OBJECTIVE: To elucidate the potential mechanisms and identify bioactive components of Suanzaoren (Ziziphi Spinosae Semen) (ZSS) and it’s processed products for insomnia treatment.

METHODS: The principal components of ZSS and its processed products were analyzed using Ultra-Performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The effects of ZSS on insomnia were assessed in para-chlorophenylalanine (PCPA)-induced rats. Additionally, to investigate the mechanisms of action in insomnia, serum and hippocampal non-targeted metabolomics were performed alongside network pharmacology and molecular docking.

RESULTS: UPLC-Q-TOF-MS was used to analyze the main components of ZSS and its processed products. In the insomnia rat model induced by PCPA, both ZSS and its processed products demonstrated therapeutic effects, with the processed products showing particularly significant effects, significantly increasing the levels of the Gamma-Aminobutyric Acid and melatonin. Non-targeted metabolomics identified 23 and 10 potential differential metabolites in serum and hippocampus, respectively, involving pathways such as lipid metabolism and amino acid metabolism. Network pharmacology identified three core targets, mainly associated with pathways such as Transient Receptor Potential channel regulation, Advanced Glycation End-products-Receptor for Advanced Glycation End-products signaling pathway, and neuroactive ligand-receptor interaction. Molecular docking confirmed that the main active components of ZSS can stably bind to these core targets, thereby exerting an effect in improving insomnia.

CONCLUSIONS: Combining in vivo experiments, metabolomics, and network pharmacology, we have identified potential pharmacological mechanisms by which ZSS and its derivatives mitigate insomnia. These findings provide a theoretical foundation for the further development and utilization of ZSS, supporting the innovation of new therapeutic agents for insomnia treatment.