Study on the Pharmacodynamic Substances and Mechanism of Danshen‐Honghua Herb Pair (DHHP) Against Myocardial Ischemia Based on the Gut Microbiota Metabolism

Danshen-Honghua Herb Pair (DHHP) is a classic combination for treating cardiovascular diseases with significant clinical efficacy. However, it exhibits low oral bioavailability, suggesting gut microbiota metabolism may enhance its biological activity. This study investigated the pharmacological basis and mechanism of DHHP against myocardial ischemia through gut microbiota metabolites. We adopted an integrated strategy combining network pharmacology, molecular docking, and animal experiments. 15 metabolite-derived components and 85 potential antimyocardial ischemia targets were identified. GO and KEGG enrichment analyses revealed that these targets were mainly involved in apoptosis-related biological processes and multiple cardiovascular signaling pathways. Molecular docking indicated that Salvianolic acid B and its methylated derivative, Lithospermic acid and its methylated and decarboxylated derivatives, as well as Hydroxysafflor Yellow A and its dehydration product exhibited lower binding energies with key targets including AKT, GSK-3β, Bcl-2, Bax, and Caspase 3. These components showed potential anti-apoptotic activity accordingly. Animal experiments confirmed DHHP metabolites significantly upregulated p-AKT, p-GSK-3β, and Bcl-2 expression in myocardial tissue (p <0.01) while downregulating Bax and Cleaved-Caspase 3 (p <0.01). These results demonstrate that DHHP, via gut microbiota metabolism, exerts antimyocardial ischemia effects through the p-AKT-mediated Bcl-2/Bax/Caspase 3 pathway.