tRF-Gly-GCC in Atretic Follicles Promotes Ferroptosis in Granulosa Cells by Down-Regulating MAPK1

Follicle development refers to the process in which the follicles in the ovary gradually develop from the primary stage to a mature state, and most primary follicles fail to develop normally, without forming a dense granular cell layer and cell wall, which is identified as atretic follicles. Granulosa cells assist follicle development by producing hormones and providing support, and interference in the interaction between granulosa cells and oocytes may lead to the formation of atretic follicles. Ferroptosis, as a non-apoptotic form of death, is caused by cells accumulating lethal levels of iron-dependent phospholipid peroxides. Healthy follicles ranging from 4 to 5 mm were randomly divided into two groups: a control group (DMSO) and treatment group (10 uM of ferroptosis inducer erastin). Each group was sequenced after three repeated cultures for 24 h. We found that ferroptosis was associated with atretic follicles and that the in vitro treatment of healthy follicles with the ferroptosis inducer erastin produced a phenotype similar to that of atretic follicles. Overall, our study elucidates that tRF-1:30-Gly-GCC-2 is involved in the apoptosis and ferroptosis of GCs. Mechanistically, tRF-1:30-Gly-GCC-2 inhibits granulosa cell proliferation and promotes ferroptosis by inhibiting Mitogen-activated protein kinase 1 (MAPK1). tRF-1:30-Gly-GCC-2 may be a novel molecular target for improving the development of atretic follicles in ovarian dysfunction. In conclusion, our study provides a new perspective on the pathogenesis of granulosa cell dysfunction and follicular atresia.