Xie Jun, Xu Xiao, Chen Yuning, Lu Yongning, Liu Miao, Feng Yi, Qi Che, Liu Suying
Reproductive Medicine Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
Cell Biol Toxicol. 2025 Jun 17;41(1):105. doi: 10.1007/s10565-025-10047-1.
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and follicular growth arrest. This study investigates the role of a newly identified long non-coding RNA, lncRNA-ZSCAN2-5:15 (HUPCOS), in the dysregulation of androgen metabolism and ovulatory function.
Clinical samples from 47 PCOS patients and 68 controls undergoing intracytoplasmic sperm injection were analyzed. Follicular fluid hormone levels and granulosa cell expression of HUPCOS, CYP19 A1, and SMAD4 were measured. A PCOS-like mouse model was established via DHEA injection, and Hupcos overexpression was induced by AAV9, with estrous cycles, hormone levels, and ovarian histology examined. Mechanistic studies in KGN cells included overexpression and knockdown assays, immunoprecipitation, ubiquitination, and dual-luciferase reporter assays.
PCOS patients showed higher HUPCOS expression (p < 0.01) and testosterone levels (p < 0.0001), and reduced CYP19 A1 in granulosa cells. Hupcos-overexpressing mice showed PCOS-like symptoms, including estrous cycle disturbances and hormonal imbalances. In vitro, HUPCOS overexpression suppressed aromatase expression and estradiol production, while enhancing androstenedione accumulation. Mechanistically, HUPCOS promoted RBPMS ubiquitination, reduced its interaction with SMAD4, and downregulated CYP19 A1 transcription. Co-overexpression of RBPMS and HUPCOS reversed these effects.
HUPCOS impairs estrogen biosynthesis in PCOS by enhancing RBPMS degradation and disrupting SMAD4-mediated transcription of CYP19 A1. These findings highlight a novel lncRNA-mediated mechanism contributing to hyperandrogenemia and follicular arrest, offering potential targets for PCOS therapy.
多囊卵巢综合征（PCOS）的特征为雄激素过多和卵泡生长停滞。本研究调查一种新发现的长链非编码RNA，即lncRNA-ZSCAN2-5:15（HUPCOS）在雄激素代谢失调和排卵功能中的作用。
分析了47例PCOS患者和68例接受胞浆内单精子注射的对照者的临床样本。检测了卵泡液激素水平以及颗粒细胞中HUPCOS、CYP19 A1和SMAD4的表达。通过注射脱氢表雄酮建立PCOS样小鼠模型，并用腺相关病毒9型（AAV9）诱导Hupcos过表达，检测动情周期、激素水平和卵巢组织学。在KGN细胞中进行的机制研究包括过表达和敲低试验、免疫沉淀、泛素化和双荧光素酶报告基因试验。
PCOS患者的HUPCOS表达较高（p < 0.01），睾酮水平较高（p < 0.0001），颗粒细胞中的CYP19 A1降低。过表达Hupcos的小鼠表现出PCOS样症状，包括动情周期紊乱和激素失衡。在体外，HUPCOS过表达抑制芳香化酶表达和雌二醇生成，同时增加雄烯二酮积累。机制上，HUPCOS促进RBPMS泛素化，减少其与SMAD4的相互作用，并下调CYP19 A1转录。RBPMS和HUPCOS共过表达可逆转这些效应。
HUPCOS通过增强RBPMS降解和破坏SMAD4介导的CYP19 A1转录来损害PCOS中的雌激素生物合成。这些发现突出了一种新的lncRNA介导的机制，该机制导致高雄激素血症和卵泡停滞，为PCOS治疗提供了潜在靶点。
