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Lysosomal membrane permeabilization (LMP) is increasingly recognized as a critical event in ischemic neuronal death, yet the endogenous mechanisms that preserve lysosomal integrity remain poorly defined. Here, we identify \u03b2\u2010adducin (\n                    <jats:italic>Add2<\/jats:italic>\n                    ) as an endogenous protector of lysosomal homeostasis in ischemic neurons. We found that \u03b2\u2010adducin was markedly reduced in neurons after cerebral ischemia in both middle cerebral artery occlusion and oxygen\u2010glucose deprivation\/reoxygenation models. Neuron\u2010specific knockdown of\n                    <jats:italic>Add2<\/jats:italic>\n                    increased infarct volume, worsened neurological deficits, and enhanced neuronal apoptosis. Mechanistically, \u03b2\u2010adducin interacted with cytosolic phospholipase A2 group IVA (PLA2G4A) and restricted its accumulation on lysosomes. Loss of \u03b2\u2010adducin enhanced lysosomal localization of PLA2G4A, promoted LMP, increased cytosolic leakage of cathepsins, and exacerbated neuronal injury, whereas silencing PLA2G4A attenuated these effects. Upstream, ischemic stress reduced FTO expression, increased\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>6<\/jats:sup>\n                    \u2010methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) modification of\n                    <jats:italic>Add2<\/jats:italic>\n                    mRNA, and accelerated\n                    <jats:italic>Add2<\/jats:italic>\n                    transcript decay. Conversely, FTO overexpression restored \u03b2\u2010adducin expression and alleviated ischemic neuronal injury. Together, these findings identify \u03b2\u2010adducin as a key component of an endogenous lysosomal defense pathway in ischemic stroke and suggest that reduced FTO\u2010mediated demethylation and consequent \u03b2\u2010adducin loss contribute to PLA2G4A\u2010associated lysosomal injury and neuronal death.\n                  <\/jats:p>","DOI":"10.1002\/advs.78183","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:13:05Z","timestamp":1791349985000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b2\u2010Adducin Restrains PLA2G4A\u2010Dependent Lysosomal Membrane Permeabilization and Neuronal Death in Ischemic Stroke"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-4891","authenticated-orcid":false,"given":"Hui\u2010qin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital 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Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai\u2010yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8230-349X","authenticated-orcid":false,"given":"Xin\u2010yu","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5288-0319","authenticated-orcid":false,"given":"Yun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital of 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