Single-cell analysis reveals synergistic therapeutic mechanisms of Shenqi Fuzheng formula against acute myocardial infarction.

The Shenqi Fuzheng (SQ) formula, made from Codonopsis Radix (Dangshen, DS) and Astragali Radix (Huangqi, HQ), has been used in Traditional Chinese Medicine (TCM) and exhibits cardio-protective effects against acute myocardial infarction (AMI). However, the molecular basis of DS-HQ synergy remains unclear. Here, we combined RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) to explore their synergistic mechanisms. Transcriptomic analyses showed that SQ influenced the AMI network more effectively than either herb alone. ScRNA-seq analysis revealed that these synergistic effects involve both direct and indirect pro-angiogenic pathways. The combination treatment enhanced pro-angiogenic responses in microvascular endothelial subpopulations and promoted angiogenesis in the border zone. It also enhanced the anti-inflammatory role of a specific reparative macrophage subset and stimulated vascular endothelial growth factor A (VEGFA) secretion from these cells, supporting the VEGFA-VEGFR signaling between macrophages and microvascular endothelial cells. This coordinated regulation provides a plausible mechanistic explanation for the reduced infarct size and improved cardiac outcomes seen in vivo, highlighting the therapeutic value of TCM.