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This study aims to examine the impacts of Scutellaria strigillosa Hemsl. (SSH) on the proliferation, apoptosis of human hepatoma cell HepG2 and screen the bioactive components. We found that SSH extract inhibited HepG2 proliferation, arrested cell division prior to S phase. Additionally, SSH extract exposure induced apoptosis, and increased the proportions of late apoptotic cells. Specifically, we focus on the inhibitory effect of SSH extract on aspartate β-hydroxylase, a key therapeutic target of hepatocellular carcinoma closely related with the proliferation and apoptosis of HepG2. We found SSH extract with notable inhibitory activity against aspartate β-hydroxylase, elucidated the main bioactive constituents by HPLC-Q-TOF/MS and Molecular docking analysis. In conclusion, these results provided the antiproliferative and proapoptotic effects of SSH on HepG2 cell, elucidated the main bioactive constituents based on aspartate β-hydroxylase inhibition. These data revealed the potential value of SSH and its bioactive components for the prevention and treatment of liver cancer for the first time. [Display omitted] • The SSH extract inhibits the proliferation of HepG2 cells. • The SSH extract has proapoptotic effect on HepG2 cells. • The SSH extract exerts ASPH inhibitory activity. • Analysis of bioactive components binding to ASPH. [ABSTRACT FROM AUTHOR]