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Increasing evidence confirms that microglia-driven neuroinflammation serves as a core mechanism driving the progression of AD. Mammalian Ste20-like kinase 1 (MST1) plays a crucial regulatory role in apoptosis, immune inflammation, and oxidative stress. Our team\u2019s previous research revealed that MST1 regulates mitochondrial oxidative stress in neurons, contributing to the pathogenesis of AD. Here, we show that MST1 is activated as p-MST1 in the peripheral blood of AD patients, the serum of 5xFAD mice, and the hippocampal and cortical brain tissues of 5xFAD mice, an effect which was associated with microglial pyroptosis under chronic inflammatory stimulation. Knocking down MST1 in hippocampal and cortical tissues of 5xFAD mice improved cognitive deficits, reduced p-tau protein levels, and alleviated neurodegeneration and neuroinflammatory responses. Concurrently, MST1 knockdown suppressed abnormal microglial activation, decreased inflammatory cytokine release, and ultimately mitigated microglial pyroptosis. Mechanistically, we found that MST1 knockdown modulated DPP8 protein expression, thereby regulating the NLRP1\/Caspase-1\/GSDMD-N signaling axis to inhibit microglial pyroptosis and attenuate neuroimmune inflammation. In summary, MST1 knockdown improved AD disease progression by preventing disruption to the immune-inflammatory homeostasis of microglia. Therefore, we propose targeting MST1 as a promising therapeutic strategy to halt neuroinflammation and progression in Alzheimer\u2019s disease.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1186\/s12974-026-03732-3","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T14:17:34Z","timestamp":1770992254000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["MST1 promotes microglial pyroptosis and neuroinflammation in alzheimer\u2019s disease by regulating the novel DPP8\/NLRP1\/Caspase-1\/GSDMD-N axis"],"prefix":"10.1186","volume":"23","author":[{"given":"Dongqing","family":"Cui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangwu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurui","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaiyong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"3732_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12929-019-0524-y","volume":"26","author":"MVF Silva","year":"2019","unstructured":"Silva MVF, Loures CMG, Alves LCV, de Souza LC, Borges KBG, Carvalho MDG. 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