β‐Adducin Restrains PLA2G4A‐Dependent Lysosomal Membrane Permeabilization and Neuronal Death in Ischemic Stroke

ABSTRACT Failure to preserve vulnerable neurons in the ischemic penumbra remains a barrier in ischemic stroke. 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 β‐adducin ( Add2 ) as an endogenous protector of lysosomal homeostasis in ischemic neurons. We found that β‐adducin was markedly reduced in neurons after cerebral ischemia in both middle cerebral artery occlusion and oxygen‐glucose deprivation/reoxygenation models. Neuron‐specific knockdown of Add2 increased infarct volume, worsened neurological deficits, and enhanced neuronal apoptosis. Mechanistically, β‐adducin interacted with cytosolic phospholipase A2 group IVA (PLA2G4A) and restricted its accumulation on lysosomes. Loss of β‐adducin 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 6 ‐methyladenosine (m 6 A) modification of Add2 mRNA, and accelerated Add2 transcript decay. Conversely, FTO overexpression restored β‐adducin expression and alleviated ischemic neuronal injury. Together, these findings identify β‐adducin as a key component of an endogenous lysosomal defense pathway in ischemic stroke and suggest that reduced FTO‐mediated demethylation and consequent β‐adducin loss contribute to PLA2G4A‐associated lysosomal injury and neuronal death.