Journal of Traditional Chinese Medicine ›› 2026, Vol. 46 ›› Issue (5): 1180-1193.DOI: 10.19852/j.cnki.jtcm.2026.05.012
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Jianpi Huayu decoction (健脾化瘀方) induces hepatocellular carcinoma apoptosis through flavonoid components targeting tumor protein p53 activation and serine-threonine protein kinase 1/B-cell lymphoma 2 inhibition: a network pharmacology-based study with experimental validation
CHEN Xiaokai1, XIE Yingjie2, WU Hui3, LI Yong4, LU Yantong5, TAN Wei6, WANG Changjun6(
), HUANG Xuhui6,7()
- 1
Department of Pharmacy ,Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University Guangzhou 510000, China
2One Departments of Cadre Ward ,General Hospital of Southern Theater Command of Chinese PLA Guangzhou 510000, China
3South China University of Technology School of Medicine Guangzhou 510000, China
4Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations ,Guangdong Pharmaceutical University Guangzhou 510000, China
5Science and Technology Innovation Center of Guangzhou University of Chinese Medicine ,Guangzhou University of Chinese Medicine Guangzhou 510000, China
6Department of Traditional Chinese Medicine ,Guangdong Geriatric institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University Guangzhou 510000, China
7School of Traditional Chinese Medicine ,Southern Medical University Guangzhou 510000, China
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Received:2025-05-30Accepted:2026-01-28Online:2026-10-15Published:2026-10-09 -
Contact:WANG Changjun, Department of Traditional Chinese Medicine, Guangdong Geriatric institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China, gzwchj@126.com; HUANG Xuhui, Department of Traditional Chinese Medicine, Guangdong Geriatric institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510000, China, api007@163.com,Telephone: +86-13544437648 -
About author:CHEN Xiaokai and XIE Yingjie are co-first authors and contributed equally to this work
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Supported by:Natural Science Foundation of Guangdong Province: the Role of Exosomal MicroRNA-122/Transforming Growth Factor-β/Smad Pathway in Inducing Myeloid-Derived Suppressor Cell Differentiation and Promoting Liver Cancer Dormancy and the Intervention Study of Jianpi Huayu Decoction(2022A1515011260);Administration of Traditional Chinese Medicine of Guangdong Province: Investigation of the Inhibitory Effect and Intervention Mechanism of Jianpi Huayu decoction on Postoperative Recurrence of Liver Cancer via the Phosphoinositide 3-Kinase/ Serine-Threonine Protein Kinase 1/Nuclear Factor Kappa-B Signaling Pathway(20251002)
Cite this article
CHEN Xiaokai, XIE Yingjie, WU Hui, LI Yong, LU Yantong, TAN Wei, WANG Changjun, HUANG Xuhui. Jianpi Huayu decoction (健脾化瘀方) induces hepatocellular carcinoma apoptosis through flavonoid components targeting tumor protein p53 activation and serine-threonine protein kinase 1/B-cell lymphoma 2 inhibition: a network pharmacology-based study with experimental validation[J]. Journal of Traditional Chinese Medicine, 2026, 46(5): 1180-1193.
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Figure 1 Network pharmacological analysis of the active components of JHD-containing serum A: venn diagram showing the intersection between potential target genes of JHD active components and HCC-related geness; B: bar chart of the top 20 intersecting targets ranked by degree value; C: GO enrichment analysis (Biological Process, Cellular Component, Molecular Function) of the top 50 intersecting targets, presented as bubble plots; PI3K: phosphatidylinositol 3-kinase; TP53: tumor protein 53; AKT1: serine-threonine kinase 1; ALB: albumin; TNF: tumor necrosis factor; INS: insulin; BCL2: B-cell lymphoma 2; EGFR: epidermal growth factor receptor; JUN: Jun proto-oncogene; SRC: SRC proto-oncogene; ESR1: estrogen receptor 1; NFKB1: nuclear factor kappa B subunit 1; HIF1A: hypoxia inducible factor 1 subunit alpha; MAPK3: mitogen-activated protein kinases 3; MMP9: matrix metallopeptidase 9; PPARG: peroxisome proliferator activated receptor gamma; IFNG: interferon gamma; PTGS2: prostaglandin-endoperoxide synthase 2; CCND1: cyclin d1; GSK3B: glycogen synthase kinase 3 beta; MDM2: MDM2 proto-oncogene; JHD: Jianpi Huayu decoction; GO: gene ontology; KEGG: kyoto encyclopedia of genes and genomes; BP: biological process; CC: cellular component; MF: molecular function.
