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

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 N⁶-methyladenosine (m⁶A) 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.