VDR-Spermidine Axis Protects Against Age-Related Granulosa Cell Dysfunction and Follicular Decline via DNMTs-Mediated p53 Methylation

作者：Haiyun Chen, Qinghe Geng, Qiuyi Wang, Yuanqin Li, Luxi Shangguan, Zhengquan Zhu, Jingwen Zhang, Wang Shuan, Xiaotian Chen, Shanmei Shen, Yanting Wen, Daojuan Wang, Yong Wang · 发表于：International Journal of Biological Sciences · 年份：2026 · DOI：10.7150/ijbs.128631 · 研究领域：Epigenetics and DNA Methylation、Polyamine Metabolism and Applications、Histone Deacetylase Inhibitors Research

). This led to SPD depletion, which in turn inhibited DNA methyltransferase (DNMTs) activity, resulting in hypomethylation of the p53 promoter and activation of the p53/p21 pathway. Crucially, supplementation with either SPD or its upstream methyl donor S-adenosylmethionine (SAM) rescued cVKO and VKO cell aging, improved hormonal profiles and promoted follicular development in cVKO mice. Furthermore, both supplements effectively delayed ovarian aging and improved fertility in naturally aged mice. Our study unveils the Vdr-spermidine-DNMTs axis as a fundamental mechanism safeguarding against ovarian aging, highlighting SPD and SAM as promising therapeutic agents for age-related female infertility.