根据多个临床试验的结果，二甲双胍治疗前列腺癌（PCa）的疗效尚不确定。二甲双胍治疗失败可能归因于转录失调频率高，导致耐药性增强。然而，其潜在机制仍不清楚。本研究发现，PCa细胞中二甲双胍耐药可能与细胞周期重新激活相关。超级增强子（SE），作为重要的调控元素，已被证明与多种癌症耐药性相关。我们对二甲双胍耐药（MetR）的PCa细胞中的SE进行分析，发现与前列腺素还原酶1（PTGR1）表达相关，通过单细胞转录组测序确定在MetR细胞簇中显著增加。我们的功能实验表明，PTGR1过表达通过促进从G0/G1到S和G2/M期的进展加速细胞周期进程，导致对二甲双胍的敏感性降低。此外，我们还确定了显著增加PTGR1表达的关键转录因子，如SRF和RUNX3，为解决PCa中二甲双胍耐药性提供了潜在的新靶点。总之，我们的研究为理解二甲双胍耐药机制以及SE-TFs-PTGR1轴的调控提供了新见解，为增强二甲双胍在PCa治疗中的疗效提供了潜在途径。© 2023. 四川大学华西医院。

The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformin's therapeutic efficacy in PCa.© 2023. West China Hospital, Sichuan University.