丙酸二甲双胍（metformin）是一种抗糖尿病药物，具有已知的抗癌作用，与其抗氧化活性有关；然而，其在前列腺癌（PCa）临床上的益处至今尚不确定。因此，本研究旨在探讨metformin在PCa中的疗效是否与NKX3.1表达状态相关，后者是一个在线粒体中发挥作用以保护前列腺免受异常氧化应激的前列腺特异性homeobox基因。 以研究NKX3.1表达与metformin在PCa中的疗效关系为目标，我们进行了体内和体外功能研究，包括采用基因工程小鼠模型和人类LNCaP细胞，以及具有正常或减少/缺失NKX3.1水平的器官培养。并使用两个独立的回顾性组织微阵列队列，以及一个回顾性前列腺活检队列进行相关研究。 在用巴拉quat处理诱导氧化应激前或后，给予metformin。功能终点包括组织学、致瘤性和线粒体功能分析。相关终点包括Kaplan-Meier曲线和Cox比例风险回归模型。 metformin在体内和体外逆转了NKX3.1缺乏在氧化应激后的不良后果，表现为减少的致瘤性和恢复的线粒体功能。低NKX3.1表达的患者在服用metformin后显示出显著的临床益处。 metformin通过对抗氧化应激和促进正常线粒体功能，可以克服NKX3.1损失对于PCa进展的不良后果。这些功能活性和临床相关仅在低NKX3.1表达时观察到。因此，metformin在PCa的临床益处可能取决于NKX3.1表达的状态。 NKX3.1表达低的前列腺癌患者可能在准确，拦截范式下从metformin治疗中获益最多，以延缓疾病进展。 版权所有 © 2023年欧洲泌尿学会。由Elsevier B.V.出版。保留所有权利。

The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1, a prostate-specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress.To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa.Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance.Metformin was administered before or after the induction of oxidative stress by treatment with paraquat.Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models.Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin.Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression.Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.