USP5 stabilizes RSK1 and promotes temozolomide resistance in glioblastoma.

Temozolomide (TMZ) resistance is a major hurdle in glioblastoma multiforme (GBM). RSK1 is associated with glioma malignancy, but its role in resistance remains unclear. We show that RSK1 is upregulated in TMZ-resistant (TR) cells and tissues, and silencing it restores TMZ sensitivity in vitro and in vivo. USP5, a deubiquitinase, stabilizes RSK1 and is overexpressed in TR-GBM. Mechanistically, USP5 directly interacts with RSK1 and removes K48-linked ubiquitin chains, thereby increasing RSK1 levels and conferring resistance; USP5 knockdown has the opposite effect. WP1130, a broad-spectrum deubiquitinase inhibitor that suppresses USP5 activity, effectively promotes RSK1 degradation and reverses TMZ resistance. In clinical samples, USP5 levels correlate with RSK1, and high expression of either predicts poor prognosis in TMZ-treated patients. Overall, these findings highlight the USP5/RSK1 axis in chemoresistance and suggest that targeting this pathway may benefit patients who are resistant to TMZ.