METTL3/IGF2BP2 stabilizes IQGAP3 via m6A modification to drive HCC metastasis through TGF-β/Smad signaling and EMT

Hepatocellular carcinoma (HCC) metastasis is a leading cause of mortality, yet its molecular drivers remain poorly defined. In this study, we identify methyltransferase-like 3 (METTL3), an N6-methyladenosine (m6A) RNA methyltransferase frequently upregulated in HCC, as a critical promoter of metastasis through m6A-mediated post-transcriptional upregulation of the oncogenic protein IQ motif-containing GTPase-activating protein 3 (IQGAP3). Using HCC cell lines in vitro and a nude mouse lung metastasis model in vivo, we demonstrate that METTL3-catalyzed m6A modification of IQGAP3 mRNA enhances IQGAP3 stability and expression, which in turn drives HCC cell migration, invasion, and lung colonization. METTL3 knockdown reduces m6A marks on IQGAP3 transcripts and decreases IQGAP3 levels and metastatic capacity, whereas ectopic IQGAP3 expression rescues the invasive phenotype. Mechanistically, RNA immunoprecipitation assays reveal that Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m6A reader protein, binds m6A-modified IQGAP3 transcripts to prolong their half-life. Consequently, the METTL3-IQGAP3 axis activates TGF-β/Smad signaling and drives an epithelial-mesenchymal transition, thereby promoting a metastatic phenotype. Concordantly, METTL3 depletion or IGF2BP2 knockdown significantly suppresses these pathways and impedes metastasis in vitro and in vivo. Overall, our findings uncover a novel m6A-dependent mechanism driving HCC metastasis. This m6A-dependent METTL3-IGF2BP2-IQGAP3 axis represents a promising therapeutic target for metastatic HCC.