HNRNPA0 Acts as a Master Upstream Regulator of NF-κB to Drive Oncogenic Phenotypes in Oral Squamous Cell Carcinoma

BACKGROUND: Oral squamous cell carcinoma (OSCC) remains a lethal malignancy with a 5-year survival rate below 50%, necessitating the identification of novel therapeutic targets. While the RNA-binding protein HNRNPA0 is implicated in various cancers, its precise role and mechanism in OSCC pathogenesis are undefined. METHODS: HNRNPA0 expression was assessed using TCGA data, clinical OSCC specimens (n = 10) and cell lines. Stable knockdown models were established in CAL-27 and SCC-15 cells via shRNA. Functional impacts on proliferation, metastasis, apoptosis and cell cycle were evaluated through CCK-8, wound healing, Transwell, flow cytometry and xenograft assays. RNA sequencing and rescue experiments with the NF-κB agonist PMA were employed to delineate the underlying mechanism. RESULTS: HNRNPA0 was significantly upregulated in OSCC tissues and cell lines, and its high expression predicted poor patient survival. HNRNPA0 knockdown potently suppressed tumour growth both in vitro and in vivo. It inhibited proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) and cell cycle progression, while promoting apoptosis. Transcriptomic analysis revealed a profound impact on the NF-κB signalling pathway. Crucially, activation of this pathway by PMA substantially reversed all anti-tumour phenotypes caused by HNRNPA0 depletion, establishing NF-κB as the critical functional downstream effector. CONCLUSION: Our study identifies HNRNPA0 as a key oncoprotein in OSCC, driving tumour progression primarily via activation of the NF-κB pathway. HNRNPA0 represents a promising prognostic biomarker and a novel therapeutic target for OSCC.