Metabolic CRISPR screening identifies RPE as a key regulator of acquired enzalutamide resistance through FKBP5 destabilization in prostate cancer.

Authors

Jintao Hu, Cong Lai, Yunfei Xiao, Zi Yan, Yongmei Tan, Junjie Wang, Jiangping Qiu, Kuiqing Li, Hao Yu, Xutao Chen, Jinli Han, Xiaolin Cai, Tianlong Luo, Chunnuan Deng, Rong Na, Wang He, Kewei Xu, Cheng Liu

Published in

Oncogene. Aug 03, 2026. Epub Aug 03, 2026.

Abstract

Enzalutamide is a cornerstone therapy for castration-resistant prostate cancer (CRPC), yet acquired resistance remains a major clinical challenge. Although metabolic enzymes are increasingly recognized as modulators of therapeutic response, their specific roles-particularly their non-enzymatic functions-in sustaining enzalutamide resistance remain incompletely understood. In this study, we performed an in vivo screen using a custom metabolic CRISPR library in enzalutamide-treated xenografts and identified the pentose phosphate pathway enzyme ribulose-5-phosphate 3-epimerase (RPE) as a critical driver of enzalutamide resistance. Silencing RPE markedly restored enzalutamide sensitivity, enhanced apoptosis in vitro, and significantly suppressed tumor growth in both cell line-derived and patient-derived xenograft models. Mechanistically, RPE promoted resistance independently of its canonical enzymatic activity. Instead, RPE physically interacted with FKBP5 and promoted its ubiquitin-proteasome-mediated degradation. Loss of FKBP5 subsequently hyperactivated AKT signaling, leading to increased p-BAD and BCL-xL levels and suppression of enzalutamide-induced cell death. Conversely, disrupting the RPE-FKBP5 interaction or silencing RPE in vivo using a PSMA-targeted lipid nanoparticle system effectively abrogated these resistance phenotypes. Together, these findings illustrate how CRPC cells hijack the non-enzymatic function of a metabolic enzyme to evade antiandrogen therapy, establishing the RPE-driven degradation of FKBP5 and consequent AKT hyperactivation as a targetable vulnerability for overcoming enzalutamide resistance.

PMID:
42547555
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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