A New Food Supplement Product Containing Ergothioneine Protects Against Cyclophosphamide‐Induced Primary Ovarian Insufficiency in Rats

ABSTRACT Primary ovarian insufficiency (POI) is characterized by disrupted estrous cycles, impaired folliculogenesis, oxidative stress, and inflammation. In this study, a cyclophosphamide (CTX)‐induced POI rat model was used to evaluate the protective effects of a nutraceutical formula (including ergothioneine, Coenzyme Q10, pyrroloquinoline quinone, hydroxytyrosol, and vitamin E) at different doses. CTX markedly prolonged the estrous cycle, reduced estrus duration, decreased ovarian weight, impaired follicular development, and elevated granulosa cell apoptosis. CTX induced oxidative stress, as evidenced by reduced catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content, alongside increased malondialdehyde (MDA) in ovarian tissue. Interventions with the product restored estrous cyclicity, increased ovarian weight, improved primordial follicle counts, and reduced atretic follicles and granulosa cell apoptosis. Hormonal balance was partially normalized, with increased E 2 and AMH and reduced LH and FSH levels. Oxidative stress markers improved significantly, with higher CAT, SOD, and GSH levels and reduced MDA concentrations. Inflammatory cytokine analysis revealed that EGT and the low‐dose product reduced TNF‐α, IL‐6, and IL‐1β in skin tissue. These findings suggest that the nutraceutical formula confers multi‐targeted protection against CTX‐induced POI with improved ovarian function, decreased oxidative stress in the ovary, and increased the expression of genes involved in mitochondrial biogenesis.