Gut Microbiota‐Derived Short‐Chain Fatty Acids Driven by N‐Carbamylglutamate Alleviates Premature Ovarian Failure Through Suppressing Ferroptosis

Premature ovarian failure (POF) is characterized by abnormal ovulatory and ovarian endocrine functions in women before the age of 40, and is a leading cause of female infertility. Currently, effective drug treatments for this condition remain lacking in clinical practice. N-Carbamylglutamate (NCG) is a bioactive substance with anti-inflammatory and antioxidant properties; however, whether it can alleviate premature ovarian failure (POF) remains unclear. In this study, we utilized a cyclophosphamide (Cy)-induced POF model, combined with network pharmacology and in vivo validation, to investigate the potential effects and underlying mechanisms of NCG on POF. Our results revealed that ovarian aging progresses alongside activated ferroptosis. NCG treatment effectively reversed the pathological phenotypes of POF and inhibited ferroptosis in the ovary. These beneficial effects were mediated by activation of the NRF2/xCT/GPX4 axis. Furthermore, fecal microbiota transplantation (FMT) experiments validated that the gut microbiota serves as a key mediator of the POF-alleviating efficacy of NCG. 16S rDNA sequencing revealed that NCG modulated the gut microbiota composition in POF mice and increased the relative abundance of Lactobacillus. Additionally, targeted metabolomics analysis showed enrichment of short-chain fatty acids (SCFAs) in colonic contents and serum, with significantly elevated total SCFAs levels in ovarian tissues following NCG treatment. Mechanistically, the inhibition of ferroptosis mediated by gut microbiota-derived SCFAs represents a critical mechanism underlying the alleviation of POF. Specifically, the anti-ferroptotic activity of NCG depends on its capacity to promote SCFA biosynthesis, thereby activating the NRF2/xCT/GPX4 axis and ultimately exerting a POF-alleviating effect. These findings deepen our understanding of the gut-ovary axis in reproductive aging.