STATH Downregulation and Poor Prognosis in Head and Neck Squamous Cell Carcinoma: Transcriptomic Analysis Reveals Poor Impact on Oral Health.

Introduction Salivary statherin, encoded by the STATH gene, maintains enamel integrity and oral microbial balance. Its downregulation has been linked to oral diseases, but its transcriptomic behavior in head and neck squamous cell carcinoma (HNSCC) remains largely unexplored. This study aimed to assess STATH as a diagnostic and prognostic biomarker in HNSCC and explore its potential biological role. Materials and methods The expression of STATH across 33 cancer types was analyzed via TIMER (Tumor Immune Estimation Resource), GEPIA (Gene Expression Profiling Interactive Analysis), and UALCAN (University of Alabama at Birmingham Cancer Data Analysis Portal), and promoter methylation and clinical correlations were explored in HNSCC. Prognostic significance was evaluated via Kaplan-Meier survival analysis (log-rank p<0.05). Immune cell infiltration was assessed by human papilloma virus (HPV) status via TIMER. Mutation data (n=674) were analyzed via cBioPortal. The findings were validated via the GEO GSE6631 dataset (n=22 paired samples). Co-expression and pathway enrichment analyses were conducted via UALCAN and Enrichr. Protein-protein interaction (PPI) networks were constructed via Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Results STATH was significantly downregulated in HNSCC tissues compared with normal tissues according to TIMER (p<0.001) and GEPIA (p<0.01), with slightly reduced promoter methylation (median β=0.611; p=0.006) and rare genetic alterations (<1%). Higher STATH expression was associated with better overall survival (hazard ratio (HR)=0.914; log-rank p=0.033), especially in HPV-positive patients (HR=0.822; log-rank p=0.039). STATH expression was correlated with immune infiltration, particularly B cells, in HPV-positive tumors (r=0.355; p=0.001). STATH downregulation was validated (adjusted p=0.004). Co-expression analysis revealed enrichment in immune and oral health-associated pathways, including salivary protein's role in periodontitis (p=0.007; OR=118.8; LYZ, LTF) and dental caries (p=0.007; OR=59.36; LYZ, CCL28). PPIs interact with histatins and mucins. Conclusion STATH is consistently downregulated in HNSCC, independent of promoter methylation or genetic mutations. Its suppression likely reflects tumor-driven remodeling of the salivary microenvironment, weakening host defenses and promoting disease progression. STATH has potential as a noninvasive diagnostic and prognostic biomarker.