eIF3A Promotes the Warburg Effect in Cervical Cancer through m⁶A-dependent Translational Regulation of ENO1

Eukaryotic translation initiation factors (eIFs) play a crucial role in tumor progression; however, which eIFs are most significant in cervical cancer (CC) remains unclear. In this study, eIF3A and eIF4E were found to be highly expressed in CC and associated with poor prognosis. Silencing either factor inhibited CC cell proliferation, induced apoptosis, and reduced glycolytic activity. Quantitative proteomic analysis and subsequent functional validation identified α-enolase (ENO1) as a common downstream effector of eIF3A and eIF4E, through which they promoted aerobic glycolysis and CC progression. Notably, eIF3A consistently exhibited a more pronounced functional effect than eIF4E. Further analyses demonstrated that eIF3A associated with N⁶-methyladenosine (m⁶A)-modified ENO1 mRNA and promoted its translation. eIF3A depletion reduced the abundance of ENO1 mRNA in actively translating polysomes and decreased the ENO1 protein-to-mRNA ratio without affecting total ENO1 mRNA abundance. Mutation of a key m⁶A site A359 in ENO1 mRNA similarly weakened its association with eIF3A and reduced ENO1 translation. Moreover, pharmacological inhibition of m⁶A-related regulation partially attenuated eIF3A-induced ENO1 expression, glycolytic activation, and tumor growth. Collectively, our results identify eIF3A as a key regulator of CC progression in an m⁶A-dependent ENO1 translation and suggest that targeting the eIF3A-m⁶A-ENO1 may have therapeutic potential for CC.