Lipocalin-2-mediated oligodendrocyte pyroptosis contributes to post-stroke secondary white matter injury.

Secondary white matter injury occurs in regions remote from the primary infarct after ischemic stroke, contributing to long-term neurological deficits. However, the mechanisms underlying oligodendrocyte loss in secondary white matter injury remain poorly understood. Using a distal middle cerebral artery occlusion (dMCAO) model in mice, we demonstrated that focal cortical ischemia induced significant oligodendrocyte pyroptosis in the contralateral corpus callosum. This pathological process was accompanied by increased interleukin-1β, interleukin-18, and canonical pyroptosis markers, including GSDMD, ASC, and caspase-1. Neutralization of LCN2 reduced pyroptotic signaling, preserved myelin integrity, and improved cognitive performance. Likewise, Lcn2 knockout mice exhibited attenuated oligodendrocyte pyroptosis and secondary white matter injury, whereas re-expression of LCN2 in astrocytes could neutralize the benefits of LCN2 ablation. These findings collectively suggest that LCN2 contributes to oligodendrocyte pyroptosis in secondary white matter injury and may represent a potential therapeutic target for ischemic stroke.