Network Pharmacology-based Approach to Investigate the Mechanism of Folium Artemisiae Argyi in the Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) mortality rates have risen significantly in recent years. Folium Artemisiae Argyi (FAA) has demonstrated anticancer properties, yet its specific mechanisms of action in HCC treatment remain unclear. This study used network pharmacology and molecular docking to investigate these mechanisms. HCC-related targets were sourced from GeneCards, NCBI, and GEPIA2 databases, while active FAA compounds and targets were identified through Swiss Target Prediction. Protein-protein interaction (PPI) networks were constructed using the STRING database and visualized with Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using ShinyGO. Autodock was employed for molecular docking, and gene expression profiling was performed to assess the prognosis and survival of HCC patients. The study identified 19,467 predicted HCC targets and 292 FAA compound targets, with 207 overlapping targets. GO/KEGG enrichment analyses indicated that FAA influences HCC by regulating biological processes related to cell proliferation and survival, particularly through pathways such as cancer pathways, proteoglycans in cancer, and the PI3K-AKT pathway. Key targets identified included AKT1, SRC, EGFR, PPARG, ESR1, BCL2, PTGS2, HSP90AA1, HIF1A, and MAPK3, with most showing upregulation linked to poor prognosis, reduced disease-free survival, and lower overall survival in HCC patients. Molecular docking analysis confirmed strong interactions between the top five core targets and FAA compounds. Among them, Quercetin, Mandenol, and Ethyl Oleate demonstrated high binding affinities with EGFR, scoring -7.98 kcal/mol, -7.17 kcal/mol, and -6.97 kcal/mol, respectively. In contrast, (R)-Naringenin showed the strongest interaction with AKT1, exhibiting a binding affinity of -8.51 kcal/mol.These findings suggest that FAA exerts a therapeutic effect on HCC via multipathway pharmacological mechanisms, offering the potential to improve patient outcomes. The study provides a foundation for clinical validation and the development of novel anti-cancer drugs.

Keywords: Folium Artemisiae Argyi, Hepatocellular Carcinoma, Network Pharmacology, Pharmacological Mechanism

Downloads

Download data is not yet available.

References

Baghy, K., Tátrai, P., Regős, E., & Kovalszky, I. (2016). Proteoglycans in liver cancer. World Journal of Gastroenterology, 22(1), 379–393. https://doi.org/10.3748/wjg.v22.i1.379
Balogh, J., Victor III, D., Asham, E. H., Burroughs, S. G., Boktour, M., Saharia, A., ... & Monsour Jr, H. P. (2016). Hepatocellular carcinoma: a review. Journal of Hepatocellular Carcinoma, 41-53. https://doi.org/10.2147/JHC.S61146
Casadei‐Gardini, A., Scartozzi, M., Tada, T., Yoo, C., Shimose, S., Masi, G., ... & Kawata, K. (2021). Lenvatinib versus Sorafenib in first‐line treatment of unresectable hepatocellular carcinoma: an inverse probability of treatment weighting analysis. Liver International, 41(6), 1389-1397. https://doi.org/10.1111/liv.14817
Chen, H. N., Chen, Y., Zhou, Z. G., Wei, Y., & Huang, C. (2019). A novel role for ketoconazole in hepatocellular carcinoma treatment: linking PTGS2 to mitophagy machinery. Autophagy, 15(4), 733-734. https://doi.org/10.1080/15548627.2019.1569934
Chu, Q., Gu, X., Zheng, Q., & Zhu, H. (2022). Regulatory mechanism of HIF-1α and its role in liver diseases: a narrative review. Annals of translational medicine, 10(2). https://doi.org/10.21037/atm-21-4222
Codenotti, S., Sandrini, L., Mandracchia, D., Lorenzi, L., Corsetti, G., Poli, M., ... & Fanzani, A. (2024). Statin-sensitive Akt1/Src/caveolin-1 signaling enhances oxidative stress resistance in rhabdomyosarcoma. Cancers, 16(5), 853.https://doi.org/10.3390/cancers16050853
Dai, W., Chen, C., Dong, G., Li, G., Peng, W., Liu, X., ... & Hu, X. (2022). Alleviation of Fufang Fanshiliu decoction on type II diabetes mellitus by reducing insulin resistance: A comprehensive network prediction and experimental validation. Journal of Ethnopharmacology, 294. https://doi.org/10.1016/j.jep.2022.115338
