Here, we report that nuclear FBP1 is degraded through the ubiquitin-proteasome pathway, and CUL4B acts as Cullin-RING E3 ubiquitin ligase (CRL) to promote the degradation of FBP1 in nucleus, while the neddylation inhibitor MLN4924 could inactivate CUL4B E3 ligase, block proteasomal degradation of FBP1 and suppress HIF target gene expression, including GLUT1, LDHA, PDK1 and VEGF, leading to decreased glucose uptake and lactate and NADPH production, thereby repressing tumor growth of ccRCC. Here, PDK1 is linked to nonpapillary renal cell carcinoma.