Xinmailong injection ameliorates Doxorubicin‑induced cardiotoxicity via the MDH2/OAA pathway

Abstract

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.