IGF2BP3 promotes progression of head and neck cancers through the circHECTD2/hsa_miR_4310/7157-5p/Smad2 signaling axis in an m(6)A modification-dependent manner.

BACKGROUND: Accumulating evidence indicates that N6-methyladenosine (m(6)A) modification of circular RNAs (circRNAs) plays a pivotal role in regulating cancer progression. However, in head and neck squamous cell carcinoma (HNSCC), the biological functions and underlying mechanisms of m(6)A modification in circRNAs remain insufficiently elucidated. METHODS: In this study, we analyzed the association between the expression of IGF2BP3—an upstream m⁶A reader—and clinical outcomes of HNSCC patients, followed by investigating the interaction between IGF2BP3 and circHECTD2 as well as the effect of m⁶A modification on this interaction. Additionally, we explored the molecular mechanism by which IGF2BP3 and circHECTD2 regulate HNSCC progression, focusing on their roles in modulating microRNAs (miRNAs) and target mRNAs, and validated the functional impacts of the IGF2BP3/circHECTD2 axis on HNSCC cell proliferation, invasion, and metastasis. RESULTS: We found high expression of the m⁶A reader IGF2BP3 was significantly associated with poor clinical outcomes in HNSCC patients. Further experiments showed that IGF2BP3 directly bound to circHECTD2 and stabilized it, and m⁶A modification of circHECTD2 enhanced this binding and stabilization effect. Mechanistically, circHECTD2 functioned as a competing endogenous RNA (ceRNA) to sponge hsa-miR-4310 and hsa-miR-7157-5p, thereby preventing the miRNA-mediated degradation of SMAD2 mRNA. Ultimately, the IGF2BP3/circHECTD2/SMAD2 axis was shown to promote HNSCC cell proliferation, invasion, and metastasis. CONCLUSION: We delineate an m(6)A-dependent IGF2BP3/circHECTD2/SMAD2 regulatory axis that contributes to HNSCC malignancy. Elevated IGF2BP3 expression correlates with poor patient outcome and enhances circHECTD2 stability through m6A-facilitated binding; circHECTD2 in turn acts as a ceRNA to sequester hsa-miR-4310 and hsa-miR-7157-5p, thereby maintaining SMAD2 expression. Functionally, this axis promotes HNSCC cell proliferation, invasion and metastasis. Collectively, these findings suggest that IGF2BP3 and circHECTD2 may serve as promising prognostic biomarkers and therapeutic targets for HNSCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-026-02619-4.