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Oxytocin (OT), a neuropeptide critical for social behavior and immune regulation, is upregulated during CSS, though its underlying mechanisms remain unclear. This study investigates the role of OT in splenic immune modulation using a murine model of CSS. Behavioral evaluations, serum oxytocin quantification, and splenic immunophenotypic analysis were performed. Splenic denervation confirmed OT\u2019s neuromodulatory role, whereas OTR antagonism revealed its endocrine function. CSS\u2010induced OT elevation was associated with immunosuppression, characterized by increased Foxp3\u207a regulatory T cells and reduced CD4\u207a T and CD19\u207a B cells. OT also modulated macrophage polarization, inhibiting M1\u2010like (pro\u2010inflammatory) and enhancing M2\u2010like (anti\u2010inflammatory) phenotypes. Denervation or pharmacological blockade of OT signaling partly reversed CSS\u2010induced splenic immunosuppression but adversely affected survival in CSS\u2010exposed mice. Additionally, denervation or OTR antagonism reduced the mice's response to social defeat, as shown by decreased social avoidance behavior. These findings suggest that OT\u2010mediated immunosuppression likely represents a compensatory mechanism in response to chronic social stress. Targeting the OT\u2013immune axis could offer innovative therapeutic approaches for stress\u2010associated disorders by restoring immune homeostasis while maintaining behavioral integrity.<\/jats:p>","DOI":"10.1002\/advs.202500849","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T06:16:05Z","timestamp":1745648165000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Oxytocin\u2010Mediate Modulation of Splenic Immunosuppression in Chronic Social Stress Through Neuroendocrine Pathways"],"prefix":"10.1002","volume":"12","author":[{"given":"Yi\u2010Shu","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Anatomy and Histology &amp; Embryology Neuroscience School of Basic Medical Sciences Lanzhou University  Lanzhou Gansu 730000 P. R. 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