This study aims to investigate the therapeutic effects and mechanisms of Cistanche phenylethanol glycosides (CPhGs) on depression-like behavior induced by chronic unpredictable mild stress (CUMS) in mice.Mice were randomly divided into control group,model group,high dose CPhGs group (700 mg/kg),middle dose CPhGs group (350 mg/kg),low dose CPhGs group (175 mg/kg),and fluoxetine group (15 mg/kg).After four weeks of corresponding drug interventions,neurobehavioral tests were conducted;enzyme-linked immunosorbent assay was used to detect levels of neurotransmitters in serum,as well as the content of inflammatory factors and mediators in hippocampal tissue.Hematoxylin-eosin and Nissl staining were employed to observe pathological changes in hippocampal tissue.Immunohistochemistry and immunofluorescence methods were used to analyze the density of astrocytes and microglia in the hippocampal tissue of mice,as well as the expression levels of toll-like receptor 4/nuclear factor κB/Nod-like receptor protein 3 (TLR4/NF-κB/NLRP3).Results showed that CPhGs could improve depression-like behavior in mice,increase the preference for sweet water,and reduce immobility time,significantly enhancing the levels of serotonin and dopamine in mouse serum,while inhibiting the expression of inflammatory mediators and factors in the hippocampus.Immunohistochemical analysis indicated that CPhGs could increase the density of astrocytes in the hippocampus,reduce the activation of microglia,and inhibit the expression of NLRP3 inflammasome-related proteins.Immunofluorescence experiments demonstrated that the mechanism through which CPhGs reduce inflammasome formation was by decreasing the activation of the TLR4/NF-κB signaling pathway in hippocampal tissue.In summary,CPhGs exhibit significant antidepressant effects on CUMS-induced depression-like behavior,potentially through the regulation of neurotransmitter levels and inhibition of neuroinflammatory responses,providing experimental evidence for its application in the treatment of depression.