ABSTRACT Rationale Depression is currently the third leading cause of disease burden worldwide by 2030. Jieyu Pills (JYP) comprise 10 herbs demonstrated clinical effectiveness in managing depression with low by‐effects. Owing to the complexity of herbal compound formulations, identifying chemical constituents is insufficient to discover the specificity and correlation between quality and therapeutic efficacy. Thus, selecting and detecting appropriate quality control (QC) markers for herbal medicines remains a challenge. Methods This study has been screened and evaluated appropriate QC markers through a correlation analysis of “ingredient–pharmacological efficacy.” Firstly, chemical components of JYP were systematically characterized in vivo and in vitro using UHPLC‐Orbitrap Fusion MS. Then, network pharmacology analysis was conducted to predict potential active components of JYP. Finally, core effectors of JYP were screened out as QC markers and subjected to targeted quantitative analysis. Results A total of 188 compounds were identified in vitro, and 47 prototype constituents plus 41 metabolites were detected in serum. Network analysis revealed 13 core targets such as AKT1 and TNF enriched in inflammation, apoptosis, and AGE‐RAGE signaling pathways, aligning with known depression mechanisms. Integrating serum‐exposed components with network results highlighted paeoniflorin, gallic acid, liquiritin, and their metabolites as central modulators of neuroinflammatory and neuroprotective processes. Based on this “chemical entity–metabolic fate–target–pathway” framework, 20 compounds were selected as potential QC markers, and quantitative analysis confirmed high batch consistency. Conclusions This study provides the first integrated in vitro–in vivo chemical and mechanistic profiling of JYP, elucidates its metabolic characteristics and core antidepressant pathways, and establishes scientifically grounded QC markers. The research provides a novel perspective for investigating complex herbal prescriptions.
Ye et al. (Thu,) studied this question.