Serine inhibits granulosa cell ferroptosis to maintain ovarian function

Cyclophosphamide (CTX) is a primary medicine for curing breast cancer which often caused premature ovarian insufficiency (POI). Our recent publication revealed that CTX induced POI by promoting the expression of SLC1A4, a transporter of serine efflux, in ovarian granulosa cells (GCs). Here, we reported that there was a closed connection between the reduction of serum serine and ovarian hypofunction in the breast cancer patients treated with CTX or women of childbearing age who were suffered from the staying-up-late. Additionally, we observed that dietary serine supplementation protected mice from CTX-induced POI without altering its anti-breast cancer. Furthermore, we demonstrated that the elevated serine promoted S1P synthesis, and in turn, inhibited the nuclear translocation of Nrf2 and consequent HO-1 expression, to suppress ferroptosis in GCs. Our study revealed that the chemotherapy-induced or idiopathic POI shared the same mechanisms, indicating that serine was a critical factor for maintaining ovarian function. Overall design: Mouse ovarian granulosa cells were stimulated with cyclophosphamide for 24 hours, after which RNA was extracted to analyze gene expression differences between unstimulated and cyclophosphamide-stimulated ovarian granulosa cells.