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Drivers involved remain incompletely understood. Sigma non\u2010opioid intracellular receptor 1 (S1R) is involved in brain inflammation. This study investigates how S1R regulates neuroinflammation associated with depression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Using integrated machine learning and single\u2010cell transcriptomics, a key gene implicated in microglial dysfunction in depression was identified. Its relevance was examined in a lipopolysaccharide (LPS)\u2010induced mouse model of depression and LPS\u2010stimulated BV\u20102 cells. Further, targeted knockdown or overexpression of this gene was performed on medial prefrontal cortex (mPFC) microglia, followed by integrated behavioural, cellular and molecular analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Plxdc2<\/jats:italic>\n                      was the key gene up\u2010regulated at both transcriptional and protein levels in blood and depression\u2010susceptible brain regions. Single\u2010cell RNA sequencing confirmed its specific enrichment in microglia, particularly within inflammatory gene sets related to N\u2010linked glycosylation (NLG). LPS\u2010treated mice, depressive\u2010like behaviours were accompanied by elevated expression of Plxdc2 and the glycosylation\u2010related enzyme \u03b2\u20101,4\u2010galactosyltransferase 1 in mPFC microglia. The S1R agonist Hypidone hydrochloride (YL\u20100919) or conditional knockdown of\n                      <jats:italic>Plxdc2<\/jats:italic>\n                      , reversed these molecular changes, reduced neuroinflammation and alleviated depressive\u2010like behaviours. Analysis demonstrated that overexpressing\n                      <jats:italic>Plxdc2<\/jats:italic>\n                      in mPFC microglia activated the JAK2\u2010STAT1 pathway, enhanced NLG, shifting microglia towards a pro\u2010inflammatory phenotype, worsening deficits in synaptic plasticity and induced depressive\u2010like behaviour. These were reversible by the NLG inhibitor tunicamycin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Plxdc2 promotes depressive\u2010like behaviours by dysregulating NLG\u2010mediated inflammatory in microglia. S1R activation has a therapeutic effect by inhibiting this pathway, positioning the S1R\u2010Plxdc2 axis as a potential target for modulating microglial function in inflammation\u2010related depression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70598","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:08:17Z","timestamp":1784099297000},"page":"5914-5934","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Activation of sigma non\u2010opioid intracellular receptor 1 (S1R) receptor inhibits plexin domain containing 2 (Plxdc2) driven microglial inflammation to ameliorate depressive\u2010like behaviours in mice"],"prefix":"10.1111","volume":"183","author":[{"given":"Jing\u2010Ya","family":"Wang","sequence":"first","affiliation":[{"name":"Academy of Military Medical Sciences  Beijing 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