Integrated metabolomics and network pharmacology approach to reveal immunomodulatory mechanisms of Yupingfeng granules

Systems biology is an approach that employs modern biological techniques and methods to combine the overall regulation of the body by Chinese herbal formulas with systems analysis at the molecular level. In this study, the underlying immunomodulatory mechanisms of yupingfeng granules (YPFG) were investigated based on the integration of metabolomics and network pharmacology methods. Selected routine peripheral blood indicators, body weight, and organ indices related to immunity were firstly measured in order to evaluate the effects of YPFG in cyclophosphamide-induced immunocompromised rats. Plasma metabolomics analyses were carried out by UPLC-Q-TOF-MS combined with a multivariate data analysis. Our study indicates that the potential regulatory mechanism was related to bile acid and glycerophospholipid metabolism, involving the regulation of 11 metabolites, including 8 bile acids, 1 phosphatidylserine, and 2 phosphatidylethanolamines. By means of network pharmacology, the compound-target network between potential active components of YPFG and immune dysregulation was constructed, which releated to estrogen receptor, PPAR, MAPK, PI3K-Akt, JNK signaling pathways, and ubiquitin-mediated protein degradation. The immunomodulatory effect of YPFG may be exerted through regulating lipid metabolism, then bile acid metabolism and inflammation were affected. Biological verification was also performed on cyclophosphamide-induced immunocompromised BALB/c mice. Flavonoid and saponin, two types of compounds in YPFG, were found to be the major active ingredients in the immunomodulatory effects of YPFG, and these components may regulate the abnormal metabolism of bile acids by enhancing the expression of FXR and LXRα. This work elucidated active ingredients, potential biomarkers, and mechanisms of action in the immunoregulatory effects of YPFG from the perspective of systems biology, which provides a scientific basis for its precise clinical medication.