{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T09:42:50Z","timestamp":1777628570484,"version":"3.51.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>To overcome the high attrition rates in glioma drug discovery, this study established a systematic \u201cGenetics-to-Drug\u201d pipeline aimed at identifying potential therapeutic targets for glioma through causal inference and discovering potent natural inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We initiated the study with a drug-target Mendelian Randomization (MR) analysis, leveraging quantitative trait loci (QTL) and large-scale genome-wide association studies (GWAS) data for all glioma, glioblastoma (GBM), and non-GBM subtypes. Based on the identified targets, we performed a virtual screening of 17,931 ZINC15 compounds utilizing LibDock, absorption, distribution, metabolism, and excretion (ADME) profiling, toxicity prediction by komputer assisted technology (TOPKAT), CDOCKER, and molecular dynamics (MD) simulations. The binding affinity of selected candidates was confirmed via biolayer interferometry (BLI), and the therapeutic efficacy of the identified small molecules were biologically validated through\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays on glioma cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The druggable MR screening of 140 genes identified EGFR as a key causal target across all glioma subtypes (GBM, non-GBM, and all glioma). Through a series of computer-aided techniques, two promising lead compounds, tremulacin (ZINC000004098458) and zeylenol (ZINC000229763735), were prioritized. Subsequent BLI assays validated a direct physical interaction between zeylenol and EGFR, and biological validation demonstrated that zeylenol treatment significantly suppressed GBM cell proliferation and migration while promoting apoptosis, supporting its therapeutic potential as a novel EGFR inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study identifies EGFR as a causally relevant therapeutic target in glioma and highlights tremulacin and zeylenol as promising natural EGFR inhibitors, warranting further preclinical development of these compounds as novel glioma therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1822595","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T01:51:31Z","timestamp":1777427491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetics-guided screening and biological validation identify zeylenol as a promising EGFR inhibitor in glioma"],"prefix":"10.3389","volume":"17","author":[{"given":"Lin","family":"Pan","sequence":"first","affiliation":[{"name":"Guangdong Sanjiu Brain Hospital","place":["Guangzhou, China"]},{"name":"Department of Neurology, Neuroscience Research Center, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center","place":["Guangzhou, China"]},{"name":"ZhongShan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhuo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiqin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neuroscience Research Center, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxin","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neuroscience Research Center, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengxuan","family":"Liu","sequence":"additional","affiliation":[{"name":"ZhongShan School of Medicine, Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zibing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neuroscience Research Center, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, First People\u2019s Hospital of Xinxiang & The Fifth Affiliated Hospital of Xinxiang Medical College","place":["Xinxiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Sanjiu Brain Hospital","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"383","DOI":"10.3390\/ijms18020383","article-title":"Splice variants of the RTK family: their role in tumour progression and response to targeted therapy","volume":"18","author":"Abou-Fay\u00e7al","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4180","DOI":"10.3390\/ijms22084180","article-title":"A comprehensive analysis into the therapeutic application of natural products as SIRT6 modulators in Alzheimer\u2019s disease, aging, cancer, inflammation, and diabetes","volume":"22","author":"Akter","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1038\/s41388-017-0045-7","article-title":"Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies","volume":"37","author":"An","year":"2018","journal-title":"Oncogene"},{"key":"B4","doi-asserted-by":"publisher","first-page":"20723","DOI":"10.1021\/acs.jmedchem.4c02736","article-title":"Natural products driven medicinal chemistry","volume":"67","author":"Bharate","year":"2024","journal-title":"J. Med. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur. J. Epidemiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.biocel.2017.05.022","article-title":"Cell biology-metabolic crosstalk in glioma","volume":"89","author":"Colquhoun","year":"2017","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e59687","DOI":"10.3791\/59687","article-title":"Application of biolayer interferometry (BLI) for studying protein-protein interactions in transcription","volume":"147","author":"Desai","year":"2019","journal-title":"J. Vis. Exp."