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Updated: Sep 18, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Xinmailong injection ameliorates Doxorubicin‑induced cardiotoxicity via the MDH2/OAA pathway
Sa Liu1, Suifen Xie1, Taoli Sun2
1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.
Background:
As a broad-spectrum anticancer drug, the clinical utility of Doxorubicin (Dox) is hampered by its side effects, known as Dox-induced cardiotoxicity (DIC). Xinmailong Injection (XML), a bioactive compound formulation extracted from the American cockroach, has been approved by China's National Medical Products Administration for the treatment of heart failure. However, whether XML could alleviate DIC still remains unclear.
Purpose:
This study aims to explore the protective role of XML against DIC and unveil the molecular mechanisms underlying its cardioprotective effects.
Methods:
The DIC models of H9c2 cells and C57BL/6 mice were established. HPLC-MS, network pharmacology, metabolomics and experimental verification were combined to identify the core target and mechanism of XML against DIC.
Results:
XML alleviated Dox-induced apoptosis in vitro and in vivo. HPLC/MS in conjunction with swissADME identified 30 effective components within XML. Network pharmacology screened 179 "co-targeted genes" related to XML and DIC. Metabolomics identified 24 differential metabolites, mainly enriched in oxaloacetate (OAA) metabolism and the TCA cycle. Four intersecting genes, including MDH2, EHMT2, CAD and MIF, were determined through Metascape and MetaboAnalyst analysis. MDH2 was chose as the core target as it regulated OAA regeneration within the TCA cycle. The levels of MDH2 and OAA were downregulated by Dox, whereas they were upregulated following XML intervention. When MDH2 was inhibited using LW6, the protective effects of XML on cell apoptosis, cardiac dysfunction, and ATP depletion were all reversed, indicating that XML alleviated DIC by upregulating MDH2.
Conclusion:
XML effectively mitigated DIC by upregulating MDH2 to promote the generation of ATP and inhibit cell apoptosis, providing new theoretical insights and strategies for the prevention and treatment of DIC.
Insights
Xinmailong Injection (XML) protects against Doxorubicin-induced cardiotoxicity (DIC) by upregulating MDH2. This mechanism enhances ATP production and inhibits apoptosis, offering new strategies for DIC prevention and treatment.
Area of Science:
- Cardiovascular Pharmacology
- Oncology Drug Safety
- Molecular Mechanisms of Toxicity
Background:
- Doxorubicin (Dox) is a vital anticancer drug, but its use is limited by cardiotoxicity (DIC).
- Xinmailong Injection (XML), derived from American cockroach, treats heart failure but its effect on DIC is unknown.
Purpose of the Study:
- To investigate the protective effects of XML against DIC.
- To elucidate the molecular mechanisms behind XML's cardioprotective action.
Main Methods:
- Established in vitro (H9c2 cells) and in vivo (C57BL/6 mice) models of DIC.
- Utilized HPLC-MS, network pharmacology, and metabolomics to identify key targets and pathways.
- Conducted experimental verification to confirm the role of identified targets.
Main Results:
- XML reduced Dox-induced apoptosis in both cell and animal models.
- Identified 30 active compounds in XML and 179 co-targeted genes related to XML and DIC.
- Metabolomics revealed enrichment in oxaloacetate (OAA) metabolism and the TCA cycle, highlighting MDH2 as a core target.
- XML upregulated MDH2 and OAA, reversing Dox-induced cardiac dysfunction and ATP depletion; inhibiting MDH2 abolished XML's protective effects.
Conclusions:
- XML effectively mitigates DIC by upregulating MDH2, thereby enhancing ATP generation and inhibiting apoptosis.
- This study provides novel insights and therapeutic strategies for preventing and treating Doxorubicin-induced cardiotoxicity.
