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We have recently reported that ketosis-stabilized HIF-1\u03b1 regulates the inflammatory response and contributes to neuroprotection in a rat stroke model. In the current investigation, we examined the downstream mechanism by which the ketogenic (KG) diet protects against brain damage after stroke in mice. Six- to seven-week-old male mice were fed the standard diet (SD) or the KG diet to mimic the metabolic state of chronic ketosis. After 4\u00a0weeks, mice were subjected to photothrombotic ischemic stroke. Behavior analysis was recorded at 24\u00a0h, 48\u00a0h, and 72\u00a0h post-stroke. After 72\u00a0h, mice were euthanized for infarction, brain edema, hemorrhage, and molecular analysis. Our results showed that the KG diet significantly alleviated infarction, brain edema, and hemorrhage; improved the neurobehavioral outcomes; and attenuated ischemic stroke-induced oxidative\/nitrative stress and apoptotic markers at 72\u00a0h post-stroke. Further, the KG diet upregulated the HIF-1\u03b1 and interleukin (IL)-10 expression and inhibited thioredoxin-interacting protein (TXNIP), NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and pro-inflammatory cytokine expression compared to SD-fed mice after stroke. We showed that the KG diet did not show neuroprotection in the NLRP3 knockout mice after stroke. Our current study demonstrates that the KG diet exerts neuroprotective effects by inhibiting TXNIP-NLRP3 inflammasome, mainly dependent on heightening the upregulation of IL-10 via HIF-1\u03b1 stabilization. Thus, the KG diet might be considered a new therapeutic strategy for ischemic patients.<\/jats:p>","DOI":"10.1007\/s12035-025-04943-0","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T07:47:10Z","timestamp":1745480830000},"page":"11238-11252","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chronic Ketosis Provides Neuroprotection Through HIF- 1\u03b1-Mediated Control of the TXNIP\/NLRP3 Axis by Regulating the Inflammatory and Apoptotic Response"],"prefix":"10.1007","volume":"62","author":[{"given":"Kehkashan","family":"Parveen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd","family":"Salman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Golnoush","family":"Mirzahosseini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arshi","family":"Parveen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tauheed","family":"Ishrat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle A.","family":"Puchowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"issue":"7","key":"4943_CR1","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/S1474-4422(15)00054-X","volume":"14","author":"M Fisher","year":"2015","unstructured":"Fisher M, Saver JL (2015) Future directions of acute ischaemic stroke therapy. 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