{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T13:06:36Z","timestamp":1788354396884,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2017YFD0502205"],"award-info":[{"award-number":["2017YFD0502205"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study utilized network pharmacology, bioinformatics, along with machine learning to investigate the multi-target synergistic anti-cancer mechanisms of three edible medicinal plants (EMPs)\u2014mulberry leaf, lotus leaf, and sea buckthorn\u2014against oral and esophageal squamous cell carcinomas (OSCC and ESCC). We identified potential active constituents and their targets through mining Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Swiss Target Prediction databases. Concurrently, integration with differential expression profiles and co-expression modules identified crucial intersection targets between the EMPs and these two cancers. Subsequent machine learning algorithms and cross-cancer analysis consistently identified Matrix Metalloproteinase-1 (MMP1) as a critical hub gene. Its overexpression is closely associated with tumor invasion and metastasis. Molecular simulations revealed stable binding interactions between active constituents from three EMPs and hub proteins. Furthermore, research on immune cell infiltration suggested that the active components of three EMPs may impact the tumor immune microenvironment in both OSCC and ESCC through the regulation of pivotal gene expression. Collectively, this work systematically elucidates the molecular basis underlying the multi-target, multi-pathway synergistic anti-cancer effects of these EMPs, providing a theoretical foundation for developing natural drugs against these squamous cell carcinomas.<\/jats:p>","DOI":"10.3390\/ijms27052141","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:35:17Z","timestamp":1772022917000},"page":"2141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigating the Mechanism of Edible Medicinal Plants Against Squamous Cell Carcinomas Based on Network Pharmacology, Bioinformatics, and Molecular Dynamics Simulation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5381-7246","authenticated-orcid":false,"given":"Shanfeng","family":"Liang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunzhen","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1028-3283","authenticated-orcid":false,"given":"Xudong","family":"Tang","sequence":"additional","affiliation":[{"name":"Shenzhen Research Institute of Lanzhou University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s41568-018-0024-5","article-title":"Deciphering the cells of origin of squamous cell carcinomas","volume":"18","author":"Blanpain","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1186\/s13059-024-03383-8","article-title":"Multi-omics reveals lactylation-driven regulatory mechanisms promoting tumor progression in oral squamous cell carcinoma","volume":"25","author":"Jing","year":"2024","journal-title":"Genome Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/bs.acr.2019.05.004","article-title":"Clinical and translational advances in esophageal squamous cell carcinoma","volume":"144","author":"Reichenbach","year":"2019","journal-title":"Adv. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1001\/jamadermatol.2013.6947","article-title":"Squamous cell carcinoma","volume":"149","author":"Davis","year":"2013","journal-title":"JAMA Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"131860","DOI":"10.1016\/j.foodchem.2021.131860","article-title":"Immunometabolism modulation, a new trick of edible and medicinal plants in cancer treatment","volume":"376","author":"Tan","year":"2021","journal-title":"Food Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.jfda.2017.12.007","article-title":"Mulberry leaf extract inhibit hepatocellular carcinoma cell proliferation via depressing IL-6 and TNF-\u03b1 derived from adipocyte","volume":"26","author":"Chang","year":"2018","journal-title":"J. Food Drug Anal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6891","DOI":"10.1021\/jf302183x","article-title":"Mulberry leaf polyphenol extract induced apoptosis involving regulation of adenosine monophosphate-activated protein kinase\/fatty acid synthase in a p53-negative hepatocellular carcinoma cell","volume":"60","author":"Yang","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cbi.2012.08.025","article-title":"Purified mulberry leaf lectin (MLL) induces apoptosis and cell cycle arrest in human breast cancer and colon cancer cells","volume":"200","author":"Deepa","year":"2012","journal-title":"Chem. Biol. Interact."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40659-021-00330-w","article-title":"Lotus leaf flavonoids induce apoptosis of human lung cancer A549 cells through the ROS\/p38 MAPK pathway","volume":"54","author":"Jia","year":"2021","journal-title":"Biol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12986-021-00549-0","article-title":"Lotus leaf extract inhibits ER(-) breast cancer cell migration and metastasis","volume":"18","author":"Tong","year":"2021","journal-title":"Nutr. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9563","DOI":"10.1007\/s13277-014-2233-1","article-title":"Inhibitory effects of sea buckthorn procyanidins on fatty acid synthase and MDA-MB-231 cells","volume":"35","author":"Wang","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.carbpol.2015.06.021","article-title":"Anticancer and immunostimulating activities of a novel homogalacturonan from Hippophae rhamnoides L. berry","volume":"131","author":"Wang","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Noor, F., Tahir Ul Qamar, M., Ashfaq, U.A., Albutti, A., Alwashmi, A.S.S., and Aljasir, M.A. (2022). Network Pharmacology Approach for Medicinal Plants: Review and Assessment. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050572"},{"key":"ref_14","first-page":"323","article-title":"Network pharmacology approaches for research of Traditional Chinese Medicines","volume":"21","author":"Li","year":"2023","journal-title":"Chin. J. Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"bbad120","DOI":"10.1093\/bib\/bbad120","article-title":"Machine learning for synergistic network pharmacology: A comprehensive overview","volume":"24","author":"Noor","year":"2023","journal-title":"Brief. Bioinform."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.21873\/anticanres.14469","article-title":"Quercetin Suppresses Proliferation of Liver Cancer Cell Lines In Vitro","volume":"40","author":"Hisaka","year":"2020","journal-title":"Anticancer Res."},{"key":"ref_17","first-page":"1941","article-title":"Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-\u03baB and matrix metalloproteinase-2\/-9 signaling pathways","volume":"33","author":"Lai","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3831\/KPI.2015.18.002","article-title":"Quercetin Down-regulates IL-6\/STAT-3 Signals to Induce Mitochondrial-mediated Apoptosis in a Nonsmall- cell Lung-cancer Cell Line, A549","volume":"18","author":"Mukherjee","year":"2015","journal-title":"J. Pharmacopuncture"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"154780","DOI":"10.1016\/j.phymed.2023.154780","article-title":"Isorhamnetin induces cell cycle arrest and apoptosis by triggering DNA damage and regulating the AMPK\/mTOR\/p70S6K signaling pathway in doxorubicin-resistant breast cancer","volume":"114","author":"Yang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.biopha.2017.02.061","article-title":"Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K\/AKT and telomerase pathways","volume":"89","author":"Kashafi","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lee, J., and Kim, J.H. (2016). Kaempferol Inhibits Pancreatic Cancer Cell Growth and Migration through the Blockade of EGFR-Related Pathway In Vitro. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155264"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chen, J.L., Lai, C.Y., Ying, T.H., Lin, C.W., Wang, P.H., Yu, F.J., Liu, C.J., and Hsieh, Y.H. (2021). Modulating the ERK1\/2-MMP1 Axis through Corosolic Acid Inhibits Metastasis of Human Oral Squamous Cell Carcinoma Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168641"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.canlet.2016.04.034","article-title":"MMP1 promotes tumor growth and metastasis in esophageal squamous cell carcinoma","volume":"377","author":"Liu","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11658-018-0127-8","article-title":"MiR-106a directly targets LIMK1 to inhibit proliferation and EMT of oral carcinoma cells","volume":"24","author":"Shi","year":"2019","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/jcb.26182","article-title":"MiR-133a-3p Inhibits Oral Squamous Cell Carcinoma (OSCC) Proliferation and Invasion by Suppressing COL1A1","volume":"119","author":"He","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44129","DOI":"10.18632\/oncotarget.9866","article-title":"Silencing DNA methyltransferase 1 (DNMT1) inhibits proliferation, metastasis and invasion in ESCC by suppressing methylation of RASSF1A and DAPK","volume":"7","author":"Bai","year":"2016","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12943-025-02248-3","article-title":"Spatial transcriptomic analysis of tumor microenvironment in esophageal squamous cell carcinoma with HIV infection","volume":"24","author":"Zuo","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1182\/blood.V100.4.1160.h81602001160_1160_1167","article-title":"Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo","volume":"100","author":"McQuibban","year":"2002","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: A database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminform."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"154658","DOI":"10.1016\/j.phymed.2023.154658","article-title":"Wumei Wan attenuates angiogenesis and inflammation by modulating RAGE signaling pathway in IBD: Network pharmacology analysis and experimental evidence","volume":"111","author":"Duan","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","article-title":"UniProt: The Universal Protein Knowledgebase in 2023","volume":"51","author":"Bateman","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103904","DOI":"10.1016\/j.jbi.2021.103904","article-title":"Evaluation of the key active ingredients of \u2018Radix Astragali and Rehmanniae Radix Mixture\u2019 and related signaling pathways involved in ameliorating diabetic foot ulcers from the perspective of TCM-related theories","volume":"123","author":"Fan","year":"2021","journal-title":"J. Biomed. Inform."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"155494","DOI":"10.1016\/j.phymed.2024.155494","article-title":"Asiaticoside exerts neuroprotection through targeting NLRP3 inflammasome activation","volume":"127","author":"He","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Xu, M., Zhou, H., Hu, P., Pan, Y., Wang, S., Liu, L., and Liu, X. (2023). Identification and validation of immune and oxidative stress-related diagnostic markers for diabetic nephropathy by WGCNA and machine learning. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1084531"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, F., Huang, Y., Liu, F., and Wang, H. (2023). Identification of immune-related genes in diagnosing atherosclerosis with rheumatoid arthritis through bioinformatics analysis and machine learning. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1126647"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"106601","DOI":"10.1016\/j.compbiomed.2023.106601","article-title":"Transcriptomic screening to identify hub genes and drug signatures for PCOS based on RNA-Seq data in granulosa cells","volume":"154","author":"Zanjirband","year":"2023","journal-title":"Comput. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Wei, C., Wei, Y., Cheng, J., Tan, X., Zhou, Z., Lin, S., and Pang, L. (2023). Identification and verification of diagnostic biomarkers in recurrent pregnancy loss via machine learning algorithm and WGCNA. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1241816"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"105389","DOI":"10.1016\/j.compbiomed.2022.105389","article-title":"Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu Decoction against sepsis","volume":"144","author":"Li","year":"2022","journal-title":"Comput. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Shi, L., Liu, Q., Yang, H., Wang, Q., Wang, J., and Fan, Y. (2022). Inflammation-related pathways involved in damaged articular cartilage of rats exposed to T-2 toxin based on RNA-sequencing analysis. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1079739"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_42","first-page":"25","article-title":"Gene ontology: Tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"The Gene Ontology Consortium. Nat. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"115847","DOI":"10.1016\/j.jep.2022.115847","article-title":"Integrating network pharmacology and pharmacological evaluation to explore the protective mechanism of Ershiwuwei Zhenzhu pill in ischemic stroke","volume":"301","author":"Wang","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Xia, R., Lv, M., Li, Z., Jin, L., Chen, X., Han, Y., Shi, C., Jiang, Y., and Jin, S. (2022). Machine-Learning Algorithm-Based Prediction of Diagnostic Gene Biomarkers Related to Immune Infiltration in Patients with Chronic Obstructive Pulmonary Disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.740513"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"107432","DOI":"10.1016\/j.compbiomed.2023.107432","article-title":"Exploring the potential mechanisms of Yi-Yi-Fu-Zi-Bai-Jiang-San therapy on the immune-inflamed phenotype of colorectal cancer via combined network pharmacology and bioinformatics analyses","volume":"166","author":"Liu","year":"2023","journal-title":"Comput. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Liu, M., Wang, Y., Deng, W., Xie, J., He, Y., Wang, L., Zhang, J., and Cui, M. (2024). Combining network pharmacology, machine learning, molecular docking and molecular dynamic to explore the mechanism of Chufeng Qingpi decoction in treating schistosomiasis. Front. Cell. Infect. Microbiol., 14.","DOI":"10.3389\/fcimb.2024.1453529"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhou, S., Lu, H., and Xiong, M. (2021). Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in Rheumatoid Arthritis by Bioinformatics Analysis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.726747"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"155212","DOI":"10.1016\/j.phymed.2023.155212","article-title":"Exploring the efficacious constituents and underlying mechanisms of sini decoction for sepsis treatment through network pharmacology and multi-omics","volume":"123","author":"Gu","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D400","DOI":"10.1093\/nar\/gkr1132","article-title":"PubChem\u2019s BioAssay Database","volume":"40","author":"Wang","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"20420188231187493","DOI":"10.1177\/20420188231187493","article-title":"Exploring the mechanism of metformin action in Alzheimer\u2019s disease and type 2 diabetes based on network pharmacology, molecular docking, and molecular dynamic simulation","volume":"14","author":"Shi","year":"2023","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"115210","DOI":"10.1016\/j.biopha.2023.115210","article-title":"Identification of bioactive compounds and potential mechanisms of scutellariae radix-coptidis rhizoma in the treatment of atherosclerosis by integrating network pharmacology and experimental validation","volume":"165","author":"Ji","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, Y., Wang, Y., Shu, X., Lu, C., Shao, S., Liu, X., Yang, C., Luo, J., and Du, Q. (2021). Using Network Pharmacology and Molecular Docking to Explore the Mechanism of Shan Ci Gu (Cremastra appendiculata) Against Non-Small Cell Lung Cancer. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.682862"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Khan, S.A., Wu, Y., Li, A.S., Fu, X.Q., and Yu, Z.L. (2022). Network pharmacology and molecular docking-based prediction of active compounds and mechanisms of action of Cnidii Fructus in treating atopic dermatitis. BMC Complement. Med. Ther., 22.","DOI":"10.1186\/s12906-022-03734-7"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2141\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:23:33Z","timestamp":1772169813000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,25]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27052141"],"URL":"https:\/\/doi.org\/10.3390\/ijms27052141","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,25]]}}}