Degan, S. E., & Gelman, I. H. (2021). Emerging roles for AKT isoform preference in cancer progression pathways. Molecular Cancer Research, 19(8), 1251-1257. https://doi.org/10.1158/1541-7786.MCR-20-1066
Delire, B., & Stärkel, P. (2015). The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. European Journal of Clinical Investigation, 45(6), 609-623.https://doi.org/10.1111/eci.12441
El-Serag, H. B. (2011). Hepatocellular Carcinoma. The New England Journal of Medicine 365(12): 1118–27. https://doi.org/10.1056/NEJMra1001683
Erdenebileg, S., Kim, M., Nam, Y., Cha, K. H., Le, T. T., Jung, S. H., & Nho, C. W. (2024). Artemisia argyi ethanol extract ameliorates nonalcoholic steatohepatitis-induced liver fibrosis by modulating gut microbiota and hepatic signaling. Journal of Ethnopharmacology, 333. https://doi.org/10.1016/j.jep.2024.118415
García-Pras, E., Fernández-Iglesias, A., Gracia-Sancho, J., & Pérez-del-Pulgar, S. (2021). Cell death in hepatocellular carcinoma: pathogenesis and therapeutic opportunities. Cancers, 14(1). https://doi.org/10.3390/cancers14010048
Ge, S. X., Jung, D., & Yao, R. (2020). ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics, 36(8), 2628-2629. https://doi.org/10.1093/bioinformatics/btz931
Gu, L., Wang, X., Shao, X., Ding, Y., & Li, Y. (2022). Study on chemical constituents of Folium Artemisiae argyi Carbonisatum, toxicity evaluation on zebrafish and intestinal hemostasis. Saudi Pharmaceutical Journal, 30(5), 532-543. https://doi.org/10.1016/j.jsps.2022.02.018
Guan, X., Ge, D., Li, S., Huang, K., Liu, J., & Li, F. (2019). Chemical composition and antimicrobial activities of Artemisia argyi Lévl. et Vant essential oils extracted by simultaneous distillation-extraction, subcritical extraction and hydrodistillation. Molecules, 24(3). https://doi.org/10.3390/molecules24030483
Guo, J., Yan, W., Duan, H., Wang, D., Zhou, Y., Feng, D., ... & Qin, X. (2024). Therapeutic effects of natural products on liver cancer and their potential mechanisms. Nutrients, 16(11). https://doi.org/10.3390/nu16111642
Hafezi, S., & Rahmani, M. (2021). Targeting BCL-2 in cancer: advances, challenges, and perspectives. Cancers, 13(6). https://doi.org/10.3390/cancers13061292
Hassanipour, S., Vali, M., Gaffari-Fam, S., Nikbakht, H. A., Abdzadeh, E., Joukar, F., ... & Mansour-Ghanaei, F. (2020). The survival rate of hepatocellular carcinoma in Asian countries: a systematic review and meta-analysis. EXCLI Journal, 19, 108–130. https://doi.org/10.17179/excli2019-1842
He, Y., Sun, M. M., Zhang, G. G., Yang, J., Chen, K. S., Xu, W. W., & Li, B. (2021). Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduction and Targeted Therapy, 6(1). https://doi.org/10.1038/s41392-021-00828-5
Hilmi, M., Vienot, A., Rousseau, B., & Neuzillet, C. (2019). Immune therapy for liver cancers. Cancers, 12(1). https://doi.org/10.3390/cancers12010077
Hon, K. W., Nag, S., Stany, B. K., Mishra, S., & Naidu, R. (2025). Identification of SRC, AKT1 and MAPK3 as therapeutic targets of apigenin and luteolin in colorectal and colon carcinoma through network pharmacology. Food Bioscience, 67. https://doi.org/10.1016/j.fbio.2025.106313
Huang, L., & Fu, L. (2015). Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharmaceutica Sinica B, 5(5), 390-401. https://doi.org/10.1016/j.apsb.2015.07.001
Hubbard, R. E., & Haider, M. K. (2010). Hydrogen bonds in proteins: role and strength. Encyclopedia of Life Sciences, 1, 1-6. https://doi.org/10.1038/npg.els.0003011
Jin, F. J., Hu, S., Wang, B. T., & Jin, L. (2021). Advances in genetic engineering technology and its application in the industrial fungus Aspergillus oryzae. Frontiers in Microbiology, 12. https://doi.org/10.3389/fmicb.2021.644404
Lee, S., Rauch, J., & Kolch, W. (2020). Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. International Journal of Molecular Sciences, 21(3). https://doi.org/10.3390/ijms21031102
Lee, Y., Yoon, Y., & Choi, K. H. (2025). Correlation of periodontitis with hepatic and intestinal inflammation and glycemic control, and effects of bioconverted Artemisia herba-alba by Lactiplantibacillus plantarum SMFM2016-RK. Journal of Oral Microbiology, 17(1). https://doi.org/10.1080/20002297.2025.2473246
