{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:47:12Z","timestamp":1787014032488,"version":"build-2736575974"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271236"],"award-info":[{"award-number":["82271236"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>High blood glucose is a well\u2010established risk factor for poor outcomes in ischemic stroke. However, the underlying molecular mechanisms linking high blood glucose to worsened stroke outcomes remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Previous studies have implicated the NLRP3 inflammasome, a key mediator of neuroinflammation, in cerebral ischemia\/reperfusion (I\/R) injury. Under high blood glucose conditions, NLRP3 activation is amplified, potentially driving a vicious cycle of inflammation and neuronal death. Yet, how high blood glucose specifically modulates NLRP3 activation and its downstream pathways remains unclear. This study aimed to investigate the specific mechanisms by which high glucose enhances NLRP3 inflammasome activity and contributes to worsened brain injury following cerebral I\/R.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed a combination of in\u00a0vitro and in\u00a0vivo experimental approaches to explore the impact of high glucose on NLRP3 inflammasome activation and its consequences on ischemic stroke outcomes. In\u00a0vitro experiments were conducted by culturing various immune cells in high\u2010glucose conditions to evaluate the activation of the NLRP3 inflammasome and the mitochondrial association of HK2. In\u00a0vivo, mice with genetic knockouts of\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      ,\n                      <jats:italic>Pycard<\/jats:italic>\n                      (the gene encoding ASC), or microglial\u2010specific\n                      <jats:italic>Hk2<\/jats:italic>\n                      were subjected to transient middle cerebral artery occlusion (tMCAO).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our findings revealed that the activation of the NLRP3 inflammasome was enhanced post cerebral I\/R under high glucose and a N\u2010terminal truncation of NLRP3 (miniNLRP3) was induced. Overexpression of PKA could promote the generation of miniNLRP3, while inhibition of PKA decreased the generation of miniNLRP3. In addition, treatment with pan serine protease could block PKA and LPS mediated generation of miniNLRP3. Overexpression of the N\u2010terminal truncation of NLRP3 could potentiate the activation of the NLRP3 inflammasome under high glucose conditions by promoting the dissociation of Hexokinase 2 (HK2) from mitochondria. In addition, knockout of\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      ,\n                      <jats:italic>Pycard<\/jats:italic>\n                      , or microglial\n                      <jats:italic>Hk2<\/jats:italic>\n                      , could all attenuate cerebral I\/R\u2010induced brain injury under high blood glucose in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study elucidates PKA\u2010mediated generation of a 30 kD N\u2010terminal truncation of NLRP3 (miniNLRP3) in a serine protease\u2010dependent manner, which could potentiate the activation of the NLRP3 inflammasome under high glucose conditions via promoting the dissociation of HK2 from mitochondria. These findings add a new dimension to our understanding of NLRP3 regulation in the context of stroke injury, and suggest that the PKA\u2010miniNLRP3\u2010HK2\u2010NLRP3 pathway is a promising therapeutic strategy to improve stroke outcomes in patients with elevated blood glucose levels.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70660","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:21:13Z","timestamp":1763533273000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["High Glucose Aggravates Cerebral Ischemia\/Reperfusion via Truncated\n                    <scp>NLRP3<\/scp>\n                    \u2010Mediated Hexokinase\u20102 Translocation"],"prefix":"10.1111","volume":"31","author":[{"given":"Hengchang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, Hengyang Medical School University of 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