Objective  To predict the underlying mechanisms of Foeniculum vulgare against hepa-tocellular carcinoma (HCC) using an integrated network pharmacology approach.

Methods  Active con-stituents of Foeniculum vulgare with reported anti-HCC activity were first identified. Subsequently, a network pharmacology framework was applied, involving the screening of bioactive compounds (oral bioavailability ≥30%, drug-likeness ≥0.18), target prediction from multiple databases (TCMSP and HERB), construction of a protein-protein interaction (PPI) network, GO and KEGG enrichment analysis, and validation via molecular docking. A multidimensional “herb-compound-target-pathway-disease” network was thereby established.

Results  19 candidate bioactive compounds were screened, corresponding to 140 potential HCC-related targets. PPI analysis identified 14 hub targets, including tyrosine kinase (SRC), AKT serine/threonine kinase 1 (AKT1), and epidermal growth factor receptor (EGFR). Enrichment analysis revealed significant associations with key oncogenic pathways, such as EGFR tyrosine kinase inhibitor resistance and central carbon metabolism in cancer. Molecular docking indicated strong binding affinities between core compounds (e.g., apiole, umbelliferone) and key targets. ADMET profiling suggested that most compounds exhibit favorable pharmacokinetic profiles, including promising oral bioavailability and metabolic stability.

Conclusion  This integrative study elucidates a potential multi-compound, multi-target, and multi-pathway mechanism underlying the anti-HCC effects of Foeniculum vulgare, providing a theoretical foundation and strategic direction for its further development as a candidate therapeutic agent.

1. 中国药典2025版. 一部[S]. 2025: 50.

2. 彭成, 主编. 中华道地药材[M]. 北京: 中国中医药出版社, 2011: 4030.

3. 付起凤, 张艳丽, 许树军, 等. 小茴香化学成分及药理作用的研究进展[J]. 中医药信息, 2008, 25(5): 24-26. [Fu QF, Zhang YL, Xu SJ, et al. Research progress on chemical constituents and pharmacological effects of Foeniculum vulgare[J]. Information on Traditional Chinese Medicine, 2008, 25(5): 24-26.] DOI: 10.19656/j.cnki.1002-2406.2008.05.011.

4. Rafieian F, Amani R, Rezaei A, et al. Exploring fennel (Foeniculum vulgare): composition, functional properties, potential health benefits, and safety[J]. Crit Rev Food Sci Nutr, 2024, 64(20): 6924-6941. DOI: 10.1080/10408398.2023.2176817.

5. Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers[J]. Cancer Metastasis Rev, 2023, 42(3): 629-652. DOI: 10.1007/s10555-023-10084-4.

6. Nooreen Z, Harer S, Rai AK, et al. An insight into research advances on herbal and phytochemical approaches to the management of hepatocellular carcinoma from january 2020 to July 2024[J]. Anticancer Agents Med Chem, 2025, 25(15): 1049-1076. DOI: 10.2174/0118715206348951241120120918.

7. Elkady AI. Anethole Inhibits the proliferation of human prostate cancer cells via induction of cell cycle arrest and apoptosis[J]. Anticancer Agents Med Chem, 2018, 18(2): 216-236. DOI: 10.2174/1871520617666170725165717.

8. Mehralikhani A, Movahedi M, Larypoor M, et al. Evaluation of the effect of foeniculum vulgare on the expression of E-Cadherin, dysadherin and Ki-67 in BALB/C mice with 4T1 model of breast cancer[J]. Nutr Cancer, 2021, 73(2): 318-328. DOI: 10.1080/01635581.2020.1746365.

9. Mohamad RH, El-Bastawesy AM, Abdel-Monem MG, et al. Antioxidant and anticarcinogenic effects of methanolic extract and volatile oil of fennel seeds (Foeniculum vulgare)[J]. J Med Food, 2011, 14(9): 986-1001.DOI: 10.1089/jmf.2008.0255.

10. Levorato S, Dominici L, Fatigoni C, et al. In vitro toxicity evaluation of estragole-containing preparations derived from Foeniculum vulgare Mill. (fennel) on HepG2 cells[J]. Food Chem Toxicol, 2018, 111(1): 616-622. DOI: 10.1016/j.fct.2017.12.014.

11. Ke W, Wang H, Zhao X, et al. Foeniculum vulgare seed extract exerts anti-cancer effects on hepatocellular carcinoma[J]. Food Funct, 2021, 12(4): 1482-1497. DOI: 10.1039/d0fo02243h.

12. Sheweita SA, El-Hosseiny LS, Nashashibi MA. Protective effects of essential oils as natural antioxidants against hepatotoxicity induced by cyclophosphamide in mice[J]. PLoS One, 2016, 11(11): e0165667. DOI: 10.1371/journal.pone.0165667.

13. Schake P, Bolz SN, Linnemann K, et al. PLIP 2025: introducing protein-protein interactions to the protein-ligand interaction profiler[J]. Nucleic Acids Res, 2025, 53(W1): W463-W465. DOI: 10.1093/nar/gkaf361.

14. Campani C, Imbeaud S, Couchy G, et al. Circulating tumour DNA in patients with hepatocellular carcinoma across tumour stages and treatments[J]. Gut, 2024, 73(11): 1870-1882. DOI: 10.1136/gutjnl-2024-331956.

15. Liu W, Zheng L, Zhang R, et al. Circ-ZEB1 promotes PIK3CA expression by silencing miR-199a-3p and affects the proliferation and apoptosis of hepatocellular carcinoma[J]. Mol Cancer, 2022, 21(1): 72. DOI: 10.1186/s12943-022-01529-5.

