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Acid-sensing ion channels (ASICs) have revised that account. When cerebral blood flow stops, the penumbra can develop prolonged extracellular acidosis, and experimental studies implicate ASIC1a in mediating sufficient Ca\u00b2\u207a entry to injure neurons even when glutamate receptors are blocked, a contribution shaped by channel expression, subunit composition, and the intracellular signaling context. However, sustained acidosis does not necessarily imply sustained channel opening, given ASIC1a desensitization. Besides acidosis, glutamate, polyamines, a paradoxical intracellular alkalization, and oxidative stress can enhance ASIC1a activity or expression, and the channel also signals through a non-conducting route, recruiting RIPK1 to trigger necroptosis independently of ion flux. The relative contributions of these conducting and non-conducting mechanisms in vivo remain incompletely defined. Endogenous mechanisms may constrain injury by internalizing the channel, altering subunit expression, including conditioning-associated ASIC2a upregulation, and degrading ASIC1a through estrogen signaling. We argue that these responses are better understood as constraints on injury than as a genuine survival program, a distinction with mechanistic and therapeutic consequences. Critically, the contribution of these mechanisms may vary over time. The same channel acts as a target of homeostatic regulation before stroke, a driver of death during ischemia, a potential target at reperfusion when acidosis persists but restored flow finally permits drug delivery, and an impediment to repair for weeks afterward. The question in ASIC-targeted neuroprotection is not only whether to inhibit the channel, but also when and for how long.<\/jats:p>","DOI":"10.1007\/s00424-026-03217-5","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:24:49Z","timestamp":1791505489000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework"],"prefix":"10.1007","volume":"478","author":[{"given":"Octavia Yifang","family":"Weng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Fei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1438-0038","authenticated-orcid":false,"given":"Tian-Le","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"3217_CR1","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.lfs.2019.04.054","volume":"227","author":"O Akanji","year":"2019","unstructured":"Akanji O, Weinzierl N, Schubert R, Schilling L (2019) Acid sensing ion channels in rat cerebral arteries: Probing the expression pattern and vasomotor activity. 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