{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T14:30:27Z","timestamp":1766068227231,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["22177054","22077067"],"award-info":[{"award-number":["22177054","22077067"]}]},{"name":"111 center","award":["22177054","22077067"],"award-info":[{"award-number":["22177054","22077067"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Natural products, characterized by their structural novelty, multi-target capabilities, and favorable toxicity profiles, represent a prominent reservoir for the discovery of innovative anticancer therapeutics. In the current investigation, we identified ajuforrestin A, a diterpenoid compound extracted from Ajuga lupulina Maxim, as a potent agent against lung cancer. In vitro, this compound markedly curtailed the proliferation of A549 cells. Mechanistic explorations revealed that ajuforrestin A could arrest A549 cells in the G0\/G1 phase of the cell cycle, provoke apoptosis in cancer cells, and impede their migration by modulating the STAT3 and FAK signaling cascades. Angiogenesis is indispensable for tumor formation, progression, and metastatic dissemination. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are established as crucial mediators in tumor neovascularization, a process fundamental to both the expansion of tumor cells and the development of new blood vessels within the tumor milieu. Through the combined application of a Tg(fli1:EGFP) zebrafish model and SPR experimentation, we furnished strong evidence for the ability of ajuforrestin A to obstruct tumor angiogenesis via selective engagement with VEGFR-2. Finally, a zebrafish xenograft tumor model demonstrated that ajuforrestin A could effectively restrain tumor growth and metastasis in vivo. Ajuforrestin A therefore shows considerable promise as a lead compound for the future development of therapies against non-small cell lung cancer (NSCLC).<\/jats:p>","DOI":"10.3390\/biology14080908","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T11:44:45Z","timestamp":1753184685000},"page":"908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ajuforrestin A Inhibits Tumor Proliferation and Migration by Targeting the STAT3\/FAK Signaling Pathways and VEGFR-2"],"prefix":"10.3390","volume":"14","author":[{"given":"Sibei","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeling","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingming","family":"Rong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuejun","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaxin","family":"Lu","sequence":"additional","affiliation":[{"name":"College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shen","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Plant Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanqiang","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.2991\/jegh.k.191008.001","article-title":"Current cancer epidemiology","volume":"9","author":"Mattiuzzi","year":"2019","journal-title":"J. Epidemiol. Glob. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e165","DOI":"10.1016\/S1470-2045(14)71180-5","article-title":"Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin","volume":"16","author":"Oser","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"288","DOI":"10.21037\/tlcr.2016.06.07","article-title":"Non-small cell lung cancer: Current treatment and future advances","volume":"5","author":"Zappa","year":"2016","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41571-020-0341-y","article-title":"Targeting apoptosis in cancer therapy","volume":"17","author":"Carneiro","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.semcancer.2019.10.002","article-title":"The potential and controversy of targeting STAT family members in cancer","volume":"60","author":"Verhoeven","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1038\/s12276-020-0447-4","article-title":"Targeting focal adhesion kinase in cancer cells and the tumor microenvironment","volume":"52","author":"Murphy","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100009","DOI":"10.1016\/j.medidd.2019.100009","article-title":"Vascular endothelial growth factor receptor (VEGFR-2)\/KDR inhibitors: Medicinal chemistry perspective","volume":"2","author":"Modi","year":"2019","journal-title":"Med. Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Naeem, A., Hu, P., Yang, M., Zhang, J., Liu, Y., Zhu, W., and Zheng, Q. (2022). Natural products as anticancer agents: Current status and future perspectives. Molecules, 27.","DOI":"10.3390\/molecules27238367"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yang, Y., Li, N., Wang, T.-M., and Di, L. (2021). Natural products with activity against lung cancer: A review focusing on the tumor microenvironment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910827"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1515\/hc-2017-0064","article-title":"Chemical and pharmacological research on the plants from genus Ajuga","volume":"23","author":"Qing","year":"2017","journal-title":"Heterocycl. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/ptr.7634","article-title":"Echinatin induces reactive oxygen species-mediated apoptosis via JNK\/p38 MAPK signaling pathway in colorectal cancer cells","volume":"37","author":"Kwak","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1002\/ptr.7682","article-title":"Lutein inhibits tumor progression through the ATR\/Chk1\/p53 signaling pathway in non-small cell lung cancer","volume":"37","author":"Zhang","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"105603","DOI":"10.1016\/j.arabjc.2024.105603","article-title":"Modification of a natural diterpene and its antitumor mechanism: Promoting apoptosis, suppressing migration, and inhibiting angiogenesis","volume":"17","author":"Liu","year":"2024","journal-title":"Arab. J. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127854","DOI":"10.1016\/j.ijbiomac.2023.127854","article-title":"Preparation and photothermal therapy of gold nanorods modified by Belamcanda chinensis (L.) DC polysaccharide","volume":"255","author":"Zhao","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/ptr.7601","article-title":"6-Methoxydihydrosanguinarine induces apoptosis and autophagy in breast cancer MCF-7 cells by accumulating ROS to suppress the PI3K\/AKT\/mTOR signaling pathway","volume":"37","author":"Zhang","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"155210","DOI":"10.1016\/j.phymed.2023.155210","article-title":"Mosloflavone from Fissistigma petelotii ameliorates oncogenic multidrug resistance by STAT3 signaling modulation and P-glycoprotein blockade","volume":"123","author":"Chien","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"107538","DOI":"10.1016\/j.jmgm.2020.107538","article-title":"Reveal the interaction mechanism of five old drugs targeting VEGFR2 through computational simulations","volume":"96","author":"Lv","year":"2020","journal-title":"J. Mol. Graph. Model."