{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:22:18Z","timestamp":1790864538833,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"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":["2020YFA0909000"],"award-info":[{"award-number":["2020YFA0909000"]}]},{"name":"National Key Research and Development Program of China","award":["82127807"],"award-info":[{"award-number":["82127807"]}]},{"name":"National Key Research and Development Program of China","award":["82003142"],"award-info":[{"award-number":["82003142"]}]},{"name":"National Key Research and Development Program of China","award":["18DZ2260400"],"award-info":[{"award-number":["18DZ2260400"]}]},{"name":"National Natural Science Foundation of China","award":["2020YFA0909000"],"award-info":[{"award-number":["2020YFA0909000"]}]},{"name":"National Natural Science Foundation of China","award":["82127807"],"award-info":[{"award-number":["82127807"]}]},{"name":"National Natural Science Foundation of China","award":["82003142"],"award-info":[{"award-number":["82003142"]}]},{"name":"National Natural Science Foundation of China","award":["18DZ2260400"],"award-info":[{"award-number":["18DZ2260400"]}]},{"DOI":"10.13039\/501100015377","name":"Shanghai Key Laboratory of Molecular Imaging","doi-asserted-by":"publisher","award":["2020YFA0909000"],"award-info":[{"award-number":["2020YFA0909000"]}],"id":[{"id":"10.13039\/501100015377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015377","name":"Shanghai Key Laboratory of Molecular Imaging","doi-asserted-by":"publisher","award":["82127807"],"award-info":[{"award-number":["82127807"]}],"id":[{"id":"10.13039\/501100015377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015377","name":"Shanghai Key Laboratory of Molecular Imaging","doi-asserted-by":"publisher","award":["82003142"],"award-info":[{"award-number":["82003142"]}],"id":[{"id":"10.13039\/501100015377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015377","name":"Shanghai Key Laboratory of Molecular Imaging","doi-asserted-by":"publisher","award":["18DZ2260400"],"award-info":[{"award-number":["18DZ2260400"]}],"id":[{"id":"10.13039\/501100015377","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Introduction: Non-small cell lung cancer (NSCLC) is a lethal type of lung cancer (LC) with a 5-year survival rate of 19%. Because drug resistance typically develops following chemotherapy, radiotherapy, and immunotherapy, a novel NSCLC therapeutic strategy is urgently demanded. Gambogenic acid (GNA), a major bioactive ingredient isolated from gamboge, has multipotent antitumor effects, although activity against NSCLC is unknown. Methods: CCK8, ethynyl deoxyuridine (EdU), the plate colony formation assay, and the transwell and wound healing (WH) assay were used to study the effect of GNA on the proliferation and migration ability of NSCLC. Flow cytometry was used to detect apoptosis and the cell cycle. Proteomic analysis and LiP-SMap were used to detect the downstream target of GNA. Ferroptosis inhibitor ferrostatin-1 was used to detect the effect of GNA on NSCLC ferroptosis. Overexpressing GCH1 was used for a rescue experiment. Subcutaneous tumor and pulmonary metastasis in a mouse model were used to study the effect of GNA on NSCLC growth and metastasis. Results: The results of the present study showed that GNA inhibited the proliferation and migration of NSCLC cells in a dose- and time-dependent manner, which arrested the cell cycle in the G0\/G1 phase. In vivo data revealed that GNA inhibited tumor growth and lung metastasis. Proteomic analysis found that GNA significantly inhibited the expression of GTP cyclohydrolase 1 (GCH1). LiP-SMap analysis showed that GNA interacted with ILE248 and ARG249 of GCH1. GCH1 overexpression had a similar role to the ferroptosis inhibitor ferrostatin-1 and restored cell proliferation and migration after GNA treatment. Also, GNA promoted reactive oxygen species (ROS) accumulation, which reduced mitochondrial membrane potential. GCH1 overexpression or ferrostatin-1 treatment reversed GNA regulation of ROS accumulation and mitochondrial membrane potential inhibition. Conclusions: Taken together, these findings confirmed that GNA suppressed the malignant progression of NSCLC by inducing GCH1-mediated ferroptosis.