Our findings reveal that CNOT4 ubiquitinates and promotes degradation of STAT5A/STAT5B in DGCs, while exosomal circCMTM3 from GSCs competitively binds to the RING domain of CNOT4 to block its E3 activity and maintain high expression of STAT5A/STAT5B, elucidating complex post-translational regulation of the JAK/STAT pathway in GBM progression. Here, STAT5A is linked to glioblastoma.