摘要This study employed Mendelian randomization(MR)analysis to confirm the association between breast cancer and the risk of anxiety and depression,and to explore the molecular mechanisms by which lipid nanoparticles of ketamine(LNP@Ket)modulate these behaviors in a mouse model of breast cancer.Through single-cell transcriptomic analysis,the study aimed to clarify nuclear factor erythroid 2-related factor 2(Nrf2)'s role in the development of anxiety and depression in these mice.Analysis of patient data from genome-wide association study(GWAS)databases supported the link between breast cancer,anxiety,and depression.In vivo experiments demonstrated that treating breast cancer mice with LNP@Ket significantly reduced anxiety and depression behaviors.The synthesis of LNP@Ket and its subsequent analysis highlighted its inhibitory effects on these behaviors.Single-cell transcriptomic sequencing identified key cells and genes affected by LNP@Ket treatment,particularly emphasizing Nrf2.Upregulation of Nrf2 in astrocytes increased the expression of antioxidant enzymes and reduced pro-inflammatory cytokines,alleviating anxiety and depression symptoms by inhibiting neuro-inflammation and neurodegeneration.This comprehensive study highlights the pivotal role of Nrf2 in the therapeutic efficacy of LNP@Ket for treating anxiety and depression in breast cancer mice.