Abstract
<title>Abstract</title> <p> Background Oral squamous cell carcinoma (OSCC) remains a therapeutic challenge with limited treatment advances. While Traditional Chinese Medicine (TCM) shows potential in cancer management, the mechanisms of complex herbal formulations remain unclear. This study investigated the Traditional Chinese Medicine Oral Cancer Prescription (OCP) through integrated network pharmacology and experimental validation. Methods To identify key targets, we multi-omics 328 TCGA-OSCC samples and 251 GEO datasets. Network pharmacology revealed OCP targets and components, followed by PPI network design and functional enrichment analysis. Hub gene prognosis was assessed using LASSO-Cox regression. CAL27 and HN30 cell lines treated with OCP decoction were tested for CCK-8. Results Of the 38 differentially expressed target genes, 18 hub genes ( <italic>IL6</italic> , <italic>MMP9</italic> , <italic>PTGS2</italic> , <italic>MET</italic> , etc.) were considerably enriched in extracellular matrix structure and inflammatory pathways (IL-17/TNF signaling). PLAU, PPARG, and MET prognostic model demonstrated substantial predictive value (AUC 0.5–0.7). OCP treatment exhibited dose- and time-dependent anti-proliferative effects, showing 62.3% (CAL27) and 58.7% (HN30) viability reduction at 48 hours (p < 0.001) Conclusion This study reveals OCP's multi-target mechanisms against OSCC through network pharmacology and experimental validation, providing scientific evidence for its potential as an adjunctive therapy. The gene signatures provide novel OSCC prognostic and therapy biomarkers. </p>