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However, whether and how astrocytes sense micro\u2010environmental changes, such as ischemic stroke\u2010associated acidification, remains largely unknown. Here we show that the proton\u2010activated chloride (PAC) channel is widely expressed in glial cells in the brain and functionally mediates acid\u2010induced chloride influx. Moreover, conditional knockout of the PAC channel in astrocytes, but not in microglia, reduced infarct volume in a mouse model of ischemic stroke induced by middle cerebral artery occlusion\/reperfusion (MCAO\/R). Rather than the classic role of chloride channels in cell volume dysregulation\u2010related cell death, activation of the PAC channel contributes to cell apoptosis via the Akt\/Bax\/Caspase 3 pathway in astrocytes and promotes inflammatory mediator release from astrocytes in response to pH oscillation and oxidative stress. Collectively, our results uncover a role of the PAC channel in astrocyte acidosis, providing a potential therapeutic target for neuroprotection in ischemic stroke.<\/jats:p>","DOI":"10.1002\/glia.70073","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T09:53:49Z","timestamp":1753696429000},"page":"2353-2368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Acid\u2010Sensing\n                    <scp>PAC<\/scp>\n                    Channel Promotes Astrocyte Acidosis in Ischemic Stroke"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8343-8939","authenticated-orcid":false,"given":"Yifei","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Science  Shanghai 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