Integrative multi-omics analysis identifies SLCO1B3 as a prognostic marker and functional oncogenic driver in head and neck squamous cell carcinoma

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer mortality with limited prognostic biomarkers. Given the role of metabolic reprogramming in tumor progression, this study investigated the clinical relevance and biological function of the lipid metabolism-associated transporter SLCO1B3 in HNSCC. METHODS: We integrated bulk transcriptomic data from The Cancer Genome Atlas (TCGA) and multiple independent cohorts with single-cell RNA sequencing, high-dimensional weighted gene co-expression network analysis (hdWGCNA), spatial transcriptomics, and in vitro loss-of-function assays in SCC9 cells. RESULTS: SLCO1B3 was significantly upregulated in HNSCC and independently predicted poor survival across multiple cohorts. Single-cell analysis localized SLCO1B3 to an epithelial subpopulation with enhanced stemness, evidenced by elevated CytoTRACE scores and pseudotime trajectory mapping. hdWGCNA identified co-expression modules enriched in cell cycle regulation and stress responses within SLCO1B3-positive epithelial cells. Spatial transcriptomics revealed preferential colocalization of SLCO1B3-positive cells with fibroblasts and smooth muscle cells. Cell-cell communication analysis further showed distinct ligand-receptor interaction patterns mediated by SLCO1B3-positive epithelial cells. Functionally, SLCO1B3 knockdown induced G0/G1 arrest, suppressed migration and invasion, and promoted apoptosis, accompanied by altered expression of Cyclin D1, PCNA, and p21. CONCLUSION: These findings establish SLCO1B3 as an independent prognostic biomarker and functional driver that sustains stemness and malignant phenotypes in HNSCC, providing a rationale for its therapeutic targeting.