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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Oral squamous cell carcinoma (OSCC) accounts for most head-and-neck cancers, and effective biological adjuvants remain limited. Gingival mesenchymal stem cells (GMSCs) exhibit anti-tumour paracrine activity, but the underlying molecular mechanisms and their relevance in patient cohorts remain incompletely understood. Consensus apoptosis\u2013reactive oxygen species (ROS) effectors were identified through integrated transcriptomic analyses of TCGA-HNSC and three GEO cohorts. Candidate genes were evaluated in primary OSCC cells exposed to GMSC-conditioned medium or indirect Transwell co-culture. Findings were further examined using patient-cohort validation, single-cell ligand\u2013receptor analysis, pathway and transcription-factor activity inference, and drug-repurposing approaches. Computational analyses identified an apoptosis\u2013ROS network centred on BAX, BCL2, CASP3, CASP9, NOX1, and GPX1. Indirect GMSC co-culture reduced intracellular ROS, increased early apoptosis, and induced G2\/M accumulation, whereas conditioned medium produced inconsistent effects, suggesting a requirement for live bidirectional paracrine signalling. BAX was the only consistently up-regulated effector. The axis demonstrated concordant differential expression across independent HPV-negative OSCC cohorts but was not independently prognostic under leakage-free cross-validation or external validation. Pathway analyses supported ROS suppression, apoptosis activation, and altered stromal\u2013tumour communication. Drug-repurposing analyses identified HSP90 inhibitors and the FDA-approved TOP2 inhibitor mitoxantrone as candidate therapeutic agents. GMSC paracrine activity targets a biologically interpretable apoptosis\u2013ROS axis in OSCC that is reproducibly expressed across patient cohorts but does not constitute an independent prognostic biomarker. The identified therapeutic candidates warrant further experimental investigation.<\/jats:p>","DOI":"10.3390\/ijms27146480","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T15:17:52Z","timestamp":1784647072000},"page":"6480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An Integrative Bioinformatics Framework Prioritises a Gingival Mesenchymal Stem Cell Paracrine Apoptosis\u2013ROS Axis in HPV-Negative Oral Squamous Cell Carcinoma: Preliminary Experimental Support and Repurposable-Drug Hypotheses"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0564-0616","authenticated-orcid":false,"given":"Abdullah","family":"Alqarni","sequence":"first","affiliation":[{"name":"Department of Oral Diagnosis, Oral Biology & Periodontology, College of Dentistry, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3579-0906","authenticated-orcid":false,"given":"Jagadish","family":"Hosmani","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis, Oral Biology & Periodontology, College of Dentistry, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3409-5725","authenticated-orcid":false,"given":"Ali Mosfer A.","family":"Alqahtani","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis, Oral Biology & Periodontology, College of Dentistry, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan Ahmed","family":"Assiri","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis, Oral Biology & Periodontology, College of Dentistry, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3080-2775","authenticated-orcid":false,"given":"Rayan Mohammedfarooq","family":"Meer","sequence":"additional","affiliation":[{"name":"Department of Preventive Dental Sciences, College of Dentistry, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7246-5497","authenticated-orcid":false,"given":"Shankargouda","family":"Patil","sequence":"additional","affiliation":[{"name":"College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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