Qizaobaoxin Decoction ameliorates doxorubicin/trastuzumab-induced cardiotoxicity by modulating gut microbiota and associated metabolites.

Abstract

Sequential treatment with anthracyclines and trastuzumab is highly effective for HER-2 positive breast cancer but poses a significant risk of cardiotoxicity. Qizaobaoxin Decoction (QZBXD), a modified Chinese herbal formula, has shown promise in protecting against antineoplastic drug-induced cardiotoxicity. This study aimed to investigate the chemical composition, efficacy, and mechanisms of QZBXD in mitigating doxorubicin/trastuzumab (DOX/TRZ)-induced cardiotoxicity. Using UPLC-Q-TOF-MS/MS, 83 compounds in QZBXD were identified, including flavonoids, organic acids, and phthalides. In DOX/TRZ-induced cardiotoxicity model, QZBXD treatment improved cardiac function (increased left ventricular ejection fraction and left ventricular fractional shortening), reduced biomarkers of myocardial injury (cTnI, BNP, LDH, CK-MB, α-HBDH), and alleviated histopathological damage. Mechanistically, 16S rDNA sequencing revealed that QZBXD restored gut microbiota diversity, reducing harmful bacteria (Ruminococcus, Oscillibacter) and increasing beneficial bacteria (Bacteroides). Untargeted metabolomics showed that QZBXD modulated tryptophan and arachidonic acid metabolism, affecting key metabolites (e.g., decreasing tryptamine and 8,9-epoxyeicosatrienoic acid, and increasing 4-hydroxy-L-tryptophan and L-formylkynurenine). Integrated analysis revealed that QZBXD confers cardioprotective effects against DOX/TRZ-induced cardiotoxicity by modulating gut microbiota composition, which subsequently influences tryptophan and arachidonic acid metabolism. This study provides a pharmacological basis for the clinical application of QZBXD in mitigating DOX/TRZ-induced cardiotoxicity.