Manganese drives ferroptosis of cancer cells via YAP/TAZ phase separation activated ACSL4 in OSCC

Abstract Objective Ferroptosis has been defined as a novel form of regulated cell death characterized by iron‐dependent lipid peroxidation. Manganese has been used to induce ferroptosis in cancer cells recently. This study aims to investigate whether manganese can induce ferroptosis in oral squamous cell carcinoma (OSCC) and the underlying biological mechanisms. Materials and Methods Cancer cells with or without manganese treatment were analyzed by RNA‐sequencing to identify ferroptosis‐related genes. Next, the activation of YAP/TAZ/ACSL4‐ferroptosis signaling pathway was detected. Bioinformatic analysis and immunofluorescence assay were used to explore the phase separation of YAP/TAZ. Finally, specimens of OSCC patients were applied to analyze the clinical significance of YAP/TAZ/ACSL4. Results RNA‐sequencing analysis showed the ferroptosis‐related genes and YAP/TAZ were upregulated after manganese treatment. The results of immunofluorescence, ELISA, western blotting, etc. further confirmed that manganese‐induced ferroptosis depends on YAP/TAZ/ACSL4 signaling pathway. Moreover, the activation of ACSL4 was achieved by YAP/TAZ phase separation. The survival analysis in OSCC specimen suggested that the higher level of YAP/TAZ‐ACSL4 axis expression indicates longer survival. Conclusions Manganese induces YAP/TAZ phase separation and subsequent ACSL4 activation via YAP/TAZ nuclear translocation, which facilitates ferroptosis of OSCC. Then YAP/TAZ‐ACSL4 axis can be used as a potential prognostic predictor of OSCC patients.