16. Xiong HJ, Yu HQ, Zhang J, et al. Elevated FBXL6 activates both wild-type KRAS and mutant KRASG12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice[J]. Mil Med Res, 2024, 11(6): 818-838. DOI: 10.1186/s40779-023-00501-8.

17. Zhang H, Su X, Burley SK, et al. mTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma[J]. Theranostics, 2022, 12(7): 3518-3533. DOI: 10.7150/thno.72581.

18. Tian LY, Smit DJ, Jücker M. The role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism[J]. Int J Mol Sci, 2023, 24(3): 2652. DOI: 10.3390/ijms24032652.

19. Zhou C, Liu C, Liu W, et al. SLFN11 inhibits hepatocellular carcinoma tumorigenesis and metastasis by targeting RPS4X via mTOR pathway[J]. Theranostics, 2020, 10(10): 4627-4643. DOI: 10.7150/thno.42869.

20. Scheiter A, Evert K, Reibenspies L, et al. RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues[J]. Mol Oncol, 2022, 16(5): 1091-1118. DOI: 10.1002/1878-0261.13135.

21. Ngamphaiboon N, Pattaranutaporn P, Lukerak S, et al. A phase I study of the CDK4/6 inhibitor palbociclib in combination with cetuximab and radiotherapy for locally advanced head and neck squamous cell carcinoma[J]. Clin Cancer Res, 2024, 30(2): 294-303. DOI: 10.1158/1078-0432.Ccr-23-2303.

22. Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial[J]. Lancet Oncol, 2024, 25(11): 1424-1439. DOI: 10.1016/s1470-2045(24)00387-5.

23. Yin XH, Han YL, Zhuang Y, et al. Geldanamycin inhibits Fas signaling pathway and protects neurons against ischemia[J]. Neurosci Res, 2017, 124(1): 33-39. DOI: 10.1016/j.neures.2017.05.003.

24. Kezic A, Popovic L, Lalic K. mTOR inhibitor therapy and metabolic consequences: where do we stand?[J]. Oxid Med Cell Longev, 2018, 2018: 2640342. DOI: 10.1155/2018/2640342.

25. Redin E, Garmendia I, Lozano T, et al. SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation[J]. J Immunother Cancer, 2021, 9(3): e001496. DOI: 10.1136/jitc-2020-001496.

26. Wei PL, Tu SH, Lien HM, et al. The in vivo antitumor effects on human COLO 205 cancer cells of the 4,7-dimethoxy-5-(2-propen-1-yl)-1,3-benzodioxole (apiole) derivative of 5-substituted 4,7-dimethoxy-5-methyl-l,3-benzodioxole (SY-1) isolated from the fruiting body of Antrodia camphorate[J]. J Cancer Res Ther, 2012, 8(4): 532-536. DOI: 10.4103/0973-1482.106529.

27. Wu KH, Lee WJ, Cheng TC, et al. Study of the antitumor mechanisms of apiole derivatives (AP-02) from Petroselinum crispum through induction of G0/G1 phase cell cycle arrest in human COLO 205 cancer cells[J]. BMC Complement Altern Med, 2019, 19(1): 188. DOI: 10.1186/s12906-019-2590-9.

28. Harakeh S, Al-Raddadi R, Alamri T, et al. Apoptosis induction in human hepatoma cell line HepG2 cells by trans-anethole via activation of mitochondria-mediated apoptotic pathways[J]. Biomed Pharmacother, 2023, 165(1): 115236. DOI: 10.1016/j.biopha.2023.115236.

29. Kornicka A, Balewski Ł, Lahutta M, et al. Umbelliferone and its synthetic derivatives as suitable molecules for the development of agents with biological activities: a review of their pharmacological and therapeutic potential[J]. Pharmaceuticals (Basel), 2023, 16(12): 1732. DOI: 10.3390/ph16121732.

30. Chen L, Xu W, Yang Q, et al. Imperatorin alleviates cancer cachexia and prevents muscle wasting via directly inhibiting STAT3[J]. Pharmacol Res, 2020, 158(1): 104871. DOI: 10.1016/j.phrs.2020.104871.

31. Vargas-Pozada EE, Ramos-Tovar E, Márquez-Quiroga LV, et al. Coffee for the liver: a mechanistic approach[J]. Biochem Pharmacol, 2025, 242(Pt 2): 117338. DOI: 10.1016/j.bcp.2025.117338.

32. Feng J, Li J, Wu L, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2020, 39(1): 126. DOI: 10.1186/s13046-020-01629-4.

33. Jin H, Shi Y, Lv Y, et al. EGFR activation limits the response of liver cancer to lenvatinib[J]. Nature, 2021, 595(7869): 730-734.DOI: 10.1038/s41586-021-03741-7.

34. 韩潇文. ESR1和ACOX2在肝细胞癌中的表达及其意义[D]. 合肥: 安徽医科大学, 2021.  DOI: 10.26921/d.cnki.ganyu.2021.000147.

35. Li CM, Zhang J, Wu W, et al. FBXO43 increases CCND1 stability to promote hepatocellular carcinoma cell proliferation and migration[J]. Front Oncol, 2023, 13(1): 1138348. DOI: 10.3389/fonc.2023.1138348.

36. Raposo A, Raheem D, Zandonadi RP, et al. Anethole in cancer therapy: mechanisms, synergistic potential, and clinical challenges[J]. Biomed Pharmacother, 2024, 180(1): 117449. DOI: 10.1016/j.biopha.2024.117449.