SERPINA1 as a Shared Biomarker in Periodontitis and Oral Squamous Cell Carcinoma

Periodontitis (PD) and oral squamous cell carcinoma (OSCC) frequently co‑occur in clinical populations. However, shared molecular determinants that could support risk assessment across diseases remain insufficiently defined. This study aimed to identify shared diagnostic biomarkers and potential mechanisms linking PD and OSCC using integrated bioinformatics and machine learning.

PD and OSCC transcriptomic datasets were analysed to identify shared programmed cell death-related biomarkers using differentially expressed genes (DEGs), WGCNA and multiple machine learning algorithms (LASSO, Random Forest, GLM). Diagnostic performance was validated in external cohorts via ROC analysis, while immune landscapes and cellular interactions were characterised using CIBERSORT and single-cell analysis. At the cellular level, we evaluated SERPINA1 expression in an LPS-induced periodontal inflammation model and conducted siRNA-mediated knockdown in CAL27 oral cancer cells to examine its effects on proliferation, migration and invasion.

Transcriptomic analyses of PD and OSCC revealed a shared immune-inflammatory signature with enrichment of programmed cell death pathways. SERPINA1 was consistently prioritised by LASSO, random forest and GLM and showed strong diagnostic performance across training and external validation cohorts (AUC > 0.8). CIBERSORT indicated remodelling of the immune microenvironment associated with SERPINA1 expression, with positive correlations to macrophage and neutrophil abundance. Single-cell analyses localised SERPINA1 to myeloid populations and suggested putative crosstalk with the pro-inflammatory mediator interleukin-1β (IL-1β). In the periodontal inflammation model, SERPINA1 expression was significantly upregulated upon LPS stimulation alongside increased inflammatory mediators such as IL-8 and IL-1β. In contrast, SERPINA1 knockdown in oral cancer cells led to reduced proliferative, migratory and invasive capacities.

SERPINA1 emerges as a cross‑disease candidate biomarker linking chronic periodontal inflammation and oral cancer biology. The integrative framework provides a transparent roadmap for identifying clinically meaningful, reproducible biomarkers across oral diseases, going forwards.