Lipocalin 2 links iron export in blood-brain barrier to fear memory consolidation in mice

Fear memory, vital for environmental adaptation, depends on enhanced synaptic plasticity in the prefrontal cortex and hippocampus. Our prior study linked brain iron deficiency to impaired contextual fear memory, though mechanisms remained unclear. Here we show that brain iron levels and endothelial ferroportin 1 (FPN1) expression rise during fear memory formation. Using endothelial Cadherin ( Cdh5 ) mediated Fpn1 knockout mice ( Fpn1 Cdh5 -CKO), we demonstrated that endothelial Fpn1 deficiency leads to brain iron deficiency, which reduces synaptic plasticity and impairs contextual fear memory. Transcriptomics analysis identified lipocalin 2 (LCN2) as a potential target linking endothelial FPN1 to synaptic plasticity. Intracerebroventricular injection of nanoliposome-encapsulated Lcn2 shRNA further confirmed the LCN2-matrix metalloproteinase 9 (MMP9) axis mediates brain-derived neurotrophic factor precursor (pro-BDNF) cleavage, thereby suppressing BDNF-tropomyosin receptor kinase B signaling and impairing plasticity and memory. Our findings suggest the LCN2-MMP9 functional axis may link iron transport in blood-brain barrier to fear memory, offering prospective therapeutic targets for iron-related disorders like post-traumatic stress disorder.