Background 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. Methods 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. Results 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. Conclusions 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. Graphical Abstract 1. lncRNA HUPCOS is significantly upregulated in granulosa cells of PCOS patients and positively correlates with serum testosterone levels. 2. Overexpression of HUPCOS in mice induces estrous cycle irregularities and PCOS-like ovarian changes. 3. Mechanistically, HUPCOS enhances RBPMS ubiquitination, reducing its interaction with SMAD4 and suppressing CYP19 A1 expression. 4. This HUPCOS-RBPMS-SMAD4 regulatory axis disrupts estrogen biosynthesis and contributes to hyperandrogenism in PCOS.

The role of lncRNA HUPCOS in androgen metabolism and follicle growth arrest in polycystic ovary syndrome

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2025年6月17日

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Jun Xie,
Xiao Xu,
Yuning Chen,
Yongning Lu,
Miao Liu,
Yi Feng,
Che Qi,
Suying Liu

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Graphical Abstract

1. lncRNA HUPCOS is significantly upregulated in granulosa cells of PCOS patients and positively correlates with serum testosterone levels.

2. Overexpression of HUPCOS in mice induces estrous cycle irregularities and PCOS-like ovarian changes.

3. Mechanistically, HUPCOS enhances RBPMS ubiquitination, reducing its interaction with SMAD4 and suppressing CYP19 A1 expression.

4. This HUPCOS-RBPMS-SMAD4 regulatory axis disrupts estrogen biosynthesis and contributes to hyperandrogenism in PCOS.