Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease characterized by its aggressive nature and resistance to anti-androgen therapies. Although PARP inhibitors (PARPis) have brought new hope for mCRPC patients with homologous recombination (HR) deficient, such as those lacking BRCA1/2, the utility of PARPi monotherapy is significantly restricted, with only 10%-15% of mCRPC patients with BRCA1/2 deficiencies achieving clinical benefit. Thus, there is a critical need for innovative therapeutic strategies for mCRPC patients without BRCA deficiency. In our current study, we elucidate the pivotal role of the ATM-TRMT10A-BRCA1 axis in mediating HR repair and PARPi resistance in mCRPC. We demonstrate that TRMT10A is phosphorylated at S28 by ATM after DNA damage. This phosphorylation is essential for the recruitment of BRCA1 to sites of DNA damage, thereby facilitating HR repair. Deletion of TRMT10A compromises HR repair, rendering tumor cells more sensitive to PARPi. Importantly, we show that TRMT10A expression is upregulated in mCRPC and is modulated by Ubiquitin Specific Peptidase 10 (USP10). Inhibition of USP10 with small molecular inhibitor Spautin-1 leads to TRMT10A degradation and enhances the sensitivity of tumors to PARPi in both cell-derived xenografts (CDX) and patient-derived xenografts (PDX). Our findings underscore the vital role of ATM-TRMT10A-BRCA1 axis in the vulnerability to PARP inhibitors and introduce a promising strategy perspective for exploring synthetic lethality. This approach, which involves the combination of PARP and USP10 inhibitors, could extend therapeutic benefits to a broader group of mCRPC patients without BRCA mutation.