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Docetaxel (DTX) is a standard chemotherapy agent for castration-resistant prostate cancer (CRPC); however, DTX resistance remains a major clinical challenge, and the underlying molecular mechanisms are not fully understood. In our study, it was found that OTUB2 was highly expressed in DTX-resistant CRPC and could be served as a key driver of DTX resistance. Mechanistically, OTUB2 stabilizes the m5C reader ALYREF by removing its K48-linked polyubiquitin chains, leading to increased ALYREF protein levels. And then, ALYREF enhances the mRNA stability and expression of ABCG4, thereby promoting ATP-dependent efflux of DTX. Moreover, the expression of OTUB2 mRNA and protein could be regulated by FOXD3-AS1 derived from cancer-associated fibroblasts (CAFs). More importantly, treatment with OTUB2 inhibitor (OTUB2-IN-1) resensitized resistant CRPC to DTX. Together, our findings establish OTUB2 as a novel driver of DTX resistance in CRPC and highlight the role of CAFs-derived FOXD3-AS1 and OTUB2/ALYREF/ABCG4 axis in modulating DTX resistance of CRPC.