HSP90 inhibition might be a promising strategy to overcome the radioresistance of some cancers. In the current study, we further explored the mechanisms of HSP90 in regulating the radiosensitivity of cervical cancer cells. Bioinformatic analysis was performed based on data from TCGA-CESC. Cellular and molecular studies were conducted using CaSki and SiHa and the derived radioresistant (RR) subclones. Through a proteomics screen, we identified HSP90 chaperones (both HSP90α and HSP90β) as CD147 binding partners supporting its stabilization. Targeting HSP90 sensitized CaSki-RR and SiHa-RR cancer cells to irradiation partially through CD147 destabilization. Mechanistically, HSP90 interacts with FBXO6 and reduces FBXO6-mediated proteasomal degradation of CD147. Enforced FBXO6 overexpression also sensitized CaSki-RR and SiHa-RR cancer cells to irradiation. These effects were enhanced by 17-AAG treatment but were weakened by CD147 overexpression. Survival analysis further confirmed the association between high FBXO6 expression and favorable progression-free survival among patients with cervical cancer. In conclusion, this study showed that HSP90 promotes radioresistance of cervical cancer cells partially via reducing FBXO6 mediated CD147 polyubiquitination. These findings help explain why HSP90 inhibitor exerts radio-sensitizing effects in cervical cancer.This article is protected by copyright. All rights reserved.