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Nfe2l2-knockout mouse model recapitulates key pathological features of keratoconus

bioinformatics
cell-biology
ophthalmology
histology

Abstract

Oxidative stress is central to keratoconus (KC) pathogenesis, and NRF2 is a key antioxidant regulator. However, an in vivo model linking