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An in vivo model of middle cerebral artery occlusion\/reperfusion (MCAO\/R) in rats and an in vitro oxygen-glucose deprivation\/reoxygenation (OGD\/R) model in BV-2 microglial cells and primary microglia were established. Inhibitors of MST1 (XMU-MP-1) or\/and Drp1 (Mdivi-1), along with genetic approaches including siMST1-mediated knockdown and plasmid-based overexpression, were utilized in the models. The expression and activation of MST1 and Drp1, mitochondrial morphology changes, microglia pro-inflammatory activation makers, pro-inflammatory cytokine release, DNA fragmentation and neurological function were evaluated. The findings indicated that reperfusion or reoxygenation led to a rise in total and phosphorylation levels of MST1 and Drp1. The reperfusion also facilitated the Drp1 translocation toward mitochondria, and resulted in increased mitochondrial morphological changes. MST1 or\/and Drp1 inhibitors decreased p-MST1 and p-Drp1(Ser616) levels, attenuated mitochondrial fission, suppressed microglia pro-inflammatory activation, pro-inflammatory factors release (TNF-\u03b1, IL-6 and IL-1\u03b2). Overall, these effects ultimately mitigated cerebral injury as evidenced by reduced DNA fragmentation, decreased cerebral infarct volumes, and improved neurological function. Combined inhibitors further exerted ameliorative effects on the above-mentioned parameters. In the in vitro experiments, siMST1 knockdown attenuated p-Drp1(Ser616) expression and suppressed microglia pro-inflammatory activation under OGD\/R conditions. These protective effects were reversed by Drp1 overexpression. These findings indicate that p-MST1 drives microglia pro-inflammatory activation via promoting the p-Drp1(Ser616)-mediated excessive mitochondrial fission during CIRI.<\/jats:p>","DOI":"10.1038\/s41598-026-57741-6","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T16:13:20Z","timestamp":1781367200000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MST1\/Drp1 axis mediates microglia pro-inflammatory activation following cerebral ischemia-reperfusion injury"],"prefix":"10.1038","volume":"16","author":[{"given":"Yao","family":"Mu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meihan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehua","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaofeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"57741_CR1","doi-asserted-by":"publisher","first-page":"155701","DOI":"10.1016\/j.phymed.2024.155701","volume":"130","author":"Z Ou","year":"2024","unstructured":"Ou, Z. et al. 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