Androgen receptor deficiency-induced TUG1 in suppressing ferroptosis to promote benign prostatic hyperplasia through the miR-188-3p/GPX4 signal pathway

• Published in: Redox biology 2024-09, Vol.75, p.103298, Article 103298
• Main Authors: Zhan, Ming, Xu, Huan, Yu, Guopeng, Chen, Qi, Yang, Ruifeng, Chen, Yanbo, Ge, Jianchao, Wang, Zhong, Yang, Ruimeng, Xu, Bin
• Format: Article
• Language: English
• Subjects: Androgen receptor; Animals; Benign prostatic hyperplasia; Disease Susceptibility; Ferroptosis; Ferroptosis - genetics; Humans; Inflammation; Male; Mice; MicroRNAs - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Prostatic Hyperplasia - genetics; Prostatic Hyperplasia - metabolism; Prostatic Hyperplasia - pathology; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA, Long Noncoding - genetics; Signal Transduction; TUG1
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2024.103298

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 in vivo. 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.