METTL3-mediated m6A modification of PAK6 drives cervical cancer progression through activating MAPK14.

N6-methyladenosine (m6A) is the most prevalent epitranscriptomic modification in mammalian mRNA. Recent studies have revealed that m6A modification is involved in cervical cancer (CC) pathogenesis, yet the precise mechanisms remain largely unexplored. In this study, we identified DDX5 as a binding partner of the methyltransferase METTL3 in CC cells, demonstrating that DDX5 interacts with METTL3 to regulate global m6A levels. Additionally, METTL3-mediated m6A modification stabilizes PAK6 mRNA through recognition by the m6A reader IGF2BP1. Gain- and loss-of-function studies revealed that PAK6 enhances the proliferation, migration and invasion capability of CC cells by phosphorylating MAPK14 at the Ser56 residue. In vivo experiments further corroborated that METTL3 promotes CC growth and metastasis by upregulating PAK6. Notably, a positive correlation between METTL3 and PAK6 expression is observed in clinical specimens of CC. Collectively, our findings highlight the critical role of METTL3/PAK6 axis in driving CC progression, offering potential therapeutic targets for patients with CC.