The m ⁶A reader HNRNPC drives osteosarcoma metastasis and cisplatin resistance by stabilizing MTDH to coordinately...

Osteosarcoma (OS) is a highly aggressive bone malignancy associated with a pronounced propensity for metastasis and the frequent development of therapeutic resistance. The epithelial-mesenchymal transition (EMT) program is a well-established driver of metastasis, and dysregulation of ferroptosis contributes to chemotherapy resistance. In this study, a prognostic signature comprising four genes associated with EMT and ferroptosis is constructed. Notably, among the four signature genes, metadherin ( MTDH) is a robust, independent biomarker for predicting overall survival. Knockdown of MTDH significantly suppresses the EMT program and markedly impairs cell migration and invasion. Moreover, depletion of MTDH sensitizes OS cells to cisplatin and increases cellular ferroptosis levels. Interestingly, bioinformatic screening using online databases reveals that HNRNPC is a potential m ⁶A reader involved in the regulation of MTDH mRNA. This finding is experimentally validated by demonstrating that knockdown of HNRNPC significantly reduces both the mRNA and protein levels of MTDH. Furthermore, RIP assay results confirm a direct interaction between MTDH mRNA and HNRNPC protein. Mechanistically, downregulation of HNRNPC impairs the stability of MTDH mRNA. Silencing HNRNPC attenuates the malignant phenotype of OS cells by inhibiting EMT progression and promoting ferroptosis. To our knowledge, this study is the first to show that the m ⁶A reader protein HNRNPC serves as a crucial upstream regulatory mechanism by stabilizing MTDH mRNA, thereby coordinately driving EMT and suppressing ferroptosis in OS. Thus, the HNRNPC-MTDH axis constitutes a potential therapeutic target for improving the treatment landscape of OS by simultaneously targeting metastasis and chemotherapy resistance.