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V-type immunoglobulin domain\u2013containing suppressor of T cell activation (VISTA), a novel inhibitory immune checkpoint, participates in myeloid cell metabolism. This study aims to investigate the molecular mechanisms of VISTA\u2019s protective effects on CIRI by modulating microglial metabolism. In this study, differentially expressed genes (DEGs) were extracted from GSE77986 to identify hub gene VISTA. Transient middle cerebral artery occlusion (tMCAO) and oxygen\u2013glucose deprivation and reoxygenation (OGD\/R) were conducted to mimic CIRI. AAVMG1.2-VSIR was injected intracerebroventricularly into Cx3cr1<jats:sup>Cre<\/jats:sup> mice, while over-expression plasmids were transfected into BV2 to intervene VISTA. The mice underwent LONGA scoring, H&amp;E, Nissl, and TTC staining. Western blot and qRT-PCR were conducted for VISTA, IL-6, TNF\u03b1, IL-1\u03b2, and IL-10. Microglial proliferation was assessed by Edu staining and CCK8. RNA-sequencing (RNA-seq) analysis was used to investigate downstream pathways. Tricarboxylic acid (TCA) cycle intermediates were measured using ELISA. ACOD1\/I\u03baB\u03b1\/NF-\u03baB pathway was validated by Western blot. Eight DE-ICGs were identified through differential analysis, with VSIR exhibiting the highest expression. Additionally, VISTA was found decreased in microglia around the infarction site. Compared with CIRI group, VISTA reduced the infarct volume, improved neurological deficit, and decreased IL-6, TNF\u03b1, and IL-1\u03b2, while increasing IL-10, and suppressing microglia proliferation. RNA-seq showed that the DEGs primarily participated in microglial glucose metabolism and the I\u03baBa\/NF-\u03baB pathway. VISTA promoted ACOD1 expression and itaconate (ITA). The protective function on CIRI and inhibitory effect on I\u03baBa\/NF-\u03baB of VISTA were abrogated by ACOD1 knockdown.<\/jats:p>","DOI":"10.1007\/s12035-025-05106-x","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T02:55:24Z","timestamp":1750301724000},"page":"13430-13448","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["VISTA Alleviates Microglia-Mediated Neuroinflammation After Cerebral Ischemia\u2013Reperfusion Injury via Regulating ACOD1\/Itaconic Acid Metabolism"],"prefix":"10.1007","volume":"62","author":[{"given":"Yilei","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"issue":"2","key":"5106_CR1","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1161\/STROKEAHA.124.048137","volume":"56","author":"Y Wang","year":"2025","unstructured":"Wang Y, Mulder IA, Westendorp WF et al (2025) Immunothrombosis in acute ischemic stroke. 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