Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome

Yishu Wang, Jiaying Wu, Gaochen Zhang, Yan Shi, Yicong Meng, Pingping Lv, Weiwei Huang, Yunfei Su, Zhiyang Zhou, Bo Wang, Xiaojun Chen, Chengliang Zhou, Jiexue Pan, Li Jin, Xiaotao Wang, Yanting Wu, Jianzhong Sheng, Xinmei Liu, Yu Zhang (), Guolian Ding (), Chuanjin Yu () and Hefeng Huang ()
Additional contact information
Yishu Wang: Shanghai Jiao Tong University
Jiaying Wu: Shanghai Jiao Tong University
Gaochen Zhang: Fudan University
Yan Shi: Fudan University
Yicong Meng: Shanghai Jiao Tong University
Pingping Lv: Zhejiang University School of Medicine
Weiwei Huang: Fudan University
Yunfei Su: Fudan University
Zhiyang Zhou: Fudan University
Bo Wang: Shanghai Jiao Tong University
Xiaojun Chen: Shanghai Jiao Tong University
Chengliang Zhou: Shanghai Jiao Tong University
Jiexue Pan: Fudan University
Li Jin: Fudan University
Xiaotao Wang: Fudan University
Yanting Wu: Fudan University
Jianzhong Sheng: Fudan University
Xinmei Liu: Fudan University
Yu Zhang: Fudan University
Guolian Ding: Fudan University
Chuanjin Yu: Fudan University
Hefeng Huang: Shanghai Jiao Tong University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62951-z

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