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. 2025;31(22):1800-1815.
doi: 10.2174/0113816128342642250111055339.

Crippled Hepatocarcinogenesis Inhibition of Quercetin in Glycolysis Pathway with Hepatic Farnesoid X Receptor Deficiency

Wusheng Zhong  1 , Tao Chen  2 , Ling Chen  1 , Yaqi Xing  1 , Haorui Lin  1 , Shuli Xie  1 , Mateen Nawaz  1 , Danmei Huang  1 , Zhanqin Huang  1 , Jun Lu  3 , Zhiming Chen  4 , Yongdong Niu  1
Affiliations

Crippled Hepatocarcinogenesis Inhibition of Quercetin in Glycolysis Pathway with Hepatic Farnesoid X Receptor Deficiency

Wusheng Zhong et al. Curr Pharm Des. 2025.

Abstract

Aim: Quercetin, a bioactive flavonoid extracted from traditional Chinese medicine, has antihepatocellular carcinoma effects. Farnesoid X receptor (FXR), a nuclear receptor highly expressed in the liver, plays important roles in maintaining hepatic glucose homeostasis, anti-inflammation, liver regeneration, and anti-cancer properties. Whether quercetin regulates the glycolysis/glycolysis pathway through FXR signaling remains unknown.

Methods: KEGG Enrichment, GO Enrichment, Protein-Protein Interaction (PPI) Network, Molecular Docking, and RNA-Seq Analysis (Swiss Target Prediction, GeneCard databases, Kaplan-Meier Plotter, etc). Cell activity, cell proliferation, and cell cycles were separately analyzed by CCK-8 assay, clone formation assay, and flow cytometry. QRT-PCR determined the mRNA levels of related genes in response to quercetin. HPLCMS/ MSHPLC-MS/MS determined the metabolite profiles. FXR deficiency Hep3B cells were used for discriminating the quercetin's effects with or without FXR.

Results: Quercetin-related genes were significantly correlated with FXR in hepatocarcinogenesis, especially in glycolysis. The top 30 related genes between FXR, quercetin, and glycolysis were enriched and chosen to further study. Furthermore, the strongest binding energy determined by the molecular docking model of between quercetin and FXR was -6.55 kcal/mol. Quercetin inhibited cell proliferation by the accumulation of Hep3B cells in the S-phase. The differential expressed genes (C-MYC, PCNA, CYCLIN-D1, and P21) associated with glycolysis were observed. Furthermore, quercetin also inhibited the expression of HK2, GAPDH, and LDHA. Meanwhile, the levels of glycolysis/gluconeogenesis-related metabolites were regulated by quercetin.

Conclusion: Quercetin makes an essential anti-HCC effect by crippling the glycolysis/gluconeogenesis process via FXR signaling.

Keywords: Farnesoid X receptor; HCC; HPLC-MS/MS; Quercetin; glycolysis; hepatocarcinogenesis..

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