Benign prostatic hyperplasia (BPH), characterized by the non-malignant enlargement of the prostate, exhibits a pronounced association with inflammation resulting from androgen receptor (AR) deficiency. Ferroptosis, a cell death mechanism triggered by iron-dependent lipid peroxidation and closely linked to inflammation, has yet to be fully understood in the context of BPH. Using RNA sequencing, we observed a significant elevation of taurine-upregulated gene 1 (TUG1) long noncoding RNA (lncRNA) in BPH tissues compared to normal prostate tissue. High levels of TUG1 exhibited a discernible correlation with both prostate volume and the extent of inflammatory infiltration in BPH patients. The suppression of TUG1 not only led to a reduction in prostate size but also ameliorated AR-deficiency-induced prostatic hyperplasia. Mechanistically, a decrease in AR in prostate luminal cells prompted macrophage aggregation and the release of IL-1β, subsequently fostering the transcription of TUG1 via MYC. Induced TUG1, through competitive binding with miR-188-3p, facilitated the expression of GPX4, thereby diminishing intracellular ROS levels and impeding ferroptosis in prostate luminal cells. Notably, the ferroptosis inducer JKE-1674 alleviated inflammation-induced prostatic hyperplasia . Together, these findings suggest that AR deficiency crucially inhibits ferroptosis, promoting BPH via the TUG1/miR-188-3p/GPX4 signaling axis, and making ferroptosis induction a promising therapeutic strategy for BPH patients with AR deficiency.

中文翻译：

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雄激素受体缺陷诱导TUG1通过miR-188-3p/GPX4信号通路抑制铁死亡促进良性前列腺增生


良性前列腺增生 (BPH) 的特征是前列腺非恶性增大，与雄激素受体 (AR) 缺乏引起的炎症有显着相关性。铁死亡是一种由铁依赖性脂质过氧化引发的细胞死亡机制，与炎症密切相关，在 BPH 背景下尚未得到充分了解。通过 RNA 测序，我们观察到与正常前列腺组织相比，BPH 组织中牛磺酸上调基因 1 (TUG1) 长非编码 RNA (lncRNA) 显着升高。高水平的 TUG1 与 BPH 患者的前列腺体积和炎症浸润程度具有明显的相关性。 TUG1 的抑制不仅导致前列腺体积减小，而且还改善了 AR 缺陷引起的前列腺增生。从机制上讲，前列腺管腔细胞中 AR 的减少促进巨噬细胞聚集和 IL-1β 的释放，随后通过 MYC 促进 TUG1 的转录。诱导的 TUG1 通过与 miR-188-3p 竞争性结合，促进 GPX4 的表达，从而降低细胞内 ROS 水平并阻止前列腺管腔细胞的铁死亡。值得注意的是，铁死亡诱导剂 JKE-1674 减轻了炎症诱导的前列腺增生。总之，这些研究结果表明，AR 缺陷关键性地抑制铁死亡，通过 TUG1/miR-188-3p/GPX4 信号轴促进 BPH，并使铁死亡诱导成为 AR 缺陷 BPH 患者有前途的治疗策略。