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Antioxidants
Volume 14
Issue 6
10.3390/antiox14060749
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Ferroptosis and Sterol Biosynthesis Dysregulation in Granulosa Cells of Patients with Diminished Ovarian Reserve

by
Yang Yu
1,2,†,
Yali Shan
1,2,†,
Jiani Lu
3,
Yexing Xian
4,
Zhengshan Tang
2,
Xinyu Guo
4,
Yan Huang
4,* and
Xin Ni
1,2,5,*
1
Department of Gynecology and Obstetrics, Xiangya Hospital Central South University, Changsha 410000, China
2
International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha 410000, China
3
Department of Rehabilitation, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
4
Center of Reproductive Medicine, General Hospital of Southern Theatre Command, Guangzhou 510010, China
5
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410000, China
*
Authors to whom correspondence should be addressed.
†
These authors equally contribute to this work.
Antioxidants 2025, 14(6), 749; https://doi.org/10.3390/antiox14060749
Submission received: 28 April 2025 / Revised: 9 June 2025 / Accepted: 12 June 2025 / Published: 17 June 2025
Versions Notes

Abstract

Granulosa cell (GC) dysfunction contributes to diminished ovarian reserve (DOR). We collected GC and follicular fluid samples from the patients of normal ovarian reserve (NOR) and DOR. RNA-seq of GCs showed that cholesterol/sterol metabolism and biosynthesis and extracellular matrix organization were enriched in the DOR group. Metabolomics of follicular fluid revealed enrichment in steroid hormone biosynthesis, tryptophan metabolism, and fatty acid β-oxidation in DOR. The apoptosis rate was increased, whereas the proliferative rate was decreased in GCs of DOR. The Prussian blue staining rate was increased whilst GPX4 and SLC7A11 expression were downregulated in GCs of DOR. Mitochondrial morphology displayed the features of ferroptosis in GCs of DOR. FSHR, CYP19A1, NR5A1, and phosphorylated CREB levels were substantially downregulated in GCs, accompanied by increased androgen levels in follicular fluids in DOR. The key factors linked to the mevalonate pathway, HMGCR, SQLE, and SREBF2, were robustly increased in DOR. FSHR and NR5A1 levels were correlated with CYP19A1 levels, whilst CYP19A1 levels were positively correlated with GPX4 and SLC7A11 levels. Our findings indicate ferroptosis and dysregulation of cholesterol/sterol metabolism and biosynthesis occurrence in GCs of DOR, which might be associated with reduced FSHR signaling and decreased conversion of androgen to estrogen.
Keywords: diminished ovarian reserve; granulosa cells; ferroptosis; cholesterol synthesis; steroid hormone synthesis; aromatase. diminished ovarian reserve; granulosa cells; ferroptosis; cholesterol synthesis; steroid hormone synthesis; aromatase.

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MDPI and ACS Style

Yu, Y.; Shan, Y.; Lu, J.; Xian, Y.; Tang, Z.; Guo, X.; Huang, Y.; Ni, X. Ferroptosis and Sterol Biosynthesis Dysregulation in Granulosa Cells of Patients with Diminished Ovarian Reserve. Antioxidants 2025, 14, 749. https://doi.org/10.3390/antiox14060749

AMA Style

Yu Y, Shan Y, Lu J, Xian Y, Tang Z, Guo X, Huang Y, Ni X. Ferroptosis and Sterol Biosynthesis Dysregulation in Granulosa Cells of Patients with Diminished Ovarian Reserve. Antioxidants. 2025; 14(6):749. https://doi.org/10.3390/antiox14060749

Chicago/Turabian Style

Yu, Yang, Yali Shan, Jiani Lu, Yexing Xian, Zhengshan Tang, Xinyu Guo, Yan Huang, and Xin Ni. 2025. "Ferroptosis and Sterol Biosynthesis Dysregulation in Granulosa Cells of Patients with Diminished Ovarian Reserve" Antioxidants 14, no. 6: 749. https://doi.org/10.3390/antiox14060749

APA Style

Yu, Y., Shan, Y., Lu, J., Xian, Y., Tang, Z., Guo, X., Huang, Y., & Ni, X. (2025). Ferroptosis and Sterol Biosynthesis Dysregulation in Granulosa Cells of Patients with Diminished Ovarian Reserve. Antioxidants, 14(6), 749. https://doi.org/10.3390/antiox14060749

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