{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:02:10Z","timestamp":1774245730126,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The synergistic carcinogenic effect of areca nut chewing and tobacco exposure is a major risk factor for oral squamous cell carcinoma (OSCC). However, the molecular mechanisms, particularly related to N6-methyladenosine (m6A) modification, remain unclear. This study explores the potential mechanisms by which arecoline and 4-nitroquinoline-1-oxide (4-NQO) induce OSCC, focusing on m6A regulatory factors and key targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptional data were obtained from Gene Expression Omnibus (GEO), with differentially expressed genes (DEGs) identified using the limma package. The intersection of DEGs and 21 m6A regulators was analyzed, and their prognostic relevance was validated with The Cancer Genome Atlas (TCGA) data. Arecoline and 4-NQO targets were identified through online databases, and compound-target and protein-protein interaction (PPI) networks were constructed. Core targets were selected using Degree, MCC, and FRIENDS algorithms. Spearman analysis assessed correlations with m6A factors, and molecular docking was performed to verify binding properties.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC), AlkB Homolog 5 (ALKBH5), and ELAV Like RNA Binding Protein 1 (ELAVL1) were identified as key genes. High HNRNPC expression correlated with poor prognosis. AKT Serine\/Threonine Kinase 1 (AKT1) was the core target across algorithms, with significant correlations between AKT1 and m6A factors. Molecular docking indicated potential binding between AKT1 and the compounds.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study establishes a regulatory network linking arecoline\/4-NQO, AKT1, m6A factors, and OSCC, and identifies key molecular targets and mechanisms underlying the carcinogenic process. These findings provide a theoretical foundation for understanding the pathogenesis of OSCC and developing targeted strategies for early intervention and treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1739418","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T05:20:43Z","timestamp":1774243243000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integration of network toxicology and transcriptomics reveals the potential regulatory role of the 'Arecoline\/4-NQO-AKT1-m6A factor' axis in the development of OSCC"],"prefix":"10.3389","volume":"16","author":[{"given":"Yongle","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Stomatology, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yamei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Qinhuangdao Haigang Hospital","place":["Qinhuangdao, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Dermotology, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Second Hospital of Shijiazhuang","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Second Hospital of Shijiazhuang","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhizheng","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Affiliated Hospital of Hebei University","place":["Baoding, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feifei","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Affiliated Hospital of Hebei University","place":["Baoding, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41368-023-00249-w","article-title":"Oral squamous cell carcinomas: state of the field and emerging directions","volume":"15","author":"Tan","year":"2023","journal-title":"Int J Oral Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA: Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","first-page":"111383","DOI":"10.1016\/j.cbi.2025.111383","article-title":"Alkaloids and nitrosamines in betel quid: A biochemical exploration of carcinogenicity","volume":"407","author":"Rangani","year":"2025","journal-title":"Chem-Biol Interact"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30727-0","article-title":"Carcinogenicity of acrolein, crotonaldehyde, and arecoline","volume":"22","author":"Marques","year":"2021","journal-title":"Lancet Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e1507","DOI":"10.6061\/clinics\/2020\/e1507","article-title":"Survival trends of patients with oral and oropharyngeal cancer treated at a cancer center in S o Paulo, Brazil","volume":"75","author":"Kowalski","year":"2020","journal-title":"Clinics"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1274519","article-title":"4-nitroquinoline 1-oxide induces immune cells death to onset early immunosuppression during oral squamous cell carcinoma development","volume":"14","author":"Sahu","year":"2023","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2022.5367","article-title":"Periodontal disease affects oral cancer progression in a surrogate animal model for tobacco exposure","volume":"60","author":"Spuldaro","year":"2022","journal-title":"Int J Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.12182\/20221160511","volume":"53","author":"Zhang","year":"2022","journal-title":"Sichuan da xue xue bao. 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