioactive components and underlying mechanisms responsible for this therapeutic effect remain incompletely understood. This investigation seeks to identify the protective bioactive components in AR against DIC and elucidate their mechanisms of action. Through network medicine analysis, astragaloside IV (AsIV) and formononetin (FMT) were identified as potential cardioprotective agents from 129 AR components. In vitro experiments using H9c2 rat cardiomyocytes revealed that the AsIV-FMT combination (AFC) effectively reduced doxorubicin-induced cell death in a dose-dependent manner, with optimal efficacy at a 1∶2 ratio. In vivo, AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models. Additionally, AFC demonstrated cardiac protection while maintaining doxorubicin's anti-cancer efficacy in a breast cancer mouse model. Lipidomic and metabolomics analyses revealed that AFC normalized doxorubicin-induced lipid profile alterations, particularly by reducing fatty acid accumulation. Gene knockdown studies and inhibitor experiments in H9c2 cells demonstrated that AsIV and FMT upregulated peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) and PPARα, respectively, two key proteins involved in fatty acid metabolism. This research establishes AFC as a promising therapeutic approach for DIC, highlighting the significance of multi-target therapies derived from natural herbals in contemporary medicine.
