Cereblon (CRBN) inhibits prostate cancer metastasis by negatively regulating 6-phosphogluconate dehydrogenase (6PGD).

Metastasis is the primary cause of mortality in advanced prostate cancer, and the emergence of resistance to androgen receptor (AR)-targeted therapies highlights the urgent need for alternative therapeutic strategies. Metabolic reprogramming has increasingly been recognized as a key driver of metastatic progression. In this study, we uncover a novel tumor-suppressive role for cereblon (CRBN), a substrate receptor of the CRL4CRBN E3 ubiquitin ligase complex, in modulating prostate cancer metastasis through regulation of 6-phosphogluconate dehydrogenase (6PGD), a critical enzyme in the oxidative pentose phosphate pathway (oxPPP). CRBN directly binds a conserved C-terminal α-helix in 6PGD, promoting its polyubiquitination and proteasomal degradation independently of immunomodulatory drugs (IMiDs). Genetic or pharmacological loss of CRBN via CRISPR/Cas9, RNA interference, or PROTAC-mediated degradation stabilized 6PGD and elevated the NADPH/NADP+ ratio. Conversely, re-expression of wild-type CRBN reduced 6PGD levels, restored NADPH/NADP+ ratio, and suppressed cell migration and invasion. Transcriptomic profiling revealed CRBN-induced upregulation of CDH1 and downregulation of the EMT marker MMP1, while CRBN degradation produced the opposite pattern-both effects were reversed by 6PGD inhibition. These regulatory effects were conserved across multiple cancer cell lines and observed in CRBN-deficient mouse tissues. Functional studies using intra-splenic xenograft models further demonstrated that CRBN suppresses metastatic dissemination. Collectively, our findings identify 6PGD as a novel endogenous substrate of CRBN and establish the CRBN-6PGD axis as a critical metabolic checkpoint in prostate cancer metastasis. Therapeutic targeting of this pathway may offer promising strategies for CRBN-deficient or 6PGD-driven cancers.