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

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 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.