Lcn2-Induced Oligodendrocyte Ferroptosis Contributes to White Matter Damage in Chronic Cerebral Hypoperfusion

Chronic cerebral hypoperfusion (CCH) is associated with cognitive impairment and white matter damage. Lipocalin-2 (Lcn2) has been reported to be associated with both white matter lesions and cognitive impairment. Our previous studies revealed an elevation of Lcn2 in astrocytes within white matter following CCH; however, its role in this process remains poorly understood. In this study, we investigated the effects of Lcn2 deficiency on CCH-induced white matter injury using Lcn2 knockout (LKO) mice. LKO mice exhibited improved cognitive performance in both spatial and recognition memory tasks, along with reduced white matter damage following CCH. Mechanistically, we demonstrated that Lcn2 promotes oligodendrocyte ferroptosis both in vivo and in vitro, contributing to white matter lesions. Furthermore, treatment with the ferroptosis inhibitor Fer-1 improved white matter integrity and rescued cognitive function in CCH mice. These findings suggest that Lcn2 exacerbates oligodendrocyte ferroptosis in CCH, playing a pivotal role in white matter injury and cognitive decline.