Objective To analyze the rationale for use of Trichosanthis fructus in traditional Chinese prescriptions and explore the

molecular mechanism of the core drug pair Trichosanthis fructus-Glycyrrhizae radix et rhizoma for treatment of phlegm syndrome diseases. Methods We analyzed the cumulative frequency of the use of Trichosanthis fructus in traditional Chinese prescriptions and the disease spectrum treated using the prescriptions containing Trichosanthis fructus. We searched TCMSP database for the chemical components of Trichosanthis fructus and Glycyrrhizae radix et rhizoma and explored their target proteins using Swiss Target Prediction database. We also searched the CooLGeN and GeneCards databases for the potential disease target proteins using the key words "phlegm syndrome". The chemical component-target protein-signal pathway network was constructed using DAVID database to analyze the molecular mechanism of Trichosanthis fructus-Glycyrrhizae radix et rhizoma drug pair for treatment of phlegm syndrome diseases, and the result was verified by molecular docking technology. Results A total of 1700 prescriptions containing Trichosanthis fructus were retrieved, which were used for treatment of 28 diseases. Phlegm syndrome was the most frequent among the 28 diseases (14.0% ). The Trichosanthis fructus-Glycyrrhizae radix et rhizoma drug pair had a cumulative frequency of 113 for use in treatment of phlegm diseases, and was the core drug pair in prescriptions containing Trichosanthis fructus. Fifty-two chemical components related to phlegm syndrome diseases were identified in the drug pair (9 in Trichosanthis fructus and 43 in Glycyrrhizae radix et rhizoma), and their therapeutic effects were mediated by a total of 41 target proteins involving the cancer pathway, NOD-like receptor signaling pathway and another 17 signal pathways. The results of molecular docking showed that 40 chemical components docking with 10 target protein molecules had total scores greater than 5. Conclusion The different formulations of Trichosanthis fructus containing prescriptions serve different therapeutic purposes. The mechanisms of the Trichosanthis fructus-Glycyrrhizae radix et rhizoma drug pair for treatment of phlegm syndrome diseases involve multiple pathways for regulating cell proliferation, apoptosis and other biological processes.