Integrated network pharmacology analysis, molecular docking, LC-MS analysis and bioassays revealed the potential active ingredients and underlying mechanism of for COVID-19.

("Huang-Qin" in Chinese) is a well-known traditional herbal medicine and popular dietary supplement in the world, extensively used in prescriptions of TCMs as adjuvant treatments for coronavirus pneumonia 2019 (COVID-19) patients in China. According to the differences in its appearance, can be classified into two kinds: ZiQin (1∼3 year-old with hard roots) and KuQin (more than 3 year-old with withered pithy roots). In accordance with the clinical theory of TCM, KuQin is superior to ZiQin in cooling down the heat in the lung. However, the potential active ingredients and underlying mechanisms of for the treatment of COVID-19 remain largely unexplored. It is still not clear whether there is a difference in the curative effect of ZiQin and KuQin for the treatment of COVID-19. In this research, network pharmacology, LC-MS based plant metabolomics, and bioassays were integrated to explore both the potential active components and mechanism of for the treatment of COVID-19. As the results, network pharmacology combined with molecular docking analysis indicated that primarily regulates the MAPK and NF-κB signaling pathways active components such as baicalein and scutellarin, and blocks SARS-CoV-2 spike binding to human ACE2 receptors. bioassays showed that baicalein and scutellarein exhibited more potent anti-inflammatory and anti-infectious effects than baicalin, the component with the highest content in . Moreover, baicalein inhibited SARS-CoV-2's entry into Vero E6 cells with an IC value of 142.50 μM in a plaque formation assay. Taken together, baicalein was considered to be the most crucial active component of for the treatment of COVID-19 by integrative analysis. In addition, our bioassay study revealed that KuQin outperforms ZiQin in the treatment of COVID-19. Meanwhile, plant metabolomics revealed that baicalein was the compound with the most significant increase in KuQin compared to ZiQin, implying the primary reason for the superiority of KuQin over ZiQin in the treatment of COVID-19.