HuMSCs-derived exosomal YBX1 participates in oxidative damage repair in granulosa cells by stabilizing COX5B mRNA in an m5C-dependent manner

作者：Xiaolan Zhu, Man Lu, Wenxin Li, Lin Li, Yueqin Liu, Jiamin Zhou, Junyu Shang, Xuyan Shi, Jingjing Lu, Jie Xing, Mengxue Zhang, Shijie Zhao, Dan Zhao · 发表于：International Journal of Biological Macromolecules · 年份：2025 · DOI：10.1016/j.ijbiomac.2025.143288 · 被引用次数：8 · 研究领域：RNA modifications and cancer、RNA Research and Splicing、RNA regulation and disease

Mitochondrial dysfunction and cell senescence are triggered by reactive oxygen species (ROS) in granulosa cells (GCs), leading to premature ovarian insufficiency (POI). Human umbilical cord mesenchymal stem cell-derived exosome (HuMSCs-Ex, H-Ex)-based treatments have been shown to alleviate ROS-induced POI, but knowledge about the underlying therapeutic mechanisms is limited. Here, we observed that the 5-methylcytosine (m5C) RNA methyltransferase tRNA aspartic acid methyltransferase 1 (TRDMT1) promoted the translation of COX subunit 5B (COX5B) in a manner dependent on its catalytic activity and downstream m5C reader Y-box binding protein 1 (YBX1), which was decreased in prematurely senescent GCs but abundant in H-Ex. Mechanistically, YBX1 released by H-Ex recognizes the TRDMT1-mediated m5C modification of COX5B and directly binds to COX5B C-153 via LYS-92, thereby reducing ROS accumulation and improving mitochondrial function in GCs under oxidative stress, providing new insights into the theoretical basis for the great clinical potential of H-Ex in the treatment of POI.