Objective To systematically analyze the mechanism of cordycepin in treating head and neck squamous cell carcinomas (HNSC) by integrating network pharmacology and bioinformatics.

Methods The in vivo toxicity of cordycepin was predicted using the pkCSM database. The intersection targets of cordycepin and HNSC were screened using PharmMapper Server and GeneCards database. The protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape 3.10.1 software, and the core targets were screened. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of the intersection targets were performed via Metascape database. The core targets were analyzed for expression differences, prognosis, and nomogram construction based on the The Cancer Genome Atlas (TCGA) database using R 4.3.2 software. HNSC samples were grouped according to the expression levels of the core targets, and differential gene expression analysis and Gene Set Enrichment Analysis (GSEA) were conducted. Finally, molecular docking was performed using the CB-Dock2 platform to validate the binding affinity.

Results The toxicity prediction results showed that cordycepin has good safety.HSP90AA1 was identified as a core target for cordycepin in treating HNSC, and was significantly enriched in signal pathways such as the C-type lectin receptor signaling pathway. The expression level ofHSP90AA1 in HNSC tumor tissues was significantly upregulated and was related to T stage and tumor grade. Patients with lowHSP90AA1 expression exhibited significantly prolonged overall survival and progression-free survival. The results of the differential analysis based onHSP90AA1 expression showed that its high expression was closely associated with biological processes including extracellular matrix remodeling and immune response regulation. Molecular docking confirmed that cordycepin exhibits excellent binding affinity forHSP90AA1.

Conclusion Cordycepin may exert its therapeutic effect on HNSC by directly targeting and inhibitingHSP90AA1, thereby modulating the complex downstream network associated with tumor progression and immune microenvironment.

1. SungH,FerlayJ,SiegelRL,et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2021,71(3):209-249.DOI:10.3322/caac.21660.

2. Rioja-BlancoE,GallardoA,Arroyo-SoleraI,et al.A novel CXCR4-targeted diphtheria toxin nanoparticle inhibits invasion and metastatic dissemination in a head and neck squamous cell carcinoma mouse model[J].Pharmaceutics,2022,14(4):887.DOI:10.3390/pharmaceutics14040887.

3. YuG,PengJ,LiL,et al.The role and mechanisms of cordycepin in inhibiting cancer cells[J].Braz J Med Biol Res,2024,57:e13889.DOI:10.1590/1414-431X2024e13889.

4. BinlatehT,UppatchaN,ThepchaiJ,et al.Cordycepin attenuates migration and invasion of HSC-4 oral squamous carcinoma cells through autophagy-dependent FAK/Akt and MMP2/MMP9 suppression[J].J Dent Sci,2022,17(4):1677-1688.DOI:10.1016/j.jds.2022.03.002.

5. LiHB,ChenJK,SuZX,et al.Cordycepin augments the chemosensitivity of osteosarcoma to cisplatin by activating AMPK and suppressing the AKT signaling pathway[J].Cancer Cell Int,2021,21(1):706.DOI:10.1186/s12935-021-02411-y.

6. LiuX,OuyangS,YuB,et al.PharmMapper server: a web server for potential drug target identification using pharmacophore mapping approach[J].Nucleic Acids Res,2010,38(Web Server issue):W609-W614.DOI:10.1093/nar/gkq300.

7. The UniProt Consortium,BatemanA,MartinMJ,et al.UniProt: the universal protein knowledgebase in 2025[J].Nucleic Acids Res,2025,53(D1):D609-D617.DOI:10.1093/nar/gkae1010.

8. StelzerG,RosenN,PlaschkesI,et al.The GeneCards Suite: from gene data mining to disease genome sequence analyses[J].Curr Protoc Bioinform,2016, 54: 1.30.1-1.30.33.DOI:10.1002/cpbi.5.

9. SzklarczykD,GableAL,NastouKC,et al.The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets[J].Nucleic Acids Res,2021,49(D1):D605-D612.DOI:10.1093/nar/gkaa1074.

10. TangZ,KangB,LiC,et al.GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis[J].Nucleic Acids Res,2019,47(W1):W556-W560.DOI:10.1093/nar/gkz430.

11. ZhangZ,LiH,JiangS,et al.A survey and evaluation of Web-based tools/databases for variant analysis of TCGA data[J].Brief Bioinform,2019,20(4):1524-1541.DOI:10.1093/bib/bby023.

12. BurleySK,BhikadiyaC,BiC,et al.RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences[J].Nucleic Acids Res,2021,49(D1):D437-D451.DOI:10.1093/nar/gkaa1038.

13. LiuY,YangX,GanJ,et al.CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting[J].Nucleic Acids Res,2022,50(W1):W159-W164.DOI:10.1093/nar/gkac394.

14. HsinKY,GhoshS,KitanoH.Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J].PLOS One,2013,8(12):e83922.DOI:10.1371/journal.pone.0083922.

15. BicciE,Di FinizioA,CalamandreiL,et al.Head and neck squamous cell carcinoma: insights from dual-energy computed tomography (DECT)[J].Tomography,2024,10(11):1780-1797.DOI:10.3390/tomography10110131.

16. SongJ,ChangI,ChenZ,et al.Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling[J].PLOS One,2010,5(7):e11456.DOI:10.1371/journal.pone.0011456.

17. WangY,HanJ,ZhuY,et al.New advances in the therapeutic strategy of head and neck squamous cell carcinoma: a review of latest therapies and cutting-edge research[J].Biochim Biophys Acta Rev Cancer,2025,1880(1):189230.DOI:10.1016/j.bbcan.2024.189230.

18. ZhangC,WangY,RuanH,et al.Research progress on treatment-associated pneumonitis in lung cancer patients undergoing radiotherapy and immunotherapy[J].Future Oncol,2025,21(19):2549-2560.DOI:10.1080/14796694.2025.2525067.

