Lipocalin 2 induces visual impairment by promoting ferroptosis in retinal ischemia-reperfusion injury.

Retinal ischemia-reperfusion (RIR) is a common pathological condition that can lead to retinal ganglion cell (RGC) death and visual impairment. However, the pathogenesis of RGC loss and visual impairment caused by retinal ischemia remains unclear. A mouse model of elevated intraocular pressure (IOP)-induced RIR injury was used. Flash visual evoked potentials (FVEPs) and electroretinography (ERG) recordings were performed to assess visual function. The structural integrity of the retina and the number of RGC were assessed using hematoxylin and eosin (HE) staining and retinal flat mounts. Ferroptosis was evaluated by testing the levels of glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPX4), and ferritin light chains (FTL) in the retina of wild-type (WT) and lipocalin-2 transgenic (LCN2-TG) mice after RIR injury. We found that LCN2 was mainly expressed in the RGC layer in the retina of wild-type mice and remarkably upregulated after RIR injury. Compared with wild-type mice, aggravated RGC death and visual impairment were exhibited in LCN2-TG mice with RIR injury. Moreover, LCN2 overexpression activated glial cells and upregulated proinflammatory factors. More importantly, we found that LCN2 strongly promoted ferroptosis signaling in RGC death and visual impairment. Liproxstatin-1, an inhibitor of ferroptosis, could significantly ameliorate RGC death and visual impairment. Furthermore, we found significantly alleviated RGC death and retinal damage in LCN2 heterozygous knockout mice. Our study provides important insights linking upregulated LCN2-mediated promotion of ferroptosis to RGC death and visual function impairment in the pathogenesis of ischemic retinopathy.