2. Academic Validation
  3. Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome

Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome

  • Nat Commun. 2025 Aug 15;16(1):7611. doi: 10.1038/s41467-025-62951-z.
Yishu Wang # 1 2,  Jiaying Wu # 1 2,  Gaochen Zhang 2,  Yan Shi 2,  Yicong Meng 1 2,  Pingping Lv 3,  Weiwei Huang 2,  Yunfei Su 2,  Zhiyang Zhou 2,  Bo Wang 4,  Xiaojun Chen 1,  Chengliang Zhou 1,  Jiexue Pan 2 5,  Li Jin 2 5,  Xiaotao Wang 2,  Yanting Wu 2 5,  Jianzhong Sheng 2 3,  Xinmei Liu 2,  Yu Zhang 6,  Guolian Ding 7 8,  Chuanjin Yu 9,  Hefeng Huang 10 11 12 13
Affiliations

Affiliations

  • 1 International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
  • 3 Institute of Medical Genetics and Development, Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4 Department of Reproductive Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 5 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
  • 6 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. zhang_yu_sfy@fudan.edu.cn.
  • 7 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. dingguolian@fudan.edu.cn.
  • 8 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. dingguolian@fudan.edu.cn.
  • 9 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. yuchuanjin1013@163.com.
  • 10 International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. huanghefg@hotmail.com.
  • 11 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. huanghefg@hotmail.com.
  • 12 Institute of Medical Genetics and Development, Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. huanghefg@hotmail.com.
  • 13 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. huanghefg@hotmail.com.
  • # Contributed equally.
PMID: 40817119 DOI: 10.1038/s41467-025-62951-z
Abstract

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.

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