Objective To explore the potential mechanism of Eucommiae cortex for the treatment of hepatocellular carcinoma (HCC) based on network pharmacology and in vitro cell experiment. Methods (1) The effective components and effect targets of Eucommiae cortex were retrieved from TCMSP database, and HCC⁃related gene expression profile data and clinical data of corresponding patients were downloaded from TCGA database. The R language software was adopted to analyze the differentially expressed genes in HCC, and the intersection of the effect targets of effective components of Eucommiae cortex and the differentially expressed genes in HCC was taken to obtain the potential effect targets of Eucommiae cortex for the treatment of HCC. Enrichment analysis was performed for potential effect targets. Genes with prognostic predictive value were screened and a risk score model was constructed. The Eucommiae cortex⁃effective component⁃effect target⁃HCC network and protein⁃to⁃protein interaction (PPI) network chart were drawn, and the main effective components and key effect targets were screened for molecular docking validation. (2) CCK⁃8 assay and scratch assay were used to detect the effects of quercetin at different concentrations on hepatoma cell HCCLM3 cell viability and migration. The effects of quercetin at different concentrations on Serpin family E menber 1 (SERPINE1) mRNA and protein expressions were detected by the real⁃time fluorescent quantitative PCR and Western blot. Results (1) A total of 60 potential effect targets of Eucommiae cortex for the treatment of HCC were obtained. These potential effect targets were primarily involved in various biological processes and signaling pathways such as response to external stimuli, postsynaptic membrane, adrenergic receptor activity, interleukin⁃17 signaling pathway, and tumor necrosis factor signaling pathway. Through further screening, 11 genes with prognostic predictive value were selected. The risk score was calculated as:risk score=KCNH2×0.007825+EGF×0.0423204+HMOX1×0.000572+CCNB1×0.020393+SERPINE1×0.000500+NQO1×0.000701+CLDN4×0.000448+SPP1×0.000025+PON1×0.001001+HK2×0.00667+CHEK1×0.018271. Eucommiae cortex⁃effective components⁃effect targets⁃disease network diagram revealed that quercetin, kaempferol, epiquinidine, and (⁃)⁃Tabernemontanine were the main effective components of Eucommiae cortex for the treatment of HCC. PPI network demonstrated that SERPINE1 served as both the key effect target of Eucommiae cortex for the treatment of HCC and one of the genes included in the risk score model construction. Molecular docking results indicated that quercetin could bind with SERPINE1 and achieved the highest docking score. (2) Compared with the control group (0 μmol/L quercetin), quercetin at concentrations higher than 25 μmol/L inhibited the cell viability of hepatoma cell HCCLM3, and the cell migration ability of hepatoma cell HCCLM3 was inhibited by quercetin at concentrations of 25 μmol/L, 100 μmol/L and 400 μmol/L. Quercetin at 100 μmol/L and 400 μmol/L concentrations inhibited the mRNA and protein expressions of SERPINE1 (P<0.05). Conclusion  Quercetin, the main effective component of Eucommiae cortex, can inhibit the activity and migration of hepatoma cell HCCLM3 and down⁃regulate the expression of SERPINE1.

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