Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome
Polycystic ovary syndrome is the primary cause of female infertility. Growing evidence suggests that dysregulation of amino acid metabolism plays a significant role in the onset and progression. However, the underlying mechanism remains unclear. In this study, we conduct targeted metabolite profiling of human follicular fluid and granulosa cells. A significant increase in glutamine uptake is observed in patients with hyperandrogenic polycystic ovary syndrome, mediated by the upregulation of SLC1A5, a specific glutamine transporter. We find that androgen excess primarily activates SLC1A5 expression. Furthermore, SLC1A5 overexpression in female mice induces polycystic ovary syndrome-like phenotypes, including hyperandrogenism and abnormal follicle development. Additionally, the pharmacological blockade of SLC1A5 provides reproductive benefits to mice exhibiting polycystic ovary syndrome-like symptoms. Mechanistically, we show that elevated flux of Gln-derived α-ketoglutarate enhances HDAC5 expression and suppresses acetylation on histone 3 lysine residue 14 and lysine residue 56. The reduction in acetylation level is associated with the downregulation of several genes related to folliculogenesis, including CYP19A1, thereby exacerbating androgenic homeostasis imbalance. These findings indicate that androgen-induced aberrant glutamine uptake via SLC1A5 is crucial for the development and progression of polycystic ovary syndrome, suggesting pharmacological blockade of SLC1A5 as a potential therapeutic strategy.
Authors
- Chuanjin Yu (ORCID: https://orcid.org/0000-0001-6071-7669)
- Yicong Meng
- Yanting Wu (ORCID: https://orcid.org/0000-0002-2293-1792)
- Weiwei Huang
- Yan Shi (ORCID: https://orcid.org/0000-0001-8424-5862)
- Jiexue Pan (ORCID: https://orcid.org/0000-0001-7125-9608)
- Yunfei Su (ORCID: https://orcid.org/0000-0002-8106-0691)
- Guolian Ding (ORCID: https://orcid.org/0000-0002-0099-9980)
- Jiaying Wu (ORCID: https://orcid.org/0000-0002-7932-538X)
- Guangping Zhang (ORCID: https://orcid.org/0000-0002-1620-0221)
- Jin Li (ORCID: https://orcid.org/0000-0002-5891-8135)
- Hefeng Huang (ORCID: https://orcid.org/0000-0003-4344-8019)
- Xiaojun Chen (ORCID: https://orcid.org/0000-0002-7796-1315)
- Yu Zhang (ORCID: https://orcid.org/0000-0002-3315-9427)
- Xin-Mei Liu (ORCID: https://orcid.org/0000-0003-4833-0490)
- Xiaotao Wang (ORCID: https://orcid.org/0000-0002-3531-2157)
- Bo Wang (ORCID: https://orcid.org/0000-0001-9111-7498)
- Yishu Wang (ORCID: https://orcid.org/0000-0003-1176-3970)
- Pingping Lv
- Jian‐Zhong Sheng (ORCID: https://orcid.org/0000-0001-8006-3965)
- Chengliang Zhou (ORCID: https://orcid.org/0000-0002-9402-1077)
- Zhiyang Zhou (ORCID: https://orcid.org/0000-0001-9951-7015)
Institutions
- Fudan University (CN)
- XinHua Hospital (CN)
- International Peace Maternity & Child Health Hospital (CN)
- Ministry of Education (TH)
- Women's Hospital, School of Medicine, Zhejiang University (CN)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1038/s41467-025-62951-z
- Citations
- 5
- Primary Topic
- Reproductive Biology and Fertility
- Type
- article
- Field-Weighted Citation Impact
- 9.39
Funders
- Ohio State University
- National Natural Science Foundation of China
- Fudan University
- Shanghai Jiao Tong University
- Xiamen University
- Shanghai Clinical Research Center
- National Key Research and Development Program of China