{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T21:37:49Z","timestamp":1774820269273,"version":"3.50.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"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. Bioinform."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Oral squamous cell carcinoma (OSCC) represents a significant global health challenge, with betel nut consumption being a major risk factor. 3-(methylnitrosamino)propionitrile (MNPN), a betel nut-derived nitrosamine, has been identified as a potential carcinogen, but its molecular targets in OSCC pathogenesis remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We employed a comprehensive computational framework integrating target prediction, transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), and machine learning approaches. Four OSCC datasets from Gene Expression Omnibus (GEO) were analyzed, and MNPN targets were predicted using ChEMBL, PharmMapper, and SwissTargetPrediction databases. Machine learning algorithms (n = 127 combinations) were evaluated for optimal biomarker identification, with model interpretability assessed using SHAP (SHapley Additive exPlanations) analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Target prediction identified 881 potential MNPN targets across three databases. WGCNA revealed 534 OSCC-associated differentially expressed genes, with 38 overlapping MNPN targets. Machine learning optimization identified 13 hub genes, with PLAU demonstrating the highest predictive performance (AUC = 0.944). SHAP analysis confirmed PLAU and PLOD3 as the most influential contributors to disease prediction. Functional enrichment analysis revealed MNPN targets\u2019 involvement in xenobiotic response, hypoxic conditions, and aberrant tissue remodeling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides the first comprehensive molecular characterization of MNPN-associated OSCC pathogenesis, identifying PLAU as a critical therapeutic target with exceptional diagnostic potential. Our findings establish a foundation for developing targeted interventions for betel nut nitrosamine-associated oral cancers and demonstrate the power of integrative computational approaches in environmental carcinogen research.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fbinf.2025.1664576","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T08:50:37Z","timestamp":1758790237000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative machine learning and transcriptomic analysis identifies key molecular targets in MNPN-associated oral squamous cell carcinoma pathogenesis"],"prefix":"10.3389","volume":"5","author":[{"given":"Xiangjun","family":"Wang","sequence":"first","affiliation":[]},{"given":"Panpan","family":"Jin","sequence":"additional","affiliation":[]},{"given":"Juan","family":"Xu","sequence":"additional","affiliation":[]},{"given":"Junyi","family":"Li","sequence":"additional","affiliation":[]},{"given":"Mengzhen","family":"Ji","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7781","DOI":"10.3390\/ijms24097781","article-title":"Machine learning models for the identification of prognostic and predictive cancer biomarkers: a systematic review","volume":"24","author":"Al-Tashi","year":"2023","journal-title":"Int. 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