RBM12 Maintains Glioma Stem Cells by Activating Amino Acid‐Dependent mTORC1 Signaling via SLC7A5 mRNA Stabilization

ABSTRACT Reprogramming of amino acid metabolism is crucial for the rapid proliferation of cancer cells, including cancer stem cells. However, the molecular mechanisms underlying this reprogramming in glioma stem cells (GSCs) remain poorly understood. Here, we report that the RNA‐binding protein RBM12 increases the intracellular levels of large neutral amino acids, thereby activating the mTORC1 pathway and promoting GSC proliferation, self‐renewal, and glioblastoma (GBM) growth. Mechanistically, RBM12 stabilizes the mRNA of the amino acid transporter SLC7A5 , thereby increasing intracellular levels of large neutral amino acids, which subsequently activates the mTORC1 pathway. Further studies reveal that RBM12 enhances SLC7A5 mRNA stability by recruiting ALKBH5 to remove m 6 A modifications on SLC7A5 mRNA. Importantly, pharmacological inhibition of the RBM12‐SLC7A5 axis using the SLC7A5 inhibitor JPH203 effectively suppresses GBM growth. These findings elucidate a novel role for RBM12‐SLC7A5 signaling in the malignant growth of GBM and highlight the therapeutic potential of targeting this axis for GBM treatment.