Sequential anthracycline and trastuzumab therapy, while highly effective for HER2-positive breast cancer, carries a significant risk of cardiotoxicity, necessitating protective strategies. Qizaobaoxin Decoction (QZBXD), a modified Chinese herbal formula, has demonstrated potential in mitigating such cardiac damage. This investigation systematically delineates the chemical composition of QZBXD and elucidates its cardioprotective efficacy and underlying mechanisms against doxorubicin/trastuzumab (DOX/TRZ)-induced injury. Utilizing UPLC-Q-TOF-MS/MS analysis, 83 compounds were identified, predominantly flavonoids, organic acids, and phthalides. In a rat model of DOX/TRZ-induced cardiotoxicity, QZBXD administration significantly improved cardiac functional parameters, including left ventricular ejection fraction and fractional shortening. It also reduced serum biomarkers of myocardial injury and ameliorated histopathological damage. Mechanistically, multi-omics approaches revealed that QZBXD restored gut microbiota diversity, enriching beneficial bacteria like Bacteroides while suppressing detrimental genera such as Ruminococcus and Oscillibacter. Concurrently, untargeted metabolomics indicated modulation of tryptophan and arachidonic acid metabolic pathways. An integrated analysis established a gut microbiota-metabolite-cardiac axis, demonstrating that QZBXD's cardioprotection is mediated through microbial remodeling and subsequent metabolic reprogramming, providing a pharmacological foundation for its clinical application.
The therapeutic challenge in HER2-positive breast cancer management lies in balancing oncological efficacy with cardiovascular safety. Anthracyclines like doxorubicin induce cumulative, dose-dependent cardiotoxicity primarily through topoisomerase IIβ inhibition, oxidative stress, and mitochondrial dysfunction. Subsequent trastuzumab treatment, which targets HER2 receptors critical for cardiomyocyte survival and repair, exacerbates this damage, leading to left ventricular dysfunction and heart failure. This synergistic toxicity limits treatment adherence and long-term outcomes, creating an urgent need for effective cardioprotective agents that do not compromise anticancer efficacy. Current strategies, including ACE inhibitors and beta-blockers, offer partial protection but often lack targeted mechanisms addressing the multifaceted nature of chemotherapy-induced cardiac injury. Traditional Chinese medicine formulas like QZBXD, derived from established remedies such as Huangqi (Astragalus) and Danshen (Salvia), present a promising avenue due to their historical use in supporting cardiovascular health and their potential multi-targeted actions.
Chemical characterization of QZBXD identified a rich profile of bioactive constituents. Flavonoids, known for their potent antioxidant and anti-inflammatory properties, were prominent, alongside organic acids and phthalides. Compounds from Astragalus roots, such as astragalosides and flavonoids, are documented to enhance mitochondrial function and reduce oxidative stress. Salvianolic acids from Danshen exhibit anticoagulant and anti-fibrotic effects. The presence of these compounds suggests a polypharmacological approach, where multiple ingredients act synergistically on different pathological pathways, offering a broader protective spectrum compared to single-target pharmaceuticals.
In vivo validation using a DOX/TRZ-induced cardiotoxicity model confirmed QZBXD's functional benefits. Echocardiographic assessments demonstrated a significant recovery of systolic function parameters, indicating preserved contractility and cardiac output. At the biochemical level, QZBXD treatment markedly lowered levels of cardiac troponin I (cTnI), brain natriuretic peptide (BNP), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and α-hydroxybutyrate dehydrogenase (α-HBDH), all sensitive markers of myocardial necrosis and stress. Histopathological examination further corroborated these findings, showing reduced myofibril disarray, inflammatory infiltration, and collagen deposition, suggesting attenuation of structural remodeling and fibrosis.
The gut microbiome has emerged as a critical modulator of cardiovascular health, influencing systemic inflammation, immune responses, and metabolite production. Chemotherapy often induces dysbiosis, disrupting this balance and contributing to toxicity. In this study, 16S rDNA sequencing revealed that DOX/TRZ treatment caused significant gut microbial dysbiosis, which was effectively reversed by QZBXD. The decoction increased the abundance of beneficial Bacteroides species, which are associated with anti-inflammatory effects and improved barrier integrity. Conversely, it decreased pro-inflammatory and pathogenic genera like Ruminococcus and Oscillibacter, which have been linked to metabolic syndrome and heart failure progression. This microbial restoration is posited to strengthen the gut barrier, reduce bacterial translocation, and decrease systemic inflammation, thereby alleviating the inflammatory burden on the heart.
Metabolomic analysis provided a deeper molecular insight, highlighting two key pathways: tryptophan and arachidonic acid metabolism. QZBXD altered the balance of tryptophan metabolites, decreasing pro-fibrotic and neuroactive tryptamine while increasing intermediates like 4-hydroxy-L-tryptophan and L-formylkynurenine, which are involved in immunomodulation. In arachidonic acid metabolism, QZBXD reduced levels of pro-inflammatory mediators such as 8,9-epoxyeicosatrienoic acid, potentially attenuating vasoconstrictive and inflammatory responses that contribute to cardiac afterload and injury. These metabolic shifts indicate a move away from pro-inflammatory and pro-fibrotic states towards a more regulated, protective environment.
The core innovation of this research lies in the integrated analysis connecting gut microbiota changes to host metabolic output. The correlation between specific bacterial taxa and altered metabolite levels suggests a causal chain: QZBXD modulates the gut microbial community, which in turn reprograms host metabolic pathways, ultimately producing cardioprotective effects. This gut-heart axis mechanism explains how a orally administered herbal formula can exert systemic benefits. By targeting the gut ecosystem, QZBXD initiates a cascade of events that counteracts the oxidative stress, inflammation, and fibrosis driven by chemotherapy, offering a holistic and mechanistically grounded approach to cardio-oncology safety.
DOI
10.1007/s11684-025-1196-5