Liu, R., Zhao, J., He, K., Zhang, X., Chang, L., & Xiang, G. (2018). Determination of Eupatilin in Folium artemisiae Argyi and its inhibitory effect on hepatoma cells. Pharmacognosy Magazine, 14(53). https://doi.org/10.4103/pm.pm_472_16
Lv, J. L., Duan, J. A., Shen, B., & Yin, Y. Y. (2013). Caffeic acid esters from Artemisia argyi and their antioxidant activities. Chemistry of Natural Compounds, 49, 8-11. https://doi.org/10.1007/s10600-013-0492-5
Majeed H., & Gupta V. (2025). Adverse Effects of Radiation Therapy. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Available at: https://www.ncbi.nlm.nih.gov/books/NBK563259/
Meng, X., & Liu, X. (2021). Therapeutic value of estrogen receptor α in hepatocellular carcinoma based on molecular mechanisms. Journal of Clinical and Translational Hepatology, 10(1). https://doi.org/10.14218/JCTH.2021.00224
Mittal, S., & El-Serag, H. B. (2013). Epidemiology of hepatocellular carcinoma: consider the population. Journal of Clinical Gastroenterology, 47, S2-S6. https://doi.org/10.1097/MCG.0b013e3182872f29
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785-2791. https://doi.org/10.1002/jcc.21256
Mroweh, M., Roth, G., Decaens, T., Marche, P. N., Lerat, H., & Macek Jílková, Z. (2021). Targeting Akt in hepatocellular carcinoma and its tumor microenvironment. International Journal of Molecular Sciences, 22(4). https://doi.org/10.3390/ijms22041794
Murugan, A. K., Grieco, M., & Tsuchida, N. (2019). RAS mutations in human cancers: Roles in precision medicine. In Seminars in Cancer Biology (Vol. 59, pp. 23-35). Academic Press. https://doi.org/10.1016/j.semcancer.2019.06.007
Nosengo, Nicola. 2016. “Can You Teach Old Drugs New Tricks?” Nature 534(7607): 314–316. https://doi.org/10.1038/534314a
O’Brien, M. H., Pitot, H. C., Chung, S. H., Lambert, P. F., Drinkwater, N. R., & Bilger, A. (2021). Estrogen receptor-α suppresses liver carcinogenesis and establishes sex-specific gene expression. Cancers, 13(10). https://doi.org/10.3390/cancers13102355
Pawar, S. S., & Rohane, S. H. (2021). Review on discovery studio: An important tool for molecular docking. Asian Journal of Research in Chemistry 14(1), 86-88. https://doi.org/10.5958/0974-4150.2021.00014.6
Pfab, C., Schnobrich, L., Eldnasoury, S., Gessner, A., & El-Najjar, N. (2021). Repurposing of antimicrobial agents for cancer therapy: what do we know?. Cancers, 13(13). https://doi.org/10.3390/cancers13133193
Pinzi, L., & Rastelli, G. (2019). Molecular docking: shifting paradigms in drug discovery. International Journal of Molecular Sciences, 20(18), https://doi.org/10.3390/ijms20184331
Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., ... & Pirmohamed, M. (2019). Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1), 41-58. https://doi.org/10.1038/nrd.2018.168
Ru, J., Li, P., Wang, J., Zhou, W., Li, B., Huang, C., ... & Yang, L. (2014). TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. Journal of Cheminformatics, 6, 1-6. https://doi.org/10.1186/1758-2946-6-13
Rumgay, H., Arnold, M., Ferlay, J., Lesi, O., Cabasag, C. J., Vignat, J., ... & Soerjomataram, I. (2022). Global burden of primary liver cancer in 2020 and predictions to 2040. Journal of Hepatology, 77(6), 1598-1606. https://doi.org/10.1016/j.jhep.2022.08.021
Rumgay, H., Ferlay, J., de Martel, C., Georges, D., Ibrahim, A. S., Zheng, R., ... & Soerjomataram, I. (2022). Global, regional and national burden of primary liver cancer by subtype. European Journal of Cancer, 161, 108-118. https://doi.org/10.1016/j.ejca.2021.11.023
Song, X., Wen, X., He, J., Zhao, H., Li, S., & Wang, M. (2019). Phytochemical components and biological activities of Artemisia argyi. Journal of Functional Foods, 52, 648-662. https://doi.org/10.1016/j.jff.2018.11.029
Sueangoen, N., Tantiwetrueangdet, A., & Panvichian, R. (2020). HCC-derived EGFR mutants are functioning, EGF-dependent, and erlotinib-resistant. Cell & Bioscience, 10(1). https://doi.org/10.1186/s13578-020-00407-1
Szklarczyk, D., Gable, A. L., Nastou, K. C., Lyon, D., Kirsch, R., Pyysalo, S., ... & von Mering, C. (2021). The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic acids research, 49(D1), D605-D612. https://doi.org/10.1093/nar/gkaa1074
