下一代雄激素受体（AR）抑制剂恩替卡韦（ENZ）是转移性前列腺癌的主要治疗方法。不幸的是，大多数患者的耐药性发展迅速，一旦出现耐药性，治疗选择有限。因此，迫切需要寻找有效的靶点以克服ENZ耐药性。在本研究中，我们使用基因组范围CRISPR-Cas9文库筛选发现，靶向糖酵解酶磷酸甘油酸变位酶PGAM2能显著增强ENZ耐药性前列腺癌细胞对ENZ治疗的敏感性，无论是体内还是体外。抑制PGAM2与ENZ治疗一起能通过降低抗凋亡蛋白BCL-xL的水平和增加促凋亡蛋白BAD的活性来诱导细胞凋亡。在机制上，PGAM2与14-3-3ζ结合并促进其与磷酸化的BAD的相互作用，从而激活BCL-xL并导致对ENZ引起的凋亡的耐药性。此外，PGAM2的高表达与AR的转录调控相关，在前列腺癌患者中与生存时间较短和快速发展ENZ耐药性有关联。综上所述，这些发现提供了PGAM2在促进ENZ耐药性方面的非代谢功能的证据，并确定PGAM2抑制作为治疗ENZ耐药性前列腺癌的有希望的治疗策略。

The next-generation androgen receptor (AR) inhibitor enzalutamide (ENZ) is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome ENZ resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of ENZ-resistant prostate cancer cells to ENZ both in vivo and in vitro. Inhibition of PGAM2 together with ENZ treatment triggered apoptosis by decreasing levels of the anti-apoptotic protein BCL-xL and increasing activity of the pro-apoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to ENZ-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of ENZ resistance in prostate cancer patients. Together, these findings provide evidence of a non-metabolic function of PGAM2 in promoting ENZ resistance and identify PGAM2 inhibition as a promising therapeutic strategy for ENZ-resistant prostate cancer.