Figure 1 Network pharmacological analysis of the active components of JHD-containing serum A: venn diagram showing the intersection between potential target genes of JHD active components and HCC-related geness; B: bar chart of the top 20 intersecting targets ranked by degree value; C: GO enrichment analysis (Biological Process, Cellular Component, Molecular Function) of the top 50 intersecting targets, presented as bubble plots; PI3K: phosphatidylinositol 3-kinase; TP53: tumor protein 53; AKT1: serine-threonine kinase 1; ALB: albumin; TNF: tumor necrosis factor; INS: insulin; BCL2: B-cell lymphoma 2; EGFR: epidermal growth factor receptor; JUN: Jun proto-oncogene; SRC: SRC proto-oncogene; ESR1: estrogen receptor 1; NFKB1: nuclear factor kappa B subunit 1; HIF1A: hypoxia inducible factor 1 subunit alpha; MAPK3: mitogen-activated protein kinases 3; MMP9: matrix metallopeptidase 9; PPARG: peroxisome proliferator activated receptor gamma; IFNG: interferon gamma; PTGS2: prostaglandin-endoperoxide synthase 2; CCND1: cyclin d1; GSK3B: glycogen synthase kinase 3 beta; MDM2: MDM2 proto-oncogene; JHD: Jianpi Huayu decoction; GO: gene ontology; KEGG: kyoto encyclopedia of genes and genomes; BP: biological process; CC: cellular component; MF: molecular function.
Figure 2 PPI and "component-target" interaction network analysis The “JHD-Blood Component-Target-Pathway-HCC” network, depicting the top 50 protein targets. Interaction analysis revealed that key serum components of JHD, apigenin, curcumenol, daidzein, naringin, and curzerenone, can act on critical targets including TP53, AKT1, ALB, TNF, INS, BCL2, EGFR, and JUN. In this network, square nodes represent chemical components, circular nodes represent protein targets, and connecting lines denote interactions between them. The number of lines originating from a component signifies its degree value, reflecting its broader influence on multiple targets. SIRT1: sirtuin 1; HIF1A: hypoxia inducible factor 1 subunit alpha; TP53: tumor protein P53; MAPK1: mitogen-activated protein kinase 1; PTGS2: prostaglandin-endoperoxide synthase 2; AR: androgen receptor; SMAD3: SMAD family member 3; MAP2K1: mitogen-activated protein kinase1; ESR1: estrogen receptor 1; NFKB1: nuclear factor kappa B subunit 1; MAPK3: mitogen-activated protein kinase 3; PRKACA: protein kinase cAMP-activated catalytic subunit alpha; APP: amyloid beta precursor protein; CXCL8: C-X-C motif chemokine ligand 8; PARP1: poly (ADP-ribose) polymerase 1; NFE2L2: NFE2 like bZIP transcription factor 2; EGFR: epidermal growth factor receptor; MAPK14: mitogen-activated protein kinase 14; AKT1: serine/threonine kinase 1; GSK3B: glycogen synthase kinase 3 beta; CDK2: cyclin dependent kinase 2; PPARG: peroxisome proliferator activated receptor gamma; PPARA: peroxisome proliferator activated receptor alpha; TNF: tumor necrosis factor; JUN: Jun proto-oncogene, AP-1 transcription factor subunit; CREB1: CAMP responsive element binding protein 1; CDK1: cyclin dependent kinase 1; JAK2: Janus kinase 2; MAPK8: mitogen-activated protein kinase 8; MMP9: matrix metallopeptidase 9; MMP2: matrix metallopeptidase 2; ERBB2: Erb-b2 receptor tyrosine kinase 2; IGF1R: insulin like growth factor 1 receptor; KDR: kinase insert domain receptor; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; IL-2: interleukin 2; RELA: RELA proto-oncogene, NF-kB subunit; STAT1: signal transducer and activator of transcription 1; INS: insulin; TLR4: toll like receptor 4; CASP1: caspase 1; PTPRC: protein tyrosine phosphatase receptor type C; ALB: Albumin; BDNF: brain derived neurotrophic factor; CCND1: cyclin D1; CDKN1A: cyclin dependent kinase inhibitor 1A; IFNG: interferon gamma; JHD: Jianpi Huayu decoction; HCC: hepatocellular carcinoma.
