BNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency

Feixia Wang, Yifeng Liu, Feida Ni, Jiani Jin, Yiqing Wu, Yun Huang, Xiaohang Ye, Xilin Shen, Yue Ying, Jianhua Chen, Ruixue Chen, Yanye Zhang, Xiao Sun, Siwen Wang, Xiao Xu, Chuan Chen, Jiansheng Guo and Dan Zhang ()
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Feixia Wang: Women’s Hospital, Zhejiang University School of Medicine
Yifeng Liu: Women’s Hospital, Zhejiang University School of Medicine
Feida Ni: Women’s Hospital, Zhejiang University School of Medicine
Jiani Jin: Women’s Hospital, Zhejiang University School of Medicine
Yiqing Wu: Women’s Hospital, Zhejiang University School of Medicine
Yun Huang: Women’s Hospital, Zhejiang University School of Medicine
Xiaohang Ye: Women’s Hospital, Zhejiang University School of Medicine
Xilin Shen: Zhejiang University
Yue Ying: Women’s Hospital, Zhejiang University School of Medicine
Jianhua Chen: Women’s Hospital, Zhejiang University School of Medicine
Ruixue Chen: Women’s Hospital, Zhejiang University School of Medicine
Yanye Zhang: Women’s Hospital, Zhejiang University School of Medicine
Xiao Sun: Women’s Hospital, Zhejiang University School of Medicine
Siwen Wang: Women’s Hospital, Zhejiang University School of Medicine
Xiao Xu: Women’s Hospital, Zhejiang University School of Medicine
Chuan Chen: Women’s Hospital, Zhejiang University School of Medicine
Jiansheng Guo: Zhejiang University
Dan Zhang: Women’s Hospital, Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, severe daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We previously identified a Basonuclin 1 (BNC1) mutation from a large Chinese POI pedigree and found that mice with targeted Bnc1 mutation exhibit symptoms of POI. In this study, we found that BNC1 plays key roles in ovarian reserve and maintaining lipid metabolism and redox homeostasis in oocytes during follicle development. Deficiency of BNC1 results in premature follicular activation and excessive follicular atresia. Mechanistically, BNC1 deficiency triggers oocyte ferroptosis via the NF2-YAP pathway. We demonstrated that pharmacologic inhibition of YAP signaling or ferroptosis significantly rescues Bnc1 mutation-induced POI. These findings uncover a pathologic mechanism of POI based on BNC1 deficiency and suggest YAP and ferroptosis inhibitors as potential therapeutic targets for POI.

Date: 2022
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DOI: 10.1038/s41467-022-33323-8

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