Tang, L. P., Liu, T., Han, X. Y., Li, B., Liu, H. D., & Gao, X. M. (2024). Unlocking the power of sesquiterpenoids: phytochemistry and bioactivities in Artemisia (2017–2023). Phytochemistry Reviews, 1-85. https://doi.org/10.1007/s11101-024-10040-2
Tang, Y., Sun, L., Wei, J., Sun, C., Gan, C., Xie, X., ... & Huang, Y. (2022). Network pharmacology identification and in Vivo validation of key pharmacological pathways of Phyllanthus reticulatus (Euphorbiaceae) leaf extract in liver cancer treatment. Journal of Ethnopharmacology, 297. https://doi.org/10.1016/j.jep.2022.115479
Terashima, T., Yamashita, T., Takata, N., Toyama, T., Shimakami, T., Takatori, H., ... & Kaneko, S. (2020). Comparative analysis of liver functional reserve during lenvatinib and sorafenib for advanced hepatocellular carcinoma. Hepatology Research, 50(7), 871-884. https://doi.org/10.1111/hepr.13505
Tian, L. Y., Smit, D. J., & Jücker, M. (2023). The role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism. International Journal of Molecular Sciences, 24(3). https://doi.org/10.3390/ijms24032652
Wei, J., Hu, M., Huang, K., Lin, S., & Du, H. (2020). Roles of proteoglycans and glycosaminoglycans in cancer development and progression. International Journal of Molecular Sciences, 21(17). https://doi.org/10.3390/ijms21175983
Xia, J. X., Zhao, B. B., Zan, J. F., Wang, P., & Chen, L. L. (2019). Simultaneous determination of phenolic acids and flavonoids in Artemisiae Argyi Folium by HPLC-MS/MS and discovery of antioxidant ingredients based on relevance analysis. Journal of Pharmaceutical and Biomedical Analysis, 175. https://doi.org/10.1016/j.jpba.2019.06.031
Xiang, X., You, X. M., & Li, L. Q. (2018). Expression of HSP90AA1/HSPA8 in hepatocellular carcinoma patients with depression. OncoTargets and Therapy, 3013-3023. https://doi.org/10.2147/OTT.S159432
Xiao, J. Q., Liu, W. Y., Sun, H. P., Li, W., Koike, K., Kikuchi, T., ... & Zhang, J. (2019). Bioactivity-based analysis and chemical characterization of hypoglycemic and antioxidant components from Artemisia argyi. Bioorganic Chemistry, 92. https://doi.org/10.1016/j.bioorg.2019.103268
Yoon, J. S., & Lee, C. W. (2022). Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma. Experimental & Molecular Medicine, 54(11), 1799-1813. https://doi.org/10.1038/s12276-022-00883-0
Yu, M., Chen, Z., Zhou, Q., Zhang, B., Huang, J., Jin, L., ... & Ye, Q. (2022). PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy. Journal of Hepatology, 77(1), 140-151. https://doi.org/10.1016/j.jhep.2022.01.026
Zhang, B., Shi, H., & Wang, H. (2023). Machine learning and AI in cancer prognosis, prediction, and treatment selection: a critical approach. Journal of Multidisciplinary Healthcare, 1779-1791. https://doi.org/10.2147/JMDH.S410301
Zhang, J., Guo, J., Yang, N., Huang, Y., Hu, T., & Rao, C. (2022). Endoplasmic reticulum stress-mediated cell death in liver injury. Cell Death & Disease, 13(12). https://doi.org/10.1038/s41419-022-05444-x
Zhang, L. B., Lv, J. L., Chen, H. L., Yan, X. Q., & Duan, J. A. (2013). Chemical constituents from Artemisia argyi and their chemotaxonomic significance. Biochemical Systematics and Ecology, 50, 455-458. https://doi.org/10.1016/j.bse.2013.06.010
Zhao, L., Zhang, H., Li, N., Chen, J., Xu, H., Wang, Y., & Liang, Q. (2023). Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. Journal of Ethnopharmacology, 309. https://doi.org/10.1016/j.jep.2023.116306
Zhao, R., Wu, Y., Wang, T., Zhang, Y., Kong, D., Zhang, L., ... & Zhang, F. (2015). Elevated Src expression associated with hepatocellular carcinoma metastasis in northern Chinese patients. Oncology Letters, 10(5), 3026-3034. https://doi.org/10.3892/ol.2015.3706
Statistics
348 Views | 169 Downloads
How to Cite
Tepap, C., & Ibrahim, R. (2025). Network Pharmacology-based Approach to Investigate the Mechanism of Folium Artemisiae Argyi in the Treatment of Hepatocellular Carcinoma. International Journal of Advancement in Life Sciences Research, 8(2), 74-94. https://doi.org/https://doi.org/10.31632/ijalsr.2025.v08i02.007