Disruption of Gut Microbiota-Mediated De Novo NAD+ Synthesis Contributes to the Development of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a severe disorder that compromises female ovarian health and elevates the risk of various diseases, including endometrial Cancer. The pathogenesis of PCOS remains poorly understood, which has hindered the development of effective interventions. In this study, it is demonstrated that patients with PCOS exhibit significant gut dysbiosis. FMT from PCOS patients (P-FMT) into mice induced PCOS-associated symptoms and histological alterations. Notably, both PCOS patients and P-FMT mice exhibit distinct metabolic profiles in the gut, suggesting a gut microbiota-mediated metabolic reprogramming. Furthermore, impaired tryptophan metabolism, particularly reduced levels of 3-hydroxyanthranilic acid (3-HAA), is observed in both PCOS patients and P-FMT mice. Administration of 3-HAA to mice alleviated DHEA-induced PCOS. Mechanistically, 3-HAA promoted NAD⁺ synthesis via the de novo biosynthesis pathway, thereby inhibiting DHEA-induced Ferroptosis by modulating the mitochondrial DNA-cGAS-STING axis. Collectively, these findings reveal the critical role of gut microbiota-mediated NAD⁺ synthesis in the pathogenesis of PCOS, underscoring the potential of targeting gut microbiota and NAD⁺ homeostasis as a therapeutic strategy for PCOS prevention and management.

3‐HAA; NAD+; PCOS; ferroptosis; gut microbiota.