{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:01:27Z","timestamp":1792641687435,"version":"4.5.0"},"reference-count":30,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T00:00:00Z","timestamp":1695772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371712"],"award-info":[{"award-number":["82371712"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Microglia play a crucial role in regulating neuroinflammation in the pathogenesis of neonatal hypoxic\u2013ischemic brain damage (HIBD). Pyroptosis, an inflammatory form of programmed cell death, has been implicated in HIBD; however, its underlying mechanism remains unclear. We previously demonstrated that high\u2010mobility group box 1 protein (HMGB1) mediates neuroinflammation and microglial damage in HIBD. In this study, we aimed to investigate the association between HMGB1 and microglial pyroptosis and elucidate the mechanism involved in rats with HIBD (both sexes were included) and in BV2 microglia subjected to oxygen\u2013glucose deprivation. Our results showed that HMGB1 inhibition by glycyrrhizin (20\u2009mg\/kg) reduced the expression of microglial pyroptosis\u2010related proteins, including caspase\u20101, the N\u2010terminus fragment of gasdermin D (N\u2010GSDMD), and pyroptosis\u2010related inflammatory factors, such as interleukin (IL) \u20101\u03b2 and IL\u201018. Moreover, HMGB1 inhibition resulted in reduced neuronal damage in the hippocampus 72\u2009h after HIBD and ultimately improved neurobehavior during adulthood, as evidenced by reduced escape latency and path length, as well as increased time and distance spent in the target quadrant during the Morris water maze test. These results revealed that HIBD\u2010induced pyroptosis is mediated by HMGB1\/receptor for advanced glycation end products (RAGE) signaling (inhibition by FPS\u2010ZM1, 1\u2009mg\/kg) and the activation of cathespin B (cat B). Notably, cat B inhibition by CA074\u2010Me (5\u2009mg\/kg) also reduced hippocampal neuronal damage by suppressing microglial pyroptosis, thereby ameliorating learning and memory impairments caused by HIBD. Lastly, we demonstrated that microglial pyroptosis may contribute to neuronal damage through the HMGB1\/RAGE\/cat B signaling pathway in vitro. In conclusion, these results suggest that HMGB1\/RAGE\/cat B inhibitors can alleviate hippocampal injury by regulating microglial pyroptosis and caspase activation in HIBD, thereby reducing the release of proinflammatory mediators that destroy hippocampal neurons and induce spatial memory impairments.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15965-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15965","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T11:52:19Z","timestamp":1695815539000},"page":"410-426","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Effects of <scp>HMGB1<\/scp>\/<scp>RAGE<\/scp>\/cathespin B inhibitors on alleviating hippocampal injury by regulating microglial pyroptosis and caspase activation in neonatal hypoxic\u2013ischemic brain damage"],"prefix":"10.1111","volume":"167","author":[{"given":"Kaiyi","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Neonatology Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3136-7986","authenticated-orcid":false,"given":"Xing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neonatology Neonatal Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neonatology Neonatal Center, Beijing Children's Hospital, Capital Medical 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Beijing Children's Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Hematology Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine The First Hospital of Shanxi Medical University, Shanxi Medical University  Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"The MOH Key Laboratory of Geriatrics Beijing Hospital, National Center of Gerontology  Beijing 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