Serine inhibits granulosa cell ferroptosis to maintain ovarian function.

Cyclophosphamide (CTX) is a primary medicine for curing breast cancer which often causes premature ovarian insufficiency (POI). Our recent publication reveals that CTX induces POI by promoting the expression of SLC1A4, a transporter of serine efflux, in ovarian granulosa cells (GCs). Here, we report that there is 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 are suffered from the staying-up-late. Additionally, we observe that dietary serine supplementation protects mice from CTX-induced POI without altering its anti-breast cancer. Furthermore, we demonstrate that the elevated serine promotes S1P synthesis, and in turn, inhibits the nuclear translocation of Nrf2 and consequent HO-1 expression, to suppress ferroptosis in GCs. Our study reveals that the chemotherapy-induced or idiopathic POI share the same mechanisms, indicating that serine is a critical factor for maintaining ovarian function.