尽管已经确定了基因组不稳定性[1]和低氧[2,3]作为中危前列腺癌患者复发的风险因素，但预测和治疗复发仍然是一项挑战。这表明在确定这些风险因素的功能影响对促进前列腺癌进展的机制时存在挑战。在这里，我们展示由前列腺肿瘤[4]中观察到的慢性低氧（CH）导致前列腺癌细胞采用雄激素无关状态。具体而言，CH导致前列腺癌细胞采用类似于去势抵抗性前列腺癌细胞的转录和代谢改变。这些改变包括转膜转运器对甲硫氨酸循环和相关途径的增加表达，导致代谢物的增加和糖酵解相关酶的表达。通过靶向葡萄糖转运蛋白1（GLUT1），我们发现雄激素无关细胞中存在糖酵解的依赖性。总的来说，我们确定了慢性低氧和雄激素无关前列腺癌的可治疗性靶点。这些发现可能提供了额外的针对低氧前列腺癌的治疗策略。©2023.作者。

Predicting and treating recurrence in intermediate-risk prostate cancer patients remains a challenge despite having identified genomic instability [1] and hypoxia [2, 3] as risk factors. This underlies challenges in assigning the functional impact of these risk factors to mechanisms promoting prostate cancer progression. Here we show chronic hypoxia (CH), as observed in prostate tumours [4], leads to the adoption of an androgen-independent state in prostate cancer cells. Specifically, CH results in prostate cancer cells adopting transcriptional and metabolic alterations typical of castration-resistant prostate cancer cells. These changes include the increased expression of transmembrane transporters for the methionine cycle and related pathways leading to increased abundance of metabolites and expression of enzymes related to glycolysis. Targeting of the Glucose Transporter 1 (GLUT1) identified a dependency on glycolysis in androgen-independent cells. Overall, we identified a therapeutically targetable weakness in chronic hypoxia and androgen-independent prostate cancer. These findings may offer additional strategies for treatment development against hypoxic prostate cancer.© 2023. The Author(s).