EFFECTS OF LIPOCALIN-2 DELETION ON KAINIC ACID-INDUCED HIPPOCAMPAL CELL DEATH IN A HIGH-FAT DIET-FED MICE

Metabolic disorders such as obesity and diabetes heighten neuronal susceptibility to excitotoxic stress, accelerating neurodegeneration. Lipocalin-2 (LCN2), a stress-responsive protein, has emerged as a critical link between systemic metabolic dysfunction and neuroinflammation. This study investigated how LCN2 modulates metabolic stress–driven vulnerability of the hippocampus to kainic acid (KA)-induced excitotoxic injury. High-fat diet (HFD)-fed diabetic wild-type (WT) and LCN2 knockout (LCN2KO) mice were exposed to KA. Systemic metabolism, hippocampal pathology, and molecular signaling events were assessed by histology, immunoblotting, and biochemical analyses. LCN2 deletion improved insulin sensitivity and alleviated hepatic steatosis under diabetic conditions. In the hippocampus, LCN2 deficiency markedly protected against KA-induced neuronal apoptosis, blood–brain barrier breakdown, and iron-dependent oxidative stress. Moreover, LCN2 ablation attenuated microglial and astrocytic activation, suppressed the expression of galectin-3 and inflammatory cytokines, and inhibited STAT3–NF-κBp65 signaling. The reduction of autophagy-related proteins and protein aggregation further indicated that LCN2 amplifies excitotoxicity through interconnected autophagic and inflammatory mechanisms. Our findings identify LCN2 as a pivotal mediator coupling metabolic dysfunction to excitotoxic neuronal injury via the microglial STAT3–NF-κB axis. Modulating LCN2 signaling offers potential therapeutic insight into metabolic disease–exacerbated hippocampal damage.