Identifying the molecular targets of Salvia miltiorrhiza (SM) in ox-LDL induced macrophage-derived foam cells based on the integration of metabolomics and network pharmacology

The identification of network targets is one of the core issues used to reveal the molecular mechanism of traditional Chinese medicine (TCM) and is also the grand challenge of modernization of TCM. In this study, a protein–protein interaction (PPI) network was constructed based on the integration of network pharmacology and metabolomics, which was used as an effective approach to elucidate the relationship between disease pathway proteins and the targets of active small-molecule compounds. The intermolecular transfer process of the drug effect of active compounds in Salvia miltiorrhiza (SM) was revealed and visualized using the PPI network. Our study indicates that PTGS2 was the most important disease protein regulated by the active compounds in SM. Furthermore, the drug targets that can be linked to PTGS2 were regarded as direct targets and the direct targets of the active compounds were identified, respectively. Western blot and co-immuno precipitation (Co-IP) were used to verify the results of the network analysis and reveal the intermolecular transfer process of the effect of Tan IIA. Biological validation revealed that Tan IIA-EDN1-PTGS2-anandamide was a major intervention way of Tan IIA on early atherosclerosis (AS). This work provides a new perspective for the discovery of drug targets and the specific approaches regulated by the active compounds in SM on disease pathway proteins, which is beneficial for understanding the mechanism of action of bioactive compounds and expanding their clinical applications.