Glioblastoma (GBM) represents one of the most prevalent types of tumors in the central nervous ystem. PPARP inhibitors are novel targeted therapies for cancer patients, primarily functioning through synthetic lethality mechanisms that selectively exploit defects in DNA repair pathways in tumor cells. However, patients with GBM have a minimal benefit from PARP inhibitor monotherapy. Hence, understanding the underlying mechanisms and devel-oping innovative strategies for enhancing their efficacy against GBM is imperative. Here, we demonstrate that blocking ferroptosis attenuates olaparib-induced cell death and impairs its anti-GBM efficacy both in vitro and in vivo. Furthermore, depleting nuclear receptor coactivator 4 (NCOA4) mitigates olaparib-induced ferroptosis. Nota-bly, we identified vimentin (VIM) as a novel NCOA4-interacting protein through multimodal screening. VIM inhi-bition markedly increased NCOA4 abundance through suppression of HERC2-mediated NCOA4 ubiquitination and degradation, subsequently potentiating the ferroptosis response. More importantly, withaferin A (WFA, a specific VIM inhibitor) combined with olaparib exhibited synergistic antitumor efficacy in orthotopic GBM xenografts via the induction of ferroptosis. Collectively, our data establishes that VIM modulates NCOA4 ubiquitination and deg-radation to govern the olaparib-induced ferroptotic response and enhances the sensitivity of GBM to olaparib treatment. These findings not only uncover a novel mechanism of VIM-mediated PARP inhibitor resistance in GBM but also provide a potential combined therapeutic strategy for clinical GBM treatment.