雄激素受体（AR）是前列腺癌（PCa）细胞代谢的已知协调者，尤其是通过诱导氧化线粒体代谢计划。有趣的是，AR调节细胞质异柠檬酸脱氢酶1（IDH1）而非线粒体内的IDH2和IDH3。本文旨在理解IDH1在PCa中的功能作用。使用小鼠模型、人类PCa细胞系和人类患者源器官样体（PDOs）研究正常前列腺和PCa中IDH酶的表达和活性。然后，将IDH1的遗传和药物抑制与细胞外荷尔蒙分泌分析和气相色谱质谱分析用于代谢组学分析和体外和体内癌细胞增殖。在PCa细胞中，超过90%的总IDH活性是通过IDH1介导的，而不是其线粒体内的对应酶。这种情况似乎源于特殊的前列腺代谢计划，如在小鼠前列腺和PDOs中观察到的。IDH1的药物和基因抑制影响线粒体呼吸作用，这表明这种细胞质酶对PCa的线粒体三羧酸循环（TCA）有贡献。基于质谱的代谢组学证实了这个假设，显示IDH1的抑制影响碳通量进入TCA循环。因此，IDH1的抑制减缓了PCa细胞在体外和体内的增殖。这些结果证明了PCa细胞具有依赖IDH1的混合型细胞质-线粒体TCA循环。这种代谢酶是PCa细胞的代谢弱点，也是潜在的新治疗靶标。本文受版权保护，所有权利均被保留。

The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1) but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analysis and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.This article is protected by copyright. All rights reserved.