<\/jats:p>","DOI":"10.3390\/ph18030374","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T06:02:13Z","timestamp":1741240933000},"page":"374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0659-450X","authenticated-orcid":false,"given":"Menghan","family":"Wang","sequence":"first","affiliation":[{"name":"Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxi","family":"Yu","sequence":"additional","affiliation":[{"name":"Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiancang","family":"Shao","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Bao","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Jin","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Huang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41586-023-05783-5","article-title":"The Evolution of Lung Cancer and Impact of Subclonal Selection in TRACERx","volume":"616","author":"Frankell","year":"2023","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ccell.2023.12.013","article-title":"Clinical and Molecular Features of Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer","volume":"42","author":"Memon","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"497","DOI":"10.6004\/jnccn.2022.0025","article-title":"Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology","volume":"20","author":"Ettinger","year":"2022","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Liu, Z., Wang, X., Li, J., Yang, X., Huang, J., Ji, C., Li, X., Li, L., Zhou, J., and Hu, Y. (2023). Gambogenic Acid Induces Cell Death in Human Osteosarcoma through Altering Iron Metabolism, Disturbing the Redox Balance, and Activating the P53 Signaling Pathway. Chem. Biol. Interact., 382.","DOI":"10.1016\/j.cbi.2023.110602"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41568-022-00459-0","article-title":"Targeting Ferroptosis as a Vulnerability in Cancer","volume":"22","author":"Lei","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12943-022-01530-y","article-title":"Ferroptosis in Cancer Therapy: A Novel Approach to Reversing Drug Resistance","volume":"21","author":"Zhang","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/cac2.12250","article-title":"Ferroptosis in Cancer and Cancer Immunotherapy","volume":"42","author":"Zhao","year":"2022","journal-title":"Cancer Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41418-022-01089-7","article-title":"SPY1 Inhibits Neuronal Ferroptosis in Amyotrophic Lateral Sclerosis by Reducing Lipid Peroxidation through Regulation of GCH1 and TFR1","volume":"30","author":"Wang","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, S., Sun, Z., Jiang, X., Lu, Z., Ding, L., Li, C., Tian, X., and Wang, Q. (2022). Ferroptosis Increases Obesity: Crosstalk between Adipocytes and the Neuroimmune System. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1049936"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.tcb.2023.04.005","article-title":"Ferroptosis: Mechanisms and Implications for Cancer Development and Therapy Response","volume":"33","author":"Fazeli","year":"2023","journal-title":"Trends Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1904197","DOI":"10.1002\/adma.201904197","article-title":"Recent Progress in Ferroptosis Inducers for Cancer Therapy","volume":"31","author":"Liang","year":"2019","journal-title":"Adv. Mater."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.3760\/cma.j.issn.0366-6999.20122582","article-title":"An Open-Labeled, Randomized, Multicenter Phase IIa Study of Gambogic Acid Injection for Advanced Malignant Tumors","volume":"126","author":"Chi","year":"2013","journal-title":"Chin. Med. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.3892\/etm.2017.4252","article-title":"Gambogenic Acid Induces Cell Growth Inhibition, Cell Cycle Arrest and Metastasis Inhibition in Choroidal Melanoma in a Dose-Dependent Manner","volume":"13","author":"Li","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, M., Cheng, H., Wu, H., Liu, C., Li, S., Li, B., Su, J., Luo, S., and Li, Q. (2022). Gambogenic Acid Antagonizes the Expression and Effects of Long Non-Coding RNA NEAT1 and Triggers Autophagy and Ferroptosis in Melanoma. Biomed. Pharmacother., 154.","DOI":"10.1016\/j.biopha.2022.113636"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.canlet.2019.10.015","article-title":"Targeting USP9x\/SOX2 Axis Contributes to the Anti-Osteosarcoma Effect of Neogambogic Acid","volume":"469","author":"Chen","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, F., Dong, L., Liang, S., Wei, X., Wang, Y., Chang, L., Guo, K., Wu, H., Chang, Y., and Yin, Y. (2022). Ultrasound-Triggered Drug Delivery for Glioma Therapy through Gambogic Acid-Loaded Nanobubble-Microbubble Complexes. Biomed. Pharmacother., 150.","DOI":"10.1016\/j.biopha.2022.113042"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1002\/cbin.12072","article-title":"Gambogenic Acid Inhibits Proliferation and Ferroptosis by Targeting the MiR-1291\/FOXA2 and AMPK\u03b1\/SLC7A11\/GPX4 Axis in Colorectal Cancer","volume":"47","author":"Ma","year":"2023","journal-title":"Cell Biol. Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hatami, E., Jaggi, M., Chauhan, S.C., and Yallapu, M.M. (2020). Gambogic Acid: A Shining Natural Compound to Nanomedicine for Cancer Therapeutics. Biochim. Biophys. Acta Rev. Cancer, 1874.","DOI":"10.1016\/j.bbcan.2020.188381"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jcis.2023.12.042","article-title":"Tetrahydrobiopterin Inhibitor-Based Antioxidant Metabolic Strategy for Enhanced Cancer Ferroptosis-Immunotherapy","volume":"658","author":"Liu","year":"2024","journal-title":"J. Colloid Interface Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eadh0545","DOI":"10.1126\/sciimmunol.adh0545","article-title":"Mast Cell-Derived BH4 and Serotonin Are Critical Mediators of Postoperative Pain","volume":"9","author":"Starkl","year":"2024","journal-title":"Sci. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1021\/acscentsci.9b01063","article-title":"GTP Cyclohydrolase 1\/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling","volume":"6","author":"Kraft","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"175112","DOI":"10.1016\/j.ejphar.2022.175112","article-title":"Neogambogic Acid Suppresses Characteristics and Growth of Colorectal Cancer Stem Cells by Inhibition of DLK1 and Wnt\/\u03b2-Catenin Pathway","volume":"929","author":"Li","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13046-017-0579-0","article-title":"Gambogic Acid Sensitizes Gemcitabine Efficacy in Pancreatic Cancer by Reducing the Expression of Ribonucleotide Reductase Subunit-M2 (RRM2)","volume":"36","author":"Xia","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eabj1531","DOI":"10.1126\/scitranslmed.abj1531","article-title":"Phenotypic Drug Screen Uncovers the Metabolic GCH1\/BH4 Pathway as Key Regulator of EGFR\/KRAS-Mediated Neuropathic Pain and Lung Cancer","volume":"14","author":"Cronin","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/s41586-018-0701-2","article-title":"The Metabolite BH4 Controls T Cell Proliferation in Autoimmunity and Cancer","volume":"563","author":"Cronin","year":"2018","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/s12276-024-01208-z","article-title":"Tetrahydrobiopterin Metabolism Attenuates ROS Generation and Radiosensitivity through LDHA S-Nitrosylation: Novel Insight into Radiogenic Lung Injury","volume":"56","author":"Feng","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e002383","DOI":"10.1136\/jitc-2021-002383","article-title":"GCH1 Induces Immunosuppression through Metabolic Reprogramming and IDO1 Upregulation in Triple-Negative Breast Cancer","volume":"9","author":"Wei","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hu, Q., Wei, W., Wu, D., Huang, F., Li, M., Li, W., Yin, J., Peng, Y., Lu, Y., and Zhao, Q. (2022). Blockade of GCH1\/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.810327"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.freeradbiomed.2022.01.012","article-title":"Mitochondrial Oxidative Stress Mediated Fe-Induced Ferroptosis via the NRF2-ARE Pathway","volume":"180","author":"Chen","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1186\/s13046-022-02518-8","article-title":"CircLRFN5 Inhibits the Progression of Glioblastoma via PRRX2\/GCH1 Mediated Ferroptosis","volume":"41","author":"Jiang","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5429","DOI":"10.2147\/IJN.S115037","article-title":"Daunorubicin and Gambogic Acid Coloaded Cysteamine-CdTe Quantum Dots Minimizing the Multidrug Resistance of Lymphoma In Vitro and In Vivo","volume":"11","author":"Zhou","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"156070","DOI":"10.1016\/j.phymed.2024.156070","article-title":"Gambogic Acid Impairs the Maintenance and Therapeutic Resistance of Glioma Stem Cells by Targeting B-Cell-Specific Moloney Leukemia Virus Insert Site 1","volume":"135","author":"Sun","year":"2024","journal-title":"Phytomedicine"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/3\/374\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:48:09Z","timestamp":1760028489000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/3\/374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,6]]},"references-count":32,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ph18030374"],"URL":"https:\/\/doi.org\/10.3390\/ph18030374","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,6]]}}}