Abstract
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.