Uridine restores oocyte quality and mitigates female reproductive aging by inhibition of ferroptosis in mice

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 are still poorly understood. 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, enhancing mitochondrial function and removing excessive reactive oxygen species (ROS). Moreover, integrating Limited Proteolysis-Small Molecule Mapping (LiP-SMap), surface plasmon resonance (SPR) analyses and siRNA-based functional assays, we identify that uridine binds Poly(rC)-binding protein 1 (PCBP1), thereby suppressing ferroptosis and preserving mitochondrial function. In conclusion, this study demonstrates that uridine supplementation can effectively improve fertility of aged female mice. Our research also provides important insights into the role of ferroptosis in oocyte aging, thereby advancing our understanding of reproductive aging mechanisms.

母体高龄是女性不孕症的关键影响因素，主要源于卵巢储备功能下降与卵母细胞质量降低。然而，目前学界对生殖衰老背后的代谢调控机制仍知之甚少。本研究发现，与年轻对照组小鼠相比，老年小鼠血浆与卵巢中的尿苷水平显著降低。基于此发现，本研究证实，无论在体内还是体外环境中，补充尿苷均可显著改善老年卵母细胞的减数分裂成熟、受精能力以及早期胚胎发育潜能。进一步的微转录组学分析显示，尿苷可通过抑制铁死亡（ferroptosis）、增强线粒体功能以及清除过量活性氧（ROS）来提升卵母细胞质量。此外，本研究整合有限蛋白水解-小分子图谱分析（Limited Proteolysis-Small Molecule Mapping, LiP-SMap）、表面等离子体共振（surface plasmon resonance, SPR）实验以及基于小干扰RNA（small interfering RNA, siRNA）的功能验证实验，证实尿苷可结合多聚胞嘧啶结合蛋白1（Poly(rC)-binding protein 1, PCBP1），进而抑制铁死亡并维持线粒体功能。综上，本研究证实补充尿苷可有效提升老年雌性小鼠的生育能力。本研究同时为铁死亡在卵母细胞衰老中的作用提供了重要见解，进而推动了学界对生殖衰老机制的认知。