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Accumulating evidence positions neuroinflammation, driven by glial dysfunction, peripheral\u2010central immune crosstalk, and associated cellular stress pathways as a pivotal upstream mechanism in the pathogenesis of depression, contributing to both neurotransmitter dysregulation and impaired synaptic plasticity. This review examines the integrative role of the Sigma\u20101 receptor (Sig\u20101R), a ligand\u2010operated chaperone predominantly localized at the mitochondria\u2010associated endoplasmic reticulum membrane (MAM), as a promising therapeutic target for mitigating this neuroinflammatory cascade. We systematically synthesize preclinical evidence demonstrating that pharmacological activation of Sig\u20101R produces broad anti\u2010neuroinflammatory effects, including the promotion of microglial homeostasis and a shift toward an anti\u2010inflammatory phenotype, attenuation of reactive astrogliosis, suppression of key pro\u2010inflammatory signaling hubs such as NF\u2010\u03baB and the NLRP3 inflammasome, and mitigation of oligodendrocyte dysfunction. Beyond immunomodulation, Sig\u20101R activation alleviates endoplasmic reticulum stress, enhances autophagic and mitophagic clearance, supports mitochondrial bioenergetics, and strengthens endogenous antioxidant defenses. Together, these actions disrupt the vicious cycle linking cellular stress, inflammation, and synaptic impairment. We also evaluate advances in representative Sig\u20101R agonists and review available clinical trial data, including results on the novel multi\u2010target agent AXS\u201005. Genetic and pharmacological loss\u2010of\u2010function studies further emphasize the essential role of Sig\u20101R in mood regulation and stress resilience. In summary, the Sigma\u20101 receptor serves as a key regulator of cellular homeostasis and adaptation. Its agonists represent a promising therapeutic strategy that moves beyond symptomatic monoaminergic modulation to mechanistically target the core inflammatory and proteostatic disturbances in depression, offering the potential for improved treatment efficacy.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70490-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70490","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T10:26:04Z","timestamp":1781000764000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting Neuroinflammation in Depression: The Integrative Role of Sigma\u20101 Receptor Modulation"],"prefix":"10.1111","volume":"170","author":[{"given":"Jing\u2010Ya","family":"Wang","sequence":"first","affiliation":[{"name":"Academy of Military Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De\u2010Yi","family":"Yang","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences  Beijing China"},{"name":"School of Clinical Pharmacy Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4643-4926","authenticated-orcid":false,"given":"Peng","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-025-10231-4"},{"key":"e_1_2_13_3_1","first-page":"1","article-title":"Targeting Endoplasmic Reticulum Stress and Protein Misfolding in Schizophrenia: The Emerging Promise of Sigma\u20101 Receptor Agonists","volume":"242","author":"Ahmed M. 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