Abstract
Advanced maternal age is a key factor in female infertility, primarily due to declines in ovarian reserve and oocyte quality. However, the metabolic mechanisms underlying reproductive aging remain unclear. Here, we show that uridine levels in the plasma and ovaries of aged mice are significantly reduced compared with young controls. Building on this, we find that uridine supplementation significantly improves meiotic maturation, fertilization, and early embryonic development of aged oocytes, both in vivo and in vitro. Further microtranscriptomic analyses reveal that uridine enhances oocyte quality by inhibiting ferroptosis and enhancing mitochondrial function. Moreover, by integrating Limited Proteolysis-Small Molecule Mapping, western blotting and siRNA-based functional assays, we identify that uridine binds to poly(rC)-binding protein 1, thereby suppressing ferroptosis and preserving mitochondrial function. Collectively, these findings demonstrate that uridine supplementation improves fertility in aged female mice and provide mechanistic insight into ferroptosis in oocyte aging.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant No. 82288102, 82502000, U24A20437) received by Y.L.Y., C.J.Y. and X.B.; the Postdoctoral Fellowship Program of CPSF (Grant No. GZC20240070) received by C.J.Y.; the Peking University Third Hospital Fund for Interdisciplinary Research (Grant No. BYSYJC2023001) received by Y.P.; Clinical Medicine Plus X-Young Scholars Project, Peking University, the Fundamental Research Funds for the Central Universities (Grant No. PKU2024LCXQ005) received by Y.P.; the Peking University Medicine Sailing Program for Young Scholars’ Scientific & Technological Innovation (Grant No. BMU2025YFJHPY028) received by C.J.Y.; the Department of Obstetrics and Gynecology, Peking University Third Hospital (Grant No. BYSYSZKF2023029) received by Y.P.; We thank Dr. Jurrien Dean for providing antibodies. We thank Dr. Cong Rao, Dr. Meng Li, Dr. Chunxiao Liu, Dr. Hongjuan Niu and M.S. Yingrui Li for their helpful comments and technical assistance. And we thank BioRender (BioRender.com) for providing the graphical tools used to create the schematics in this study (Fig. 1b, Fig. 4a, Fig. 6a and Supplementary Fig. S9).
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Chen, J., Shen, J., Li, D. et al. Uridine restores oocyte quality and mitigates female reproductive aging by inhibition of ferroptosis in mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72406-8
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DOI: https://doi.org/10.1038/s41467-026-72406-8
