Transfer RNA‐Derived Small RNA‐5’tiRNAGln Drives HNRNPC Phase Separation to Promote Breast Cancer Bone Metastasis by Regulating IGF1R

Transfer RNA-derived small RNAs (tsRNAs) are emerging tumor regulators, yet their roles in breast cancer (BC) bone metastasis (BM) remain poorly understood. Here, we identify 5'tiRNA-Gln as a key pro-metastatic tsRNA markedly upregulated in BM tissues. Functionally, 5'tiRNA-Gln robustly enhances BC cell migration, invasion, and osteoclast differentiation. Mechanistically, 5'tiRNA-Gln directly binds to the RRM domain of heterogeneous nuclear ribonucleoprotein C (HNRNPC), a novel phase-separating protein. Biophysically, 5'tiRNA-Gln acts as a "molecular glue" to accelerate HNRNPC liquid-liquid phase separation. These phase-separated condensates preferentially bind to the coding sequence (CDS) region of IGF1R mRNA, increasing its stability and hyperactivating downstream ERK signaling. Clinically, HNRNPC is amplified in BM tissues and predicts poor prognosis. Silencing HNRNPC dramatically suppresses bone-destructive lesions and tumor burden in vivo. In conclusion, our study uncovers a novel biophysical mechanism wherein a tsRNA regulates protein phase separation to drive tumor metastasis. The 5'tiRNA-Gln/HNRNPC/IGF1R axis represents a promising biomarker and therapeutic target for BC bone metastasis.