Figure 2 PPI and "component-target" interaction network analysis The “JHD-Blood Component-Target-Pathway-HCC” network, depicting the top 50 protein targets. Interaction analysis revealed that key serum components of JHD, apigenin, curcumenol, daidzein, naringin, and curzerenone, can act on critical targets including TP53, AKT1, ALB, TNF, INS, BCL2, EGFR, and JUN. In this network, square nodes represent chemical components, circular nodes represent protein targets, and connecting lines denote interactions between them. The number of lines originating from a component signifies its degree value, reflecting its broader influence on multiple targets. SIRT1: sirtuin 1; HIF1A: hypoxia inducible factor 1 subunit alpha; TP53: tumor protein P53; MAPK1: mitogen-activated protein kinase 1; PTGS2: prostaglandin-endoperoxide synthase 2; AR: androgen receptor; SMAD3: SMAD family member 3; MAP2K1: mitogen-activated protein kinase1; ESR1: estrogen receptor 1; NFKB1: nuclear factor kappa B subunit 1; MAPK3: mitogen-activated protein kinase 3; PRKACA: protein kinase cAMP-activated catalytic subunit alpha; APP: amyloid beta precursor protein; CXCL8: C-X-C motif chemokine ligand 8; PARP1: poly (ADP-ribose) polymerase 1; NFE2L2: NFE2 like bZIP transcription factor 2; EGFR: epidermal growth factor receptor; MAPK14: mitogen-activated protein kinase 14; AKT1: serine/threonine kinase 1; GSK3B: glycogen synthase kinase 3 beta; CDK2: cyclin dependent kinase 2; PPARG: peroxisome proliferator activated receptor gamma; PPARA: peroxisome proliferator activated receptor alpha; TNF: tumor necrosis factor; JUN: Jun proto-oncogene, AP-1 transcription factor subunit; CREB1: CAMP responsive element binding protein 1; CDK1: cyclin dependent kinase 1; JAK2: Janus kinase 2; MAPK8: mitogen-activated protein kinase 8; MMP9: matrix metallopeptidase 9; MMP2: matrix metallopeptidase 2; ERBB2: Erb-b2 receptor tyrosine kinase 2; IGF1R: insulin like growth factor 1 receptor; KDR: kinase insert domain receptor; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; IL-2: interleukin 2; RELA: RELA proto-oncogene, NF-kB subunit; STAT1: signal transducer and activator of transcription 1; INS: insulin; TLR4: toll like receptor 4; CASP1: caspase 1; PTPRC: protein tyrosine phosphatase receptor type C; ALB: Albumin; BDNF: brain derived neurotrophic factor; CCND1: cyclin D1; CDKN1A: cyclin dependent kinase inhibitor 1A; IFNG: interferon gamma; JHD: Jianpi Huayu decoction; HCC: hepatocellular carcinoma.
Figure 3 Apigenin, curcumenol, daidzein, naringin, and curzerenone promote apoptosis of HepG2 cells A: CCK-8 assay was employed to evaluate cell apoptosis; A1: bar chart of cell viability in the apigenin group; A2: bar chart of cell viability in the naringin group; A3: bar chart of cell viability in the daidzein group; A4: bar chart of cell viability in the curcumenol group; A5: bar chart of cell viability in the curzerenone group. B: Annexin V-FITC and PI staining was utilized to assess cell apoptosis via flow cytometry; B1: blank group; B2: 20 μM apigenin group; B3: 120 μM curcumenol group; B4: 70 μM daidzein group; B5: 40 μM apigenin group; B6: 200 μM curcumenol group; B7: 140 μM daidzein group; B8: 60 μM curzerenone group; B9: 140 μM curzerenone group; B10: 20 μM naringin group; B11: 40 μM naringin group; B12: bar gaph of statistics. C: Annexin V-FITC and PI staining was utilized to assess cell apoptosis via flow cytometry; C1: blank group; C2: 120 μM curcumenol group; C3: 20 μM naringin group; C4: 60 μM curzerenone group; C5: 200 μM curcumenol group; C6: 40 μM naringin group; C7: 140 μM curzerenone group; C8: bar gaph of statistics. For A: HepG2 cells were treated with apigenin, curcumenol, daidzein, naringin, and curzerenone for 24 h in vitro (n = 6); For B: HepG2 cells were exposed to these monomers for 24 h in vitro (n = 4); For C: HepG2 cells were exposed to these monomers for 48 h in vitro (n = 4). PI: propidium iodide; FITC: fluorescein isothiocyanate; HepG2: human hepatoma G2 cell line; CCK-8: cell counting kit-8. Differences between groups were compared using independent samples t-tests. aP < 0.001, bP < 0.01, cP < 0.05, compared with the 0 μM group. dP < 0.001, eP < 0.01, fP < 0.05, compared with the blank group.
