Abstract
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.
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Data availability
The RNA-seq data in this study have been deposited in the GEO database under accession number GSE314714. The amino acid-targeted metabolomics data in this study have been deposited in the MetaboLights database under accession number MTBLS13561. All other relevant source data supporting the key findings of this study are provided in this paper. Source data are provided with this paper.
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Acknowledgements
We extend a special thanks to the Laboratory Animal Center of the Institute of Translational Medicine, Nanchang University. We especially thank Suzhou PANOMIX Biomedical Tech. Co. Ltd. for its contribution to amino acid-targeted metabolomic sequencing. We especially thank Novogene for its contribution to transcriptomic sequencing. This work was supported by the National Key Research and Development Program of China (2022YFA1104300 to Hongbo Xin and Keyu Deng), the National Natural Science Foundation of China (82470454 and 82270302 to Hongbo Xin, 81970256 to Keyu Deng and 82560089 to Lingfang Wang), the Natural Science Foundation of Jiangxi Province, China (2025BAC240701 to Lingfang Wang), and the Jiangxi Province Key Laboratory of Bioengineering Drugs (No. 2024SSY07061).
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H.B.X. and K.Y.D. led the project and contributed to the conception and design of the study, data analysis and interpretation, and manuscript revising. H.C.G. performed the most experiments and data analysis. Y.Q.Z., Y.W.Z., Y.K.W., H.T.L., J.Q.W., S.Q.T., and X.Y.W. performed animal models and cell experiments. D.S.L., L.Q.C., Z.H.L., and Y.Y.W. were responsible for clinical sample collection and patient testing result collection. Y.Q.Z. was responsible for clinical sample metabolome sequencing and result analysis. H.C.G. and L.F.W. wrote the manuscript draft. All authors read and approved the final version of the manuscript.
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Gu, HC., Zhuo, YQ., Wang, LF. et al. Serine inhibits granulosa cell ferroptosis to maintain ovarian function. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68440-1
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DOI: https://doi.org/10.1038/s41467-026-68440-1
