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Its biological effects in vivo depend substantially on metabolic conversion to NNAL and cytochrome P450-mediated formation of reactive intermediates. In this study, predicted NNK-associated proteins were integrated with lung cancer transcriptomic data sets, followed by network analysis and machine-learning-based feature prioritization. Five genes, SNAI2, PLAU, DNMT3A, FAP, and CCNB1, were prioritized based on their contributions to the multigene classification framework. Exploratory molecular docking generated computational ligand-placement models with modest docking scores; these results were used only as structural visualizations and do not demonstrate direct biochemical binding. In the metabolically limited A549 cell model, micromolar exposure to parent NNK produced higher CCK-8 signals, altered cell-cycle distributions, increased Transwell migration and invasion counts, and changes in candidate-gene mRNA expression. These parallel observations do not establish that the candidate genes mediate the cellular phenotypes. Moreover, because intact NNK is rapidly metabolized in vivo and is not an established biomarker of systemic exposure in human blood, urine, or saliva, the parent-compound exposure used here does not represent an established human internal-exposure scenario. This study provides a hypothesis-generating framework for prioritizing candidate molecular features for future investigation rather than direct evidence of NNK target engagement or causal gene function.<\/jats:p>","DOI":"10.1021\/acsomega.6c04401","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:02:18Z","timestamp":1790593338000},"page":"61052-61064","source":"Crossref","is-referenced-by-count":0,"title":["Integration of\nNetwork Toxicology and Machine Learning\nto Prioritize Candidate Molecular Features Associated with NNK-Related\nLung Cancer"],"prefix":"10.1021","volume":"11","author":[{"given":"Ying","family":"Li","sequence":"first","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Ji","sequence":"additional","affiliation":[{"name":"University of Electronic Science and Technology of China , , , ,","place":["Chengdu, Sichuan Province, China, 610072"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6102-2949","authenticated-orcid":true,"given":"Yongwen","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]},{"name":"Tianjin Medical University General Hospital , , ,","place":["Tianjin, China, 300052"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"5","key":"2026101315104065700_cit1","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1055\/a-2651-0612","article-title":"Emerging Trends in Global Lung Cancer Burden","volume":"46","author":"Shong","year":"2025","journal-title":"Semin. 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Rev."},{"issue":"8","key":"2026101315104065700_cit5","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1002\/cac2.12463","article-title":"Lung cancer\nrisk score for ever and never smokers in China","volume":"43","author":"Ma","year":"2023","journal-title":"Cancer Commun."},{"key":"2026101315104065700_cit6","doi-asserted-by":"crossref","unstructured":"Warren, G. W.; Cummings, K. M.\n          Tobacco and Lung Cancer:\nRisks, Trends, and Outcomes in Patients with Cancer; American Society of Clinical Oncology educational book American Society\nof Clinical Oncology Annual Meeting, 2013; pp 359\u2013364.","DOI":"10.14694\/EdBook_AM.2013.33.359"},{"issue":"10","key":"2026101315104065700_cit7","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/nrc1190","article-title":"Tobacco\ncarcinogens, their biomarkers and tobacco-induced cancer","volume":"3","author":"Hecht","year":"2003","journal-title":"Nat. Rev. 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Toxicol."},{"issue":"3","key":"2026101315104065700_cit16","doi-asserted-by":"publisher","first-page":"198","DOI":"10.2174\/1872312811206030007","article-title":"Metabolism\nof nicotine and 4-(methylnitrosamino)-l-(3-pyridyl)-lbutanone\n(NNK) in menthol and non-menthol cigarette smokers","volume":"6","author":"Sarkar","year":"2013","journal-title":"Drug Metab. Lett."},{"issue":"1","key":"2026101315104065700_cit17","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1021\/acs.chemrestox.7b00281","article-title":"Methyl DNA Phosphate Adduct Formation in Rats\nTreated Chronically with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone\nand Enantiomers of Its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol","volume":"31","author":"Ma","year":"2018","journal-title":"Chem. Res. 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Sci."},{"issue":"2","key":"2026101315104065700_cit25","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/s00204-013-1137-y","article-title":"Direct\nanalysis of tobacco-specific nitrosamine NNK and its metabolite NNAL\nin human urine by LC\u2013MS\/MS: evidence of linkage to methylated\nDNA lesions","volume":"88","author":"Hu","year":"2014","journal-title":"Arch. Toxicol."},{"issue":"6312","key":"2026101315104065700_cit26","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1126\/science.aag0299","article-title":"Mutational signatures associated with tobacco\nsmoking in human cancer","volume":"354","author":"Alexandrov","year":"2016","journal-title":"Science"},{"issue":"1","key":"2026101315104065700_cit27","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13062-024-00452-7","article-title":"PLAU promotes growth\nand attenuates\ncisplatin chemosensitivity in ARID1A-depleted non-small cell lung\ncancer through interaction with TM4SF1","volume":"19","author":"Zheng","year":"2024","journal-title":"Biol.\nDirect"},{"issue":"8","key":"2026101315104065700_cit28","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1007\/s12033-022-00465-5","article-title":"MiR-139\u20135p\ntargeting CCNB1 modulates proliferation,\nmigration, invasion and cell cycle in lung adenocarcinoma","volume":"64","author":"Bao","year":"2022","journal-title":"Mol. Biotechnol."},{"issue":"5","key":"2026101315104065700_cit29","doi-asserted-by":"publisher","first-page":"669","DOI":"10.4161\/epi.28324","article-title":"The de novo DNA methyltransferase\nDNMT3A in development\nand cancer","volume":"9","author":"Chen","year":"2014","journal-title":"Epigenetics"},{"issue":"48","key":"2026101315104065700_cit30","doi-asserted-by":"publisher","first-page":"41479","DOI":"10.1074\/jbc.M111.284687","article-title":"Oligomerization\nof DNMT3A controls the mechanism of de novo DNA methylation","volume":"286","author":"Holz-Schietinger","year":"2011","journal-title":"J. Biol. Chem."},{"issue":"12","key":"2026101315104065700_cit31","doi-asserted-by":"publisher","first-page":"3613","DOI":"10.1172\/JCI38988","article-title":"Targeting\nfibroblast activation protein inhibits tumor stromagenesis and growth\nin mice","volume":"119","author":"Santos","year":"2009","journal-title":"J. Clin. 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Saf."},{"issue":"1","key":"2026101315104065700_cit35","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.canlet.2011.12.008","article-title":"NNK\npromotes migration and invasion of lung cancer cells through\nactivation of the c-Src\/PKC\u03b9\/FAK loop","volume":"318","author":"Shen","year":"2012","journal-title":"Cancer Lett."},{"issue":"6","key":"2026101315104065700_cit36","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1038\/s12276-023-00994-2","article-title":"The tobacco-specific\ncarcinogen NNK induces pulmonary\ntumorigenesis via nAChR\/Src\/STAT3-mediated activation of the renin\u2013angiotensin\nsystem and IGF-1R signaling","volume":"55","author":"Boo","year":"2023","journal-title":"Exp. Mol. 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Biol.: Anim."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c04401","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/40\/61052\/68675016\/acsomega.6c04401.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/40\/61052\/68675016\/acsomega.6c04401.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:50:12Z","timestamp":1791921012000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/40\/61052\/5439854\/Integration-of-Network-Toxicology-and-Machine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":37,"journal-issue":{"issue":"40","published-online":{"date-parts":[[2026,9,28]]},"published-print":{"date-parts":[[2026,10,13]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c04401","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}