Background: To investigate the prognostic significance and related mechanisms of the expression of enhancer of polycomb homolog 1 ( EPC1 ) in head and neck squamous cell carcinoma (HNSCC) from a multi-omics perspective. Methods: The Kaplan-Meier plotter was used to evaluate the prognostic significance of EPC1 . Based on the LinkedOmics, UALCAN, and Timer platforms, the multi-omics expression of EPC1 in HNSCC was explored to investigate mechanisms affecting prognoses. Results: At the genetic

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... l, 8208 genes were negatively correlated with EPC1 expression, and 11,956 genes were positively correlated with EPC1 expression. For the noncoding region, a competing endogenous RNA (ceRNA) network was constructed, and 6 microRNAs (miRNAs) and 3 long noncoding RNAs (lncRNAs) were identified. At the protein level, a protein-protein interaction (PPI) network related to EPC1 expression was constructed and was involved in human papillomavirus (HPV) infection, endocrine resistance, and multiple cancer pathways. At the immune level, EPC1 expression was correlated with a variety of immune cells, immune molecules, and chemokine receptors, which together constitute the immune microenvironment of tumors. According to the clinical data, high EPC1 expression in HNSCC was a predictor of patient prognosis (hazard ratio (HR)=0.64; 95% confidence interval (CI) 0.49-0.83; P<0.01). EPC1 expression differentiated clinical subtypes and was related to key factors such as TP53 and HPV (P<0.05). Conclusion: High EPC1 expression is a protective factor in HNSCC and benefits patient survival. EPC1 may participate in the genomics, transcriptomics, proteomics, and immunomics of HNSCC, and the results can provide a reference for the development of targeted drugs and the evaluation of patient prognosis.