Paridis Rhizoma is recorded as a minor poison in Chinese Pharmacopoeia，but its toxic mechanism has not been clarified.With the attention paid to the safety of Chinese medicine in recent years，the safety and mechanism of Paridis Rhizoma in clinical use also need to be clarified.The purpose of this paper is to clarify the hepatotoxicity mechanism of Paridis Rhizoma extract.Methods:The acute hepatotoxicity was verified by zebrafish.The zebrafish with 4 days of post-fertilization(4 dpf) were exposed to Paridis Rhizoma extract，acridine orange staining was carried out after 24 h，and the hepatotoxicity was proved by histopathological section.The hepatotoxicity targets of Paridis Rhizoma were predicted by network pharmacology and molecular docking technology，and real-time polymerase chain reaction(RT-PCR) was used to verify the network prediction targets and pathways.Results:According to the experimental results，yellow-green fluorescent spots appeared in the liver of zebrafish in the Paridis Rhizoma water extract group and alcohol extract group after exposure treatment for 24 h.Histopathological sections showed that the arrangement of hepatocytes was disordered and loose，and nuclear apoptosis and vacuoles appeared，indicating hepatotoxicity.The results of network pharmacology predicted that the hepatotoxicity of Paridis Rhizoma may be related to the Ras signaling pathway of cell proliferation，phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) signaling pathway，mitogen-activated protein kinase(MAPK) signaling pathway，and Janus kinase-signal transducer and activator of transcription(JAK/STAT) signaling pathway related to energy metabolism and signal transduction.Vascular endothelial growth factor A(VEGFA)，platelet-derived growth factor receptor beta(PDGFRB)，murine double minute 2(MDM2)，signal transducers and activators of transcription 3(STAT3)，mammalian target of rapamycin(MTOR)，MET，Bcl-2-like protein 1(BCL2L1)，fibroblast growth factor 2(FGF2)，interleukin-2(IL-2)，and MAPK14 may be the core targets of hepatotoxicity caused by Paridis Rhizoma.The results of RT-PCR experiments verified the above speculation.Conclusion:Paridis Rhizoma may affect the signal transduction of hepatocyte proliferation and energy metabolism，which leads to hepatotoxicity.