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However, the role of SFXN1 in cerebral ischemia\u2013reperfusion (I\/R)\u2010induced neuronal death remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We employed in\u00a0vivo injury models of transient middle cerebral artery occlusion (tMCAO) and in\u00a0vitro models of lipopolysaccharide (LPS) stimulation and oxygen\u2013glucose deprivation\/reperfusion (OGD\/R) to investigate the regulatory effects of SFXN1 on neuroinflammation and brain injury. Western blotting, immunofluorescence, and real\u2010time quantitative PCR were utilized to assess SFXN1 expression, proinflammatory signaling pathways activation, and cytokine levels in\u00a0vitro. Cerebral infarction was evaluated using 2,3,5\u2010triphenyltetrazolium chloride (TTC) staining and Nissl staining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SFXN1 expression was upregulated following cerebral I\/R injury. Both neurons and microglia exhibited increased SFXN1 expression after oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) treatment. SFXN1 knockdown reduced OGD\/R\u2010induced neuronal death and alleviated cerebral I\/R injury. Additionally, conditioned medium from SFXN1\u2010knockdown microglia reduced neurotoxicity in\u00a0vitro. Mechanistically, SFXN1 induced mitochondrial dysfunction and neuronal death after OGD\/R in an iron\u2010independent manner. Furthermore, SFXN1 promoted the production of proinflammatory cytokines by promoting NF\u2010\u03baB activation, partially through iron transport in microglia after OGD\/R.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study reveals the novel role of SFXN1 in exacerbating cerebral I\/R injury by reducing neuronal survival through the modulation of mitochondrial function and promotion of microglia\u2010mediated neuroinflammation via NF\u2010\u03baB activation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70457","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:49:52Z","timestamp":1748306992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>SFXN1<\/scp> Reduction Alleviates Cerebral Ischemia\u2013Reperfusion Injury by Promoting Neuronal Survival and Reducing 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