19. QinX,WuH,PanJ,et al.Immune-metabolic crosstalk in HNSCC: mechanisms and therapeutic opportunities[J].Front Oncol,2025,15:1553284.DOI:10.3389/fonc.2025.1553284.

20. TangF,LiY,PanM,et al.HSP90AA1 promotes lymphatic metastasis of hypopharyngeal squamous cell carcinoma by regulating epithelial-mesenchymal transition[J].Oncol Res,2023,31(5):787-803.DOI:10.32604/or.2023.030081.

21. MiyataY,NakamotoH,NeckersL.The therapeutic target Hsp90 and cancer hallmarks[J].Curr Pharm Des,2013,19(3):347-365.DOI:10.2174/138161213804143725.

22. ZhouL,FangH,ChenM,et al.Identification and risk modelling of bacterial lipopolysaccharide-related subtypes in head and neck squamous cell carcinoma to predict prognostic and immunological properties[J].J Stomatol Oral Maxillofac Surg,2025,126(5S):102422.DOI:10.1016/j.jormas.2025.102422.

23. 邹琸玥,张伟健,陈宇,等.基于网络药理学与分子对接探讨虫草素治疗舌鳞状细胞癌的作用机制[J].右江民族医学院学报,2025,47(4):583-590, 599.ZouZY,ZhangWJ,ChenY,et al.Investigating the mechanism of cordycepin in the treatment of tongue squamous cell carcinoma (TSCC) based on network pharmacology and molecular docking[J].Journal of Youjiang Medical University for Nationalities,2025,47(4):583-590, 599.DOI:10.3969/j.issn.1001-5817.2025.04.006.

24. QiuX,LiC,WangJ,et al.Cordycepin inhibits proliferation, migration, and promotes apoptosis in fibrosarcoma HT1080 cells by targeting Akt1 and kinase activity through network pharmacology analysis[J].Cell Biochem Funct,2025,43(7):e70103.DOI:10.1002/cbf.70103.

25. 司鹏龙,郜靓,刘怡,等.冬虫夏草治疗慢性肾病的系统评价及基于网络药理学的机制探讨[J].中药新药与临床药理,2025,36(6):995-1009.SiPL,GaoL,LiuY,et al.Systematic review of cordyceps in treating chronic kidney disease and mechanism exploration based on network pharmacology[J].Traditional Chinese Drug Research and Clinical Pharmacology,2025,36(6):995-1009.DOI:10.19378/j.issn.1003-9783.2025.06.017.

26. PanZ,BaoY,HuM,et al.Role of NAT10-mediated ac4C-modified HSP90AA1 RNA acetylation in ER stress-mediated metastasis and lenvatinib resistance in hepatocellular carcinoma[J].Cell Death Discov,2023,9(1):56.DOI:10.1038/s41420-023-01355-8.

27. 董晓玉,钟涛,叶元滋,等.血清HSP90α和癌组织基因HSP90AA1在肺癌中的高表达及预后价值[J].安徽医科大学学报,2022,57(7):1034-1040.DongXY,ZhongT,YeYZ,et al.Expression and clinical analysed of serum HSP90α and cancer tissue geneHSP90AA1 in the diagnosis and prognosis of lung cancer[J].Acta Universitatis Medicinalis Anhui,2022,57(7):1034-1040.DOI:10.19405/j.cnki.issn1000-1492.2022.07.005.

28. 马为,张和良,刘重元,等.热休克蛋白90在胃癌研究中的进展[J].中南医学科学杂志,2018,46(1):98-101, 112.MaW,ZhangHL,LiuZY,et al.Research progress of heat shock protein 90 in gastric cancer[J].Medical Science Journal of Central South China,2018,46(1):98-101, 112.DOI:10.15972/j.cnki.43-1509/r.2018.01.024.

29. XieX,JiangY,LiuS,et al.Integrating molecular docking and network pharmacology to reveal the molecular mechanisms of Anemarrhena asphodeloides in the treatment of non-small cell lung cancer[J].Discov Oncol,2025,16(1):1399.DOI:10.1007/s12672-025-03178-8.

30. KurokawaY,HonmaY,SawakiA,et al.Pimitespib for advanced gastrointestinal stromal tumor: a plain language summary of the CHAPTER-GIST-301 study[J].Future Oncol,2025,21(19):2401-2413.DOI:10.1080/14796694.2025.2525060.

31. ConcinN,BraicuI,CombeP,et al.GANNET53 Part II: a European phase I/II trial of the HSP90 inhibitor ganetespib in high-grade platinum-resistant ovarian cancer—a study of the GANNET53 consortium[J].Clin Cancer Res,2025,31(15):3160-3174.DOI:10.1158/1078-0432.CCR-24-3705.

32. HouY,PangH,XuX,et al.Identifying and validating an angiogenesis-related signature for the prognosis of head and neck squamous cell carcinoma[J].Curr Med Chem,2025,32(27):5828-5842.DOI:10.2174/0109298673306245240514064119.

33. ZhangM,WangY,SunZ,et al.Cordycepin potentiates photodynamic therapy efficacy in esophageal cancer cells via Modulation of the PI3K/AKT/FOXO3 signaling pathway[J].Photodiagn Photodyn Ther,2025,55:104725.DOI:10.1016/j.pdpdt.2025.104725.

34. ZhongM,FengM,ChenX,et al.Cordycepin attenuated cyclophosphamide (CTX)-induced immunosuppression in mice via EGFR/Nrf2 antioxidant signaling pathway[J].Int Immunopharmacol,2025,163:115235.DOI:10.1016/j.intimp.2025.115235.