{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T07:26:25Z","timestamp":1786778785773,"version":"build-2736575974"},"reference-count":43,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Oral cancer (OC) remains a therapeutic challenge due to limited validated targets. Cis\u2010pQTLs from the deCODE cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200935,559) were harmonized with OC\u2010GWAS (3547 cases and 691,466 controls) meta\u2010data through a two\u2010sample Mendelian randomization (MR) framework. Robust Validation included replication in the UKB\u2010PPP dataset, colocalization analysis, SMR (Summary\u2010based MR), HEIDI (Heterogeneity in Dependent Instruments) tests, and eQTL evidence. Additional analyses encompassed protein\u2013protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes annotation (KEGG)\/Gene Ontology (GO) pathway enrichment, mediation, Druggability and side effects analysis. Oral cancer (OC) remains a therapeutic challenge due to limited validated targets. Cis\u2010pQTLs from the deCODE cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200935,559) were harmonized with OC\u2010GWAS (3547 cases and 691,466 controls) meta\u2010data through a two\u2010sample Mendelian randomization (MR) framework. Robust Validation included replication in the UKB\u2010PPP dataset, colocalization analysis, SMR (Summary\u2010based MR), HEIDI (Heterogeneity in Dependent Instruments) tests, and eQTL evidence. Additional analyses encompassed protein\u2013protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes annotation (KEGG)\/Gene Ontology (GO) pathway enrichment, mediation, Druggability and side effects analysis. To experimentally corroborate the MR findings, the quantitative real\u2010time PCR (qRT\u2010PCR) was performed to examine the mRNA expression levels of selected genes in oral squamous cell carcinoma (OSCC) cell lines (SCC\u20109 and SCC\u201025) and normal human oral epithelial cells (HOEC). Multi\u2010omics MR identified TNFSF8 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20092.49\u2009\u00d7\u200910\n                    <jats:sup>\u22128<\/jats:sup>\n                    , OR\u2009=\u20091.24) as a Tier 1 target. XXYLT1 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.41\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    , OR\u2009=\u20091.34) and HSD17B14 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04, OR\u2009=\u20092.00) achieved Tier 2. eQTLs\u2010pQTLs Relationship revealed XXYLT1 expression explained 24.65% of risk through elevated plasma protein levels, TNFSF8 eQTLs mediated 72.80% via protein upregulation. Mediation analyses on CD4 on HLA DR+ CD4+ T cells (7.18%) contributed to the risk of OC by upregulating plasma HSD17B14, while daily cigarette consumption (20.63%) and CD8+ T cell percentage leukocytes (12.06%) contributed to the risk of OC by upregulating plasma TNFSF8. Drug safety assessments highlighted systemic TNFSF8 inhibition may elevate skin cancer risk. Multi\u2010omics MR prioritizes TNFSF8 as a therapeutic target for oral cancer. Multi\u2010omics MR identified TNFSF8 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20092.49\u2009\u00d7\u200910\n                    <jats:sup>\u22128<\/jats:sup>\n                    , OR\u2009=\u20091.24) as a Tier 1 target. XXYLT1 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.41\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    , OR\u2009=\u20091.34) and HSD17B14 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04, OR\u2009=\u20092.00) achieved Tier 2. eQTLs\u2010pQTLs Relationship revealed XXYLT1 expression explained 24.65% of risk through elevated plasma protein levels, TNFSF8 eQTLs mediated 72.80% via protein upregulation. Mediation analyses on CD4 on HLA DR+ CD4+ T cells (7.18%) contributed to the risk of OC by upregulating plasma HSD17B14, while daily cigarette consumption (20.63%) and CD8+ T cell percentage leukocytes (12.06%) contributed to the risk of OC by upregulating plasma TNFSF8. Drug safety assessments highlighted systemic TNFSF8 inhibition may elevate skin cancer risk. qRT\u2010PCR confirmed significant upregulation of XXYLT1 and HSD17B14 in both SCC\u20109 and SCC\u201025 cell lines (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), which is consistent with MR predictions. TNFSF8 was not reliably detected in these cancer cells, aligning with its proposed immune\u2010mediated mechanism. Multi\u2010omics MR prioritizes TNFSF8 as a therapeutic target for oral cancer. qPCR validation confirms the dysregulation of XXYLT1 and HSD17B14, while findings regarding TNFSF8 underscore its immune origin. These findings warrant further functional studies.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71272","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:13:43Z","timestamp":1785831223000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Omics Profiling Identifies Novel Therapeutic Targets and Pathobiological Mechanisms in Oral Cancer"],"prefix":"10.1111","volume":"30","author":[{"given":"Meishan","family":"Huang","sequence":"first","affiliation":[{"name":"College &amp; Hospital of Stomatology Guangxi Medical University  Nanning China"},{"name":"Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction  Nanning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1887-5158","authenticated-orcid":false,"given":"Hongwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Beihai Hospital of Chinese Medicine Beihai Hospital Affiliated to Guangxi University of Chinese Medicine  Beihai Guangxi China"},{"name":"Youjiang Medical University for Nationalities  Baise Guangxi China"},{"name":"Key Laboratory of Tumor Molecular Pathology of Baise  Baise Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqiang","family":"Mo","sequence":"additional","affiliation":[{"name":"Youjiang Medical University for Nationalities  Baise Guangxi China"},{"name":"Medical College of Guangxi University  Nanning Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Huang","sequence":"additional","affiliation":[{"name":"Youjiang Medical University for Nationalities  Baise Guangxi China"},{"name":"Key Laboratory of Tumor Molecular Pathology of Baise  Baise Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liang","sequence":"additional","affiliation":[{"name":"Youjiang Medical University for Nationalities  Baise Guangxi China"},{"name":"Key Laboratory of Tumor Molecular Pathology of Baise  Baise Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuwen","family":"Mo","sequence":"additional","affiliation":[{"name":"Youjiang Medical University for Nationalities  Baise Guangxi China"},{"name":"Key Laboratory of Tumor Molecular Pathology of Baise  Baise Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minsi","family":"Li","sequence":"additional","affiliation":[{"name":"College &amp; Hospital of Stomatology Guangxi Medical University  Nanning China"},{"name":"Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction  Nanning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Fu","sequence":"additional","affiliation":[{"name":"Youjiang Medical University for Nationalities  Baise Guangxi China"},{"name":"Key Laboratory of Tumor Molecular Pathology of Baise  Baise Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xidai","family":"Long","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tumor Molecular Pathology of Baise  Baise Guangxi China"},{"name":"Medical College of Guangxi University  Nanning Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanping","family":"Huang","sequence":"additional","affiliation":[{"name":"College &amp; Hospital of Stomatology Guangxi Medical University  Nanning China"},{"name":"Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction  Nanning China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19082413"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"issue":"8","key":"e_1_2_14_4_1","article-title":"Interventions for the Treatment of Oral Cavity and Oropharyngeal Cancers: Surgical Treatment","volume":"8","author":"Worthington H. 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