},{"key":"B9","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1158\/0008-5472.CAN-13-2381","article-title":"ERKs in cancer: friends or foes?","volume":"74","author":"Desch\u00eanes-Simard","year":"2014","journal-title":"Cancer Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/bjc.2011.590","article-title":"Phase I first-in-human study of TAK-285, a novel investigational dual HER2\/EGFR inhibitor, in cancer patients","volume":"106","author":"Doi","year":"2012","journal-title":"Br. J. Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1038\/s41588-021-00978-w","article-title":"Large-scale integration of the plasma proteome with genetics and disease","volume":"53","author":"Ferkingstad","year":"2021","journal-title":"Nat. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"eaag1166","DOI":"10.1126\/scitranslmed.aag1166","article-title":"The druggable genome and support for target identification and validation in drug development","volume":"9","author":"Finan","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41591-021-01310-z","article-title":"Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19","volume":"27","author":"Gaziano","year":"2021","journal-title":"Nat. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3270","DOI":"10.1038\/sj.emboj.7600342","article-title":"LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation","volume":"23","author":"Gur","year":"2004","journal-title":"EMBO J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"Elife"},{"key":"B16","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1021\/ci049714+","article-title":"ZINC--a free database of commercially available compounds for virtual screening","volume":"45","author":"Irwin","year":"2005","journal-title":"J. Chem. Inf. Model."},{"key":"B17","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.bmcl.2006.10.051","article-title":"Evaluating scoring functions for docking and designing beta-secretase inhibitors","volume":"17","author":"Katharine Holloway","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.2174\/1568026614666140929124445","article-title":"Structure-based virtual screening for drug discovery: principles, applications and recent advances","volume":"14","author":"Lionta","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/s41419-023-05611-8","article-title":"Differential regulation of H3K9\/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell","volume":"14","author":"Liu","year":"2023","journal-title":"Cell. Death Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1260941","DOI":"10.3389\/fimmu.2023.1260941","article-title":"Bidirectional mendelian randomization analysis investigating the genetic association between primary breast cancer and colorectal cancer","volume":"14","author":"Liu","year":"2023","journal-title":"Front. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/j.ncl.2016.06.014","article-title":"Epidemiology of brain tumors","volume":"34","author":"McNeill","year":"2016","journal-title":"Neurol. Clin."},{"key":"B22","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/ng.3823","article-title":"Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors","volume":"49","author":"Melin","year":"2017","journal-title":"Nat. Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1097\/01.nrl.0000250928.26044.47","article-title":"Glioma therapy in adults","volume":"12","author":"Norden","year":"2006","journal-title":"Neurologist"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2288","DOI":"10.1200\/JCO.2006.08.0705","article-title":"Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma","volume":"25","author":"Pelloski","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.phrs.2018.11.014","article-title":"Small molecule inhibitors targeting the EGFR\/erbB family of protein-tyrosine kinases in human cancers","volume":"139","author":"Roskoski","year":"2019","journal-title":"Pharmacol. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41392-025-02299-4","article-title":"Glioblastoma at the crossroads: current understanding and future therapeutic horizons","volume":"10","author":"Singh","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1326245","DOI":"10.3389\/fphar.2023.1326245","article-title":"Cyclohexene oxide CA, a derivative of zeylenone, exhibits anti-cancer activity in glioblastoma by inducing G0\/G1 phase arrest through interference with EZH2","volume":"14","author":"Su","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41586-018-0175-2","article-title":"Genomic atlas of the human plasma proteome","volume":"558","author":"Sun","year":"2018","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"197","DOI":"10.2174\/156800912799277557","article-title":"Targeting EGFR for treatment of glioblastoma: molecular basis to overcome resistance","volume":"12","author":"Taylor","year":"2012","journal-title":"Curr. Cancer Drug Targets"},{"key":"B31","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.molcel.2011.08.009","article-title":"Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation","volume":"43","author":"Vorlov\u00e1","year":"2011","journal-title":"Mol. Cell."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"V\u00f5sa","year":"2021","journal-title":"Nat. