IGF2BP3 Promotes Head and Neck Squamous Cell Carcinoma Progression via the M6A-LDHA-Lactate-H4K8la Axis and E2F2 Activation

Introduction Head and neck squamous cell carcinoma (HNSCC) is characterized by metabolic reprogramming and poor prognosis. While lactate accumulates in HNSCC, how upstream RNA regulation coordinates lactate-associated epigenetic alterations during tumor progression remains unclear. Methods We integrated TCGA-HNSCC analyses, paired clinical specimens, and in vitro functional assays with mechanistic readouts including RIP-qPCR and LDHA 3′UTR luciferase reporters. Lactate was quantified in culture supernatants, H4K8la was assessed by immunoblotting and tissue IF, and H4K8la CUT&Tag was performed as an exploratory chromatin profiling assay. Results IGF2BP3 was upregulated in HNSCC and associated with adverse survival in public datasets. IGF2BP3 silencing inhibited proliferation, migration, and invasion. Mechanistically, IGF2BP3 bound LDHA mRNA and promoted LDHA expression via an m 6 A-site-dependent LDHA 3′UTR mechanism, increasing lactate and H4K8la; exogenous lactate partially restored H4K8la under pH-matched conditions. Exploratory H4K8la CUT&Tag suggested increased H4K8la signal at the E2F2 locus with enrichment of cell-cycle programs upon lactate treatment. Conclusion These findings support an IGF2BP3-LDHA-lactate-H4K8la axis linking post-transcriptional regulation to metabolic and chromatin remodeling in HNSCC.