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Ypel5 preserves female fertility by regulating folliculogenesis and oocyte maturation

Cell Death & Differentiation (2026) Cite this article

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Abstract

Maintaining the primordial follicle pool and precisely regulating folliculogenesis are critical for female fertility. Despite advances in understanding ovarian development, the molecular mechanisms safeguarding follicle survival and oocyte maturation remain incompletely defined. Here, we identify YPEL5 as an essential regulator of folliculogenesis and oocyte development. Using an oocyte-specific conditional knockout (cKO) mouse model, we demonstrate that Ypel5 deletion causes complete female infertility, characterized by accelerated depletion of the primordial follicle pool, defective antral follicle formation, and impaired oocyte maturation. Loss of Ypel5 results in increased DNA damage, disrupted mitochondrial homeostasis, elevated oxidative stress, and ultimately triggers apoptotic depletion of primordial follicle oocytes. Moreover, Ypel5-deficient oocytes exhibit severe abnormalities in spindle organization and mitochondrial distribution, culminating in defective oocyte maturation. Collectively, these findings establish YPEL5 as a critical regulator of follicle development and oocyte maturation, and provide mechanistic insights into the molecular basis of female infertility.

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Fig. 1: Expression and subcellular localization of YPEL5 during oocyte growth and maturation in mice.
The alternative text for this image may have been generated using AI.
Fig. 2: Oocyte-specific deletion of Ypel5 induces female infertility and oocyte maturation defects.
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Fig. 3: Oocyte-specific deletion of Ypel5 disrupts folliculogenesis.
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Fig. 4: Transcriptome alterations in Ypel5-cKO primordial follicle oocytes at PD9.
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Fig. 5: Loss of Ypel5 triggers oocyte intrinsic defects.
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Fig. 6: Ypel5 deficiency in oocytes impairs oocyte quality.
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Fig. 7: Schematic model illustrating the molecular events leading to POI in the absence of YPEL5.
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Data availability

The Smart-seq2 transcriptomic raw data in this study have been deposited to Genome Sequence Archive (GSA) with the accession number: CRA026221.

Code availability

This study did not generate original code. All computational analyses were performed using publicly available tools, as described in the Methods section. All data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to Prof. Hengyu Fan (Zhejiang University) for providing the Gdf9-Cre transgenic mouse line.

Funding

This work was supported by the National Natural Science Foundation of China (82288102 to LY and JQ, 82125013 to LY, 82201838 to PY and 82401954 to QG); Clinical Medicine Plus X—Young Scholars Project of Peking University and the Fundamental Research Funds for the Central Universities (PKU2025PKULCXQ036 to PY).

Author information

Author notes

  1. These authors contributed equally: Ling Ding, Qianying Guo, Yao Li, Fanqing Xu.

Authors and Affiliations

  1. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China

    Ling Ding, Qianying Guo, Yao Li, Fanqing Xu, Qiang Liu, Shaogang Qin, Ying Kuo, Jie Qiao, Peng Yuan & Liying Yan

  2. National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China

    Ling Ding, Qianying Guo, Yao Li, Fanqing Xu, Qiang Liu, Shaogang Qin, Ying Kuo, Jie Qiao, Peng Yuan & Liying Yan

  3. State Key Laboratory of Female Fertility Promotion, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China

    Ling Ding, Qianying Guo, Yao Li, Fanqing Xu, Qiang Liu, Shaogang Qin, Ying Kuo, Jie Qiao, Peng Yuan & Liying Yan

  4. Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China

    Ling Ding, Qianying Guo, Yao Li, Fanqing Xu, Qiang Liu, Shaogang Qin, Ying Kuo, Jie Qiao, Peng Yuan & Liying Yan

  5. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China

    Ling Ding, Qianying Guo, Yao Li, Fanqing Xu, Qiang Liu, Shaogang Qin, Ying Kuo, Jie Qiao, Peng Yuan & Liying Yan

  6. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

    Jie Qiao

  7. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Jie Qiao

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  1. Ling Ding
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Contributions

These authors contributed equally: Ling Ding, Qianying Guo, Yao Li and Fanqing Xu. LY, PY, and JQ conceived and supervised the project. LD, QG, YL and FX prepared the figures and wrote the manuscript. LD, QG, and QL conducted mouse crossing and genotyping. QG and LD performed RNA-seq of mouse oocytes, immunofluorescence staining, western blotting, immunohistochemistry, and RT-qPCR experiments. QG, LD and SQ collected primordial follicles. YL and FX conducted the bioinformatics analysis with help from PY and YK.

Corresponding authors

Correspondence to Jie Qiao, Peng Yuan or Liying Yan.

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All animal experiments were conducted in accordance with the guidelines of the Institutional Animal Welfare and Ethics Committee of Peking University Third Hospital (license number: A2022090).

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Ding, L., Guo, Q., Li, Y. et al. Ypel5 preserves female fertility by regulating folliculogenesis and oocyte maturation. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01744-3

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