Multi-Omics Profiling Identifies Novel Therapeutic Targets and Pathobiological Mechanisms in Oral Cancer

Oral cancer (OC) remains a therapeutic challenge due to limited validated targets. Cis-pQTLs from the deCODE cohort (n = 35,559) were harmonized with OC-GWAS (3547 cases and 691,466 controls) meta-data through a two-sample Mendelian randomization (MR) framework. Robust Validation included replication in the UKB-PPP dataset, colocalization analysis, SMR (Summary-based MR), HEIDI (Heterogeneity in Dependent Instruments) tests, and eQTL evidence. Additional analyses encompassed protein-protein 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-pQTLs from the deCODE cohort (n = 35,559) were harmonized with OC-GWAS (3547 cases and 691,466 controls) meta-data through a two-sample Mendelian randomization (MR) framework. Robust Validation included replication in the UKB-PPP dataset, colocalization analysis, SMR (Summary-based MR), HEIDI (Heterogeneity in Dependent Instruments) tests, and eQTL evidence. Additional analyses encompassed protein-protein 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-time PCR (qRT-PCR) was performed to examine the mRNA expression levels of selected genes in oral squamous cell carcinoma (OSCC) cell lines (SCC-9 and SCC-25) and normal human oral epithelial cells (HOEC). Multi-omics MR identified TNFSF8 (p = 2.49 × 10^-8, OR = 1.24) as a Tier 1 target. XXYLT1 (p = 1.41 × 10^-4, OR = 1.34) and HSD17B14 (p = 0.04, OR = 2.00) achieved Tier 2. eQTLs-pQTLs 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-omics MR prioritizes TNFSF8 as a therapeutic target for oral cancer. Multi-omics MR identified TNFSF8 (p = 2.49 × 10^-8, OR = 1.24) as a Tier 1 target. XXYLT1 (p = 1.41 × 10^-4, OR = 1.34) and HSD17B14 (p = 0.04, OR = 2.00) achieved Tier 2. eQTLs-pQTLs 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-PCR confirmed significant upregulation of XXYLT1 and HSD17B14 in both SCC-9 and SCC-25 cell lines (p < 0.001), which is consistent with MR predictions. TNFSF8 was not reliably detected in these cancer cells, aligning with its proposed immune-mediated mechanism. Multi-omics 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.