Figure 3 Apigenin, curcumenol, daidzein, naringin, and curzerenone promote apoptosis of HepG2 cells A: CCK-8 assay was employed to evaluate cell apoptosis; A1: bar chart of cell viability in the apigenin group; A2: bar chart of cell viability in the naringin group; A3: bar chart of cell viability in the daidzein group; A4: bar chart of cell viability in the curcumenol group; A5: bar chart of cell viability in the curzerenone group. B: Annexin V-FITC and PI staining was utilized to assess cell apoptosis via flow cytometry; B1: blank group; B2: 20 μM apigenin group; B3: 120 μM curcumenol group; B4: 70 μM daidzein group; B5: 40 μM apigenin group; B6: 200 μM curcumenol group; B7: 140 μM daidzein group; B8: 60 μM curzerenone group; B9: 140 μM curzerenone group; B10: 20 μM naringin group; B11: 40 μM naringin group; B12: bar gaph of statistics. C: Annexin V-FITC and PI staining was utilized to assess cell apoptosis via flow cytometry; C1: blank group; C2: 120 μM curcumenol group; C3: 20 μM naringin group; C4: 60 μM curzerenone group; C5: 200 μM curcumenol group; C6: 40 μM naringin group; C7: 140 μM curzerenone group; C8: bar gaph of statistics. For A: HepG2 cells were treated with apigenin, curcumenol, daidzein, naringin, and curzerenone for 24 h in vitro (n = 6); For B: HepG2 cells were exposed to these monomers for 24 h in vitro (n = 4); For C: HepG2 cells were exposed to these monomers for 48 h in vitro (n = 4). PI: propidium iodide; FITC: fluorescein isothiocyanate; HepG2: human hepatoma G2 cell line; CCK-8: cell counting kit-8. Differences between groups were compared using independent samples t-tests. aP < 0.001, bP < 0.01, cP < 0.05, compared with the 0 μM group. dP < 0.001, eP < 0.01, fP < 0.05, compared with the blank group.
Figure 4 Apigenin is the main active monomer of JHD in promoting the apoptosis of HepG2 cells A: electrophoresis band images of AKT1, BCL2, TP53, JUN, EGFR, and GAPDH; B: bar chart of TP53 expression in each group; C: bar chart of AKT1 expression in each group; D: bar chart of BCL2 expression in each group; E: bar chart of JUN expression in each group; F: bar chart of EGFR expression in each group. The protein expressions of AKT1, BCL2, TP53, JUN, and EGFR were analyzed using Western blotting. Specifically, apigenin and daidzein were used to stimulate HepG2 cells in vitro for 24 h, while curcumenol, curzerenone, and naringin were applied to stimulate HepG2 cells in vitro for 48 h (n = 3). TP53: tumor protein 53; AKT1: serine-threonine kinase 1; BCL2: B-cell lymphoma 2; EGFR: epidermal growth factor receptor; JUN: Jun proto-oncogene; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HepG2: human hepatoma G2 cell line; JHD: Jianpi Huayu decoction. The statistical method used was independent samples t-tests. aP < 0.001, compared with the 24 h control group; bP < 0.05, compared with the 48 h control group.
Figure 4 Apigenin is the main active monomer of JHD in promoting the apoptosis of HepG2 cells A: electrophoresis band images of AKT1, BCL2, TP53, JUN, EGFR, and GAPDH; B: bar chart of TP53 expression in each group; C: bar chart of AKT1 expression in each group; D: bar chart of BCL2 expression in each group; E: bar chart of JUN expression in each group; F: bar chart of EGFR expression in each group. The protein expressions of AKT1, BCL2, TP53, JUN, and EGFR were analyzed using Western blotting. Specifically, apigenin and daidzein were used to stimulate HepG2 cells in vitro for 24 h, while curcumenol, curzerenone, and naringin were applied to stimulate HepG2 cells in vitro for 48 h (n = 3). TP53: tumor protein 53; AKT1: serine-threonine kinase 1; BCL2: B-cell lymphoma 2; EGFR: epidermal growth factor receptor; JUN: Jun proto-oncogene; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HepG2: human hepatoma G2 cell line; JHD: Jianpi Huayu decoction. The statistical method used was independent samples t-tests. aP < 0.001, compared with the 24 h control group; bP < 0.05, compared with the 48 h control group.
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