The long non-coding RNA FOXD2-AS1 promotes oral squamous cell carcinoma metastasis by recruiting the ADAR1-HuR complex to stabilize MYC mRNA

Abstract Metastasis remains a primary driver of poor outcomes in oral squamous cell carcinoma (OSCC), yet the underlying molecular mechanisms are incompletely understood. Here, we identify the long non-coding RNA FOXD2-AS1 as a critical regulator of OSCC metastasis through comprehensive analysis of GEO and TCGA datasets, followed by validation in an independent cohort of 82 OSCC patients via chromogenic in situ hybridization. FOXD2-AS1 expression is markedly elevated in metastatic OSCC tissues and correlates with lymph node metastasis, advanced clinical stage, and reduced survival. Functionally, FOXD2-AS1 potentiates OSCC cell migration, invasion, and metastatic capacity in vitro and in vivo, while its silencing suppresses these malignant phenotypes. Mechanistically, FOXD2-AS1 operates through a previously unrecognized scaffolding function, physically recruiting ADAR1 and HuR through distinct structural modules to facilitate their nuclear-to-cytoplasmic translocation. This ADAR1/HuR complex, independent of ADAR1’s RNA-editing activity, directly engages MYC mRNA to enhance its stability, thereby upregulating c-Myc expression and driving metastatic progression. The clinical relevance of this axis is underscored by the positive correlation between FOXD2-AS1 and c-Myc protein levels in OSCC specimens. Notably, pharmacological inhibition of c-Myc with MYCi975 effectively abrogates FOXD2-AS1-driven metastatic phenotypes in both cell-based and preclinical models. These findings establish FOXD2-AS1 as a key orchestrator of OSCC metastasis via ADAR1/HuR-mediated MYC mRNA stabilization and highlight the therapeutic potential of targeting the FOXD2-AS1/c-Myc axis in metastatic OSCC.