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18281","DOI":"10.1073\/pnas.1207759109","article-title":"Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors","volume":"109","author":"McTigue","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand\u2013protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1298","DOI":"10.1002\/wcms.1298","article-title":"Using PyMOL as a platform for computational drug design","volume":"7","author":"Yuan","year":"2017","journal-title":"WIREs Comput. Mol. Sci."},{"key":"ref_21","first-page":"e124401","article-title":"Antitumor Activity and Mechanism Study of Riluzole and Its Derivatives","volume":"19","author":"Wu","year":"2018","journal-title":"Iran J. Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/sj.cdd.4400339","article-title":"Apoptosis and the cell cycle: The p53 connection","volume":"5","year":"1998","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mohrherr, J., Uras, I.Z., Moll, H.P., and Casanova, E. (2020). STAT3: Versatile functions in non-small cell lung cancer. Cancers, 12.","DOI":"10.3390\/cancers12051107"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrc.2016.123","article-title":"Cancer cell motility: Lessons from migration in confined spaces","volume":"17","author":"Paul","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.jare.2017.06.006","article-title":"Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies\u2014A review","volume":"8","author":"Alamoudi","year":"2017","journal-title":"J. Adv. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gamble, J., Elson, D., Greenwood, J., Tanguay, R., and Kolluri, S. (2021). The zebrafish xenograft models for investigating cancer and cancer therapeutics. Biology, 10.","DOI":"10.3390\/biology10040252"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e06321","DOI":"10.1016\/j.heliyon.2021.e06321","article-title":"Recent progress in surface plasmon resonance based sensors: A comprehensive review","volume":"7","author":"Yesudasu","year":"2021","journal-title":"Heliyon"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alsehli, M., Ali, A.A.S., Nafie, M.S., Bardaweel, S., Aljuhani, A., Darwish, K.M., Alraqa, S.Y., Rezki, N., and Aouad, M.R. (2025). Discovery of novel tris-1,2,3-triazole-based hybrids as VEGFR2 inhibitors with potent anti-proliferative and cytotoxicity through apoptosis induction. Bioorganic Chem., 155.","DOI":"10.1016\/j.bioorg.2025.108131"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"115626","DOI":"10.1016\/j.ejmech.2023.115626","article-title":"Quinazoline-based VEGFR-2 inhibitors as potential anti-angiogenic agents: A contemporary perspective of SAR and molecular docking studies","volume":"259","author":"Moradi","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/ijc.33588","article-title":"Cancer statistics for the year 2020: An overview","volume":"149","author":"Ferlay","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Pfeffer, C.M., and Singh, A.T.K. (2018). Apoptosis: A target for anticancer therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020448"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3722","article-title":"Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy","volume":"15","author":"Czabotar","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, Y., Wang, H., Liu, W., Hou, J., Xu, J., Guo, Y., and Hu, P. (2022). Cratoxylumxanthone C, a natural xanthone, inhibits lung cancer proliferation and metastasis by regulating STAT3 and FAK signal pathways. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.920422"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Han, Z., Li, Q., Wang, Y., Wang, L., Li, X., Ge, N., Wang, Y., and Guo, C. (2019). Niclosamide Induces Cell Cycle Arrest in G1 Phase in Head and Neck Squamous Cell Carcinoma Through Let-7d\/CDC34 Axis. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01544"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"154118","DOI":"10.1016\/j.phymed.2022.154118","article-title":"A natural xanthone suppresses lung cancer growth and metastasis by targeting STAT3 and FAK signaling pathways","volume":"102","author":"Zhao","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nprot.2007.30","article-title":"In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro","volume":"2","author":"Liang","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"331","DOI":"10.2144\/000112909","article-title":"Real-time imaging of mitochondria in transgenic zebrafish expressing mitochondrially targeted GFP","volume":"45","author":"Kim","year":"2008","journal-title":"BioTechniques"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"119794","DOI":"10.1016\/j.carbpol.2022.119794","article-title":"Structure, anti-tumor activity, and potential anti-tumor mechanism of a fungus polysaccharide from Fomes officinalis","volume":"295","author":"Zhang","year":"2022","journal-title":"Carbohydr. Polym."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.jpha.2021.11.006","article-title":"A strategy of screening and binding analysis of bi-oactive components from traditional Chinese medicine based on surface plasmon resonance biosensor","volume":"12","author":"Lv","year":"2022","journal-title":"J. Pharma-Ceutical Anal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.apsb.2020.01.017","article-title":"20(S)-Protopanaxatriol promotes the binding of P53 and DNA to regulate the antitumor network via multiomic analysis","volume":"10","author":"Wang","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5205","DOI":"10.2147\/IJN.S115956","article-title":"Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7\/ADR breast carcinoma","volume":"11","author":"Zhang","year":"2016","journal-title":"Int. J. Nanomed."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/8\/908\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:13:48Z","timestamp":1760033628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/8\/908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["biology14080908"],"URL":"https:\/\/doi.org\/10.3390\/biology14080908","relation":{},"ISSN":["2079-7737"],"issn-type":[{"type":"electronic","value":"2079-7737"}],"subject":[],"published":{"date-parts":[[2025,7,22]]}}}