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In this study, thermal proteome profiling (TPP) was applied to systematically identify lathyrol-binding proteins in non-small cell lung cancer (NSCLC) cells. TPP analysis identified glucose-6-phosphate dehydrogenase (G6PD) as a candidate target of lathyrol. A cellular thermal shift assay (CETSA) confirmed increased thermal stability of G6PD upon treatment. Molecular docking indicated a potential interaction between lathyrol and G6PD. The peptide-centric local stability assay (PELSA) revealed localized conformational changes in the C-terminal region of G6PD consistent with the predicted interaction interface. Enzymatic assays showed reduced G6PD activity accompanied by decreased intracellular NADPH levels. Quantitative proteomics indicated alterations in the pathways associated with glucose metabolism and redox regulation. These findings identify G6PD as a functional target of lathyrol in NSCLC cells and link its inhibition to disruption of cellular redox balance and metabolic homeostasis.<\/jats:p>","DOI":"10.1021\/acsomega.6c03709","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T02:08:11Z","timestamp":1784599691000},"page":"45176-45185","source":"Crossref","is-referenced-by-count":0,"title":["Lathyrol Targets\nG6PD to Disrupt Redox Homeostasis\nin Non-Small Cell Lung Cancer"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2821-4755","authenticated-orcid":true,"given":"Zhaoxuan","family":"Li","sequence":"first","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine , ,","place":["Shanghai, China, 201203"]},{"name":"Shanghai Integrated Traditional Chinese and Western Medicine Hospital , ,","place":["Shanghai, China, 200082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Integrated Traditional Chinese and Western Medicine Hospital , ,","place":["Shanghai, China, 200082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyan","family":"Zhen","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine , ,","place":["Shanghai, China, 201203"]},{"name":"Shanghai University of Traditional Chinese Medicine , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglu","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine , ,","place":["Shanghai, China, 201203"]},{"name":"Shanghai Integrated Traditional Chinese and Western Medicine Hospital , ,","place":["Shanghai, China, 200082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8625","authenticated-orcid":true,"given":"Yan","family":"Ren","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jia","sequence":"additional","affiliation":[{"name":"Shanghai Integrated Traditional Chinese and Western Medicine Hospital , ,","place":["Shanghai, China, 200082"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"issue":"10","key":"2026080409254231600_cit1","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1002\/cac2.12359","article-title":"Non-Small Cell Lung Cancer in China","volume":"42","author":"Chen","year":"2022","journal-title":"Cancer Commun."},{"issue":"1","key":"2026080409254231600_cit2","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1097\/JS9.0000000000001921","article-title":"Salvage Surgery\nand Conversion Surgery for Patients with Nonsmall Cell Lung Cancer:\nA Narrative Review","volume":"111","author":"Yan","year":"2025","journal-title":"Int. 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Ethnopharmacol."},{"key":"2026080409254231600_cit8","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2023.113784","article-title":"Yuexiandajisu\nDiterpenoids From Euphorbia Ebracteolata Hayata (Langdu Roots): An\nOverview","volume":"213","author":"Bailly","year":"2023","journal-title":"Phytochemistry"},{"key":"2026080409254231600_cit9","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.jep.2018.08.024","article-title":"The Phytochemistry,\nPharmacokinetics,\nPharmacology and Toxicity of Euphorbia Semen","volume":"227","author":"Zhu","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"2026080409254231600_cit10","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.114123","article-title":"Lathyrol Promotes Er\nStress-Induced Apoptosis and Proliferation Inhibition in Lung Cancer\nCells by Targeting Serca2","volume":"158","author":"Chen","year":"2023","journal-title":"Biomed. Pharmacother."},{"issue":"3","key":"2026080409254231600_cit11","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural\nProducts in Drug Discovery: Advances\nand Opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026080409254231600_cit12","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.157556","article-title":"Unraveling Traditional Chinese Medicine with Single-Cell\nRna Sequencing: Current Applications and Future Frontiers","volume":"149","author":"Chen","year":"2025","journal-title":"Phytomedicine"},{"key":"2026080409254231600_cit13","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1146\/annurev-pharmtox-052120-013205","article-title":"Drug Target Identification in Tissues by Thermal Proteome\nProfiling","volume":"62","author":"Mateus","year":"2022","journal-title":"Annu. Rev. Pharmacol. 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Methods."},{"issue":"15","key":"2026080409254231600_cit28","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e35158","article-title":"Analysis\nof the Interlink Between\nGlucose-6-Phosphate Dehydrogenase (G6Pd) and Lung Cancer through Multi-Omics\nDatabases","volume":"10","author":"Thakor","year":"2024","journal-title":"Heliyon"},{"issue":"19","key":"2026080409254231600_cit29","doi-asserted-by":"publisher","first-page":"3096","DOI":"10.1021\/acs.accounts.5c00524","article-title":"Developing\nNew Strategies to Construct Pseudo-Natural\nMacrocycles for Undruggable Targets","volume":"58","author":"Wang","year":"2025","journal-title":"Acc. Chem.\nRes."},{"key":"2026080409254231600_cit30","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109663","article-title":"Lathyrane\nDiterpenes From Euphorbia Lathyris and the Potential Mechanism to\nReverse the Multi-Drug Resistance in Hepg2\/Adr Cells","volume":"121","author":"Yang","year":"2020","journal-title":"Biomed. Pharmacother."},{"issue":"31","key":"2026080409254231600_cit31","doi-asserted-by":"publisher","first-page":"16193","DOI":"10.1021\/acs.est.5c01206","article-title":"Advanced Proteomics\nApproaches Hold Potential for the Risk Assessment of Metabolism-Disrupting\nChemicals as Omics-Based Nam: A Case Study Using the Phthalate Substitute\nDinch","volume":"59","author":"Aldehoff","year":"2025","journal-title":"Environ. Sci. Technol."},{"issue":"9","key":"2026080409254231600_cit32","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26093940","article-title":"Applications\nof the Cellular Thermal Shift Assay to Drug Discovery in Natural Products:\nA Review","volume":"26","author":"Song","year":"2025","journal-title":"Int. J. Mol. Sci."},{"issue":"D1","key":"2026080409254231600_cit33","doi-asserted-by":"publisher","first-page":"D1211","DOI":"10.1093\/nar\/gky869","article-title":"Iprox: An Integrated Proteome Resource","volume":"47","author":"Ma","year":"2019","journal-title":"Nucleic.\nAcids. Res."},{"issue":"D1","key":"2026080409254231600_cit34","doi-asserted-by":"publisher","first-page":"D1522","DOI":"10.1093\/nar\/gkab1081","article-title":"Iprox in 2021: Connecting\nProteomics Data Sharing with Big Data","volume":"50","author":"Chen","year":"2022","journal-title":"Nucleic.\nAcids. Res."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c03709","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/30\/45176\/66068964\/acsomega.6c03709.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/30\/45176\/66068964\/acsomega.6c03709.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:26:06Z","timestamp":1785849966000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/30\/45176\/5222668\/Lathyrol-Targets-G6PD-to-Disrupt-Redox-Homeostasis"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":34,"journal-issue":{"issue":"30","published-online":{"date-parts":[[2026,7,20]]},"published-print":{"date-parts":[[2026,8,4]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c03709","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}