Multi-Omics Analysis of Lactylation-Related Gene Signature for Prognosis, Immune Microenvironment, and Therapeutic Target Discovery in Oral Squamous Cell Carcinoma

Background Lysine lactylation has emerged as a critical molecular bridge between tumor metabolic reprogramming and epigenetic regulation, but its role in oral squamous cell carcinoma (OSCC) remains poorly characterized. Methods The study analyzed TCGA-HNSCC (n = 353 OSCC) and two GEO validation cohorts (GSE41613 n = 97, GSE42743 n = 74) using DESeq2 for differential expression, STRING PPI network analysis, random survival forest (RSF) and elastic net Cox regression with 10-repeated 5-fold cross-validation for prognostic modeling, ssGSEA/CIBERSORT/TIDE for immune profiling, oncoPredict for drug sensitivity, and AutoDock Vina for molecular docking. Results 25 core LRGs were identified, forming CENPA-AURKA-KIF20A-CDK1-HMMR mitotic and CA9-P4HA1 hypoxia sub-networks. The RSF_Top5 model achieved 5-year AUC of 0.891 (CV = 0.777), with RiskScore as an independent prognostic factor (HR = 1.04, P  < 0.001). External validation in GSE41613 confirmed survival differences (P = 0.0095). High-risk patients were enriched for mast cells and neutrophils, with sensitivity to EGFR (Osimertinib, Afatinib) and DDR (Wee1) inhibitors. Molecular docking identified LDHA as the optimal target (− 7.95 kcal/mol); Osimertinib–LDHA showed strongest binding (− 8.53 kcal/mol). Conclusions This study establishes the first lactylation-centered multi-omics framework for OSCC, delineating a metabolic–epigenetic–immune regulatory axis and identifying actionable therapeutic vulnerabilities, including the LDHA off-target mechanism of EGFR inhibitors for therapeutic repositioning.