Sphingosine 1-phosphate alleviates radiation-induced ferroptosis in ovarian granulosa cells by upregulating glutathione peroxidase 4.

Ferroptosis is a form of cell death caused by the accumulation of lipid peroxidation products due to abnormal iron metabolism. However, it remains unknown whether ferroptosis participates in the process of radiation-induced ovarian injury. Sphingosine-1-phosphate (S1P) is an important bioactive sphingolipid that has a protective effect on ovarian injury. The present study aims to determine whether X-ray radiation induces ferroptosis in the ovarian granulosa KGN cell line, and explore the potential effect of S1P and its mechanism in radiation-induced ferroptosis. The results indicated that irradiation reduced the viability of KGN cells, altered the mitochondrial morphology, induced the intracellular accumulation of iron ions, increased oxidative stress, and induced lipid peroxidation. Furthermore, the radiation exposure triggered the ferroptosis in KGN cells. S1P can alleviate radiation-induced ferroptosis. Furthermore, the protective effect of S1P was reversed after the application of siRNA to interfere with the glutathione peroxidase 4 expression. Ferroptosis might be pervasive in radiation-induced ovarian injury, and S1P may serve as a potential therapeutic approach to protect against the toxic effect of radiation in female gonads by inhibiting ferroptosis.