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"eaat8464","DOI":"10.1126\/science.aat8464","article-title":"Comprehensive functional genomic resource and integrative model for the human brain","volume":"362","author":"Wang","year":"2018","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13045-016-0290-1","article-title":"EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer","volume":"9","author":"Wang","year":"2016","journal-title":"J. Hematol. Oncol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.canlet.2019.10.030","article-title":"EGFR-Mediated autophagy in tumourigenesis and therapeutic resistance","volume":"469","author":"Wu","year":"2020","journal-title":"Cancer Lett."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1002\/jcc.10306","article-title":"Detailed analysis of grid-based molecular docking: a case study of CDOCKER-A CHARMm-based MD docking algorithm","volume":"24","author":"Wu","year":"2003","journal-title":"J. Comput. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.3390\/molecules23092149","article-title":"Zeylenone induces mitochondrial apoptosis and inhibits migration and invasion in gastric cancer","volume":"23","author":"Yang","year":"2018","journal-title":"Molecules"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1060012","DOI":"10.3389\/fnins.2022.1060012","article-title":"New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor \u03b1) based on computational study for high-grade glioma therapy","volume":"16","author":"Yang","year":"2022","journal-title":"Front. Neurosci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1097\/CAD.0000000000001428","article-title":"Computational study of novel natural inhibitors targeting kirsten rat sarcoma viral oncogene homolog G12C","volume":"34","author":"Yang","year":"2023","journal-title":"Anticancer Drugs"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1161\/STROKEAHA.124.046544","article-title":"Genome-wide Mendelian randomization study reveals druggable genes for cerebral small vessel disease","volume":"55","author":"Yang","year":"2024","journal-title":"Stroke"},{"key":"B40","doi-asserted-by":"publisher","first-page":"10057","DOI":"10.1038\/s41467-025-64985-9","article-title":"Multivariate genome-wide analyses of insulin resistance unravel novel loci and therapeutic targets for cardiometabolic health","volume":"16","author":"Ye","year":"2025","journal-title":"Nat. Commun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1002\/1878-0261.13717","article-title":"Functional loss of ERBB receptor feedback inhibitor 1 (MIG6) promotes glioblastoma tumorigenesis by aberrant activation of epidermal growth factor receptor (EGFR)","volume":"19","author":"Yi","year":"2025","journal-title":"Mol. Oncol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ccr.2006.12.017","article-title":"Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity","volume":"11","author":"Yun","year":"2007","journal-title":"Cancer Cell."},{"key":"B43","doi-asserted-by":"publisher","first-page":"5572","DOI":"10.3892\/mmr.2018.9564","article-title":"Zeylenone represses the progress of human prostate cancer by downregulating the Wnt\/\u03b2-catenin pathway","volume":"18","author":"Zeng","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1038\/s41598-017-01804-2","article-title":"Zeylenone, a naturally occurring cyclohexene oxide, inhibits proliferation and induces apoptosis in cervical carcinoma cells via PI3K\/AKT\/mTOR and MAPK\/ERK pathways","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1162540","DOI":"10.3389\/fphar.2023.1162540","article-title":"Development of an MCL-1-related prognostic signature and inhibitors screening for glioblastoma","volume":"14","author":"Zhang","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"11197","DOI":"10.3390\/ijms222011197","article-title":"Mechanisms of long non-coding RNAs in biological characteristics and aerobic glycolysis of glioma","volume":"22","author":"Zhao","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1052721","DOI":"10.3389\/fendo.2022.1052721","article-title":"Revealing oxidative stress-related genes in osteoporosis and advanced structural biological study for novel natural material discovery regarding MAPKAPK2","volume":"13","author":"Zhao","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.18632\/aging.103986","article-title":"Effective natural inhibitors targeting poly ADP-ribose polymerase by computational study","volume":"13","author":"Zhong","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"12003","DOI":"10.1080\/21655979.2021.2011631","article-title":"Identification of novel natural inhibitors targeting AKT serine\/threonine kinase 1 (AKT1) by computational study","volume":"13","author":"Zhong","year":"2022","journal-title":"Bioengineered"},{"key":"B50","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1186\/s12916-023-03142-9","article-title":"Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis","volume":"21","author":"Zhong","year":"2023","journal-title":"BMC Med."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1822595\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T01:51:33Z","timestamp":1777427493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1822595\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":50,"alternative-id":["10.3389\/fgene.2026.1822595"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1822595","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]},"article-number":"1822595"}}