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NLRP3 inflammasome-induced pyroptosis, the inflammatory programmed cell death, has been reported to contribute to the development of VaD. ChemR23 is a G protein-coupled receptor that has emerging roles in regulating inflammation. However, the role of ChemR23 signalling in NLRP3 inflammasome-induced pyroptosis in CCH remains elusive. In this study, a CCH rat model was established by permanent bilateral common carotid artery occlusion (BCCAO) surgery. Eight weeks after the surgery, the rats were intraperitoneally injected with the ChemR23 agonist Resolvin E1 (RvE1) or chemerin-9 (C-9). Additionally, primary rat hippocampal neurons and SH-SY5Y cells were adopted to mimic CCH injury in vitro. Our results showed that the levels of ChemR23 expression were decreased from the 8\n                    <jats:sup>th<\/jats:sup>\n                    week after BCCAO, accompanied by significant cognitive impairment. Further analysis revealed that CCH induced neuronal damage, synaptic injury and NLRP3-related pyroptosis activation in hippocampal neurons. However, pharmacologic activation of ChemR23 with RvE1 or C-9 counteracted these changes. In vitro experiments also showed that ChemR23 activation prevented primary neuron pyroptosis induced by chronic hypoxia. In addition, manipulating ChemR23 expression markedly regulated NLRP3 inflammasome-induced neuronal pyroptosis through PI3K\/AKT\/Nrf2 signalling in SH-SY5Y cells under hypoglycaemic and hypoxic conditions. Collectively, our data demonstrated that ChemR23 activation inhibits NLRP3 inflammasome-induced neuronal pyroptosis and improves cognitive function via the PI3K\/AKT\/Nrf2 signalling pathway in CCH models. ChemR23 may serve as a potential novel therapeutic target to treat CCH-induced cognitive impairment.\n                  <\/jats:p>","DOI":"10.1038\/s41419-023-06237-6","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T09:03:06Z","timestamp":1699261386000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["ChemR23 activation attenuates cognitive impairment in chronic cerebral hypoperfusion by inhibiting NLRP3 inflammasome-induced neuronal pyroptosis"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8369-2126","authenticated-orcid":false,"given":"Yaxuan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-8336","authenticated-orcid":false,"given":"Xiuzhe","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1749-461X","authenticated-orcid":false,"given":"Jianliang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,6]]},"reference":[{"key":"6237_CR1","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.1016\/S0140-6736(15)00463-8","volume":"386","author":"JT O\u2019Brien","year":"2015","unstructured":"O\u2019Brien JT, Thomas A. 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