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This study investigates the role of the volume\u2010regulated anion channel subunit leucine\u2010rich repeat\u2010containing protein 8\u2009A (LRRC8A) in ischemia\u2010induced neuronal damage. In a rat model of middle cerebral artery occlusion (MCAO) and in cultured neurons under oxygen\u2010glucose deprivation (OGD), ischemia\/hypoxia rapidly upregulated LRRC8A expression in apoptotic neurons. Knockdown of\n                    <jats:italic>lrrc8a<\/jats:italic>\n                    via small interfering RNA (siRNA) attenuated brain infarction, improved neurological deficits, and reduced neuronal apoptosis. Mechanistically,\n                    <jats:italic>lrrc8a<\/jats:italic>\n                    knockdown suppressed the activation of the mitochondrial Bax\/Bcl\u20102\/Caspase\u20109\/Caspase\u20103 apoptotic pathway. Furthermore,\n                    <jats:italic>lrrc8a<\/jats:italic>\n                    knockdown reversed OGD\u2010induced hyperactivation of NMDA receptors (NMDARs) and weakened the enhanced interaction between LRRC8A and the obligatory NMDAR subunit GluN1, which was predicted by structural modeling. These findings reveal that cerebral ischemia upregulates neuronal LRRC8A, which may promote NMDAR hyperactivity via interaction with GluN1, thereby triggering mitochondrial apoptosis. LRRC8A represents a potential therapeutic target for mitigating neuronal apoptosis in ischemic stroke.\n                  <\/jats:p>","DOI":"10.1002\/cbin.70118","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T13:02:53Z","timestamp":1766408573000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LRRC8A Mediates Ischemic Neuronal Injury by Potentiating NMDA Receptor Activity and Activating Mitochondrial Apoptotic Pathway"],"prefix":"10.1002","volume":"50","author":[{"given":"Chengli","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine Zhongnan Hospital of Wuhan University Wuhan Hubei China"},{"name":"Hubei Polytechnic Institute School of Medical Science Xiaogan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linshu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Zhongnan Hospital of Wuhan University Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Zhongnan Hospital of Wuhan University Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianghao","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Zhongnan Hospital of Wuhan University Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical Science Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei China"},{"name":"Department of Neurology Zhongnan Hospital of Wuhan University Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiapei","family":"Dai","sequence":"additional","affiliation":[{"name":"Wuhan Institute for Neuroscience and Neuroengineering South\u2010Central University for Nationalities Wuhan Hubei China"},{"name":"College of Life Sciences South\u2010Central University for Nationalities Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Zhongnan Hospital of Wuhan University Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Research Center for Molecular Diagnostics Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201100173"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.1c00456"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106669"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.4161\/chan.27287"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2021.183716"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2003.10.048"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000124127.57946.a1"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01429-4"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30030-4"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.106027"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adw0424"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.29"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-021-01187-4"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.20.1.84"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.118.022330"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-022-00859-0"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2023.2287339"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-015-1765-6"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctm.2019.03.001"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14186"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.024"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00142"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1990.47"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00256.2015"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2022.12619"},{"key":"e_1_2_10_27_1","doi-asserted-by":"crossref","unstructured":"Tauskela J. 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