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Objective:Hepatolenticular degeneration(HLD)is an autosomal recessive disorder that manifests as mul-tiorgan damage due to impaired copper(Cu)metabolism.Female patients with HLD often experience reproductive impairments.This study investigated the protective effect of berberine against ovarian dam-age in toxic-milk(TX)mice,a murine model for HLD.Methods:Mice were categorized into control group,HLD TX group(HLD group),penicillamine(Cu chelator)-treated TX group and berberine-treated TX group.Body weight,ovary weight and the number of ovulated eggs were recorded.Follicular morphology and cellular ultrastructure were examined.Total iron,ferrous iron(Fe2+)and trivalent iron(Fe3+)levels,as well as malondialdehyde(MDA),glutathione(GSH)and oxidized glutathione(GSSG),were measured in the ovaries.Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum(ER)stress.Results:Ovarian tissue damage was evident in the HLD group,with a significant increase in ferroptosis and ER stress compared to the control group.This damage was inhibited by treatment with penicillamine,a Cu chelator.Compared with the HLD group,berberine increased the number of ovulations,and improved ovarian morphology and ultrastructure.Further,we found that berberine reduced total iron,Fe2+,MDA and GSSG levels,elevated GSH levels,decreased the expression of the ferroptosis marker pro-tein prostaglandin-endoperoxide synthase 2(PTGS2),and increased glutathione peroxidase 4(GPX4)expression.Furthermore,berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase(PERK)pathway.Conclusion:Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice.Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress.