VIRMA utilizes m6A-IGF2BP2 to mediate NDRG1, thereby increasing sensitivity to iron-chelating agents and subsequently inhibiting the proliferation and metastasis of oral squamous cell carcinoma.

N6-methyladenosine (m6A) methylation, a key epigenetic modification, plays a critical role in regulating cellular processes such as proliferation, differentiation, apoptosis, and metastasis. VIR-like m6A methyltransferase associated (VIRMA), a major driver of m6A methylation and the largest known component of the m6A machinery, is essential for m6A-dependent biological functions. However, its precise role in oral squamous cell carcinoma (OSCC) progression remains poorly understood. This study demonstrates that VIRMA expression correlates closely with OSCC progression, as evidenced by clinical sample analysis and functional studies. We found that VIRMA knockdown reduces m6A levels, weakens the interaction of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) with N-myc downregulated gene 1 (NDRG1) mRNA, leading to NDRG1 mRNA destabilization and degradation, and ultimately inhibiting OSCC progression. Desferrioxamine (DFO), a trivalent iron chelator, and N-dimethylhydrazine thioformamide (Dp44mT), a selective bivalent iron chelator, both suppress OSCC progression by upregulating NDRG1 expression. However, the NDRG1 instability caused by VIRMA knockdown cannot be rescued by these iron chelators. Interestingly, VIRMA knockdown enhances OSCC sensitivity to DFO and Dp44mT, resulting in a synergistic inhibitory effect on OSCC growth. These findings highlight the critical role of the VIRMA-IGF2BP2-NDRG1 axis in OSCC progression and suggest its potential to enhance the therapeutic efficacy of iron chelators, providing new insights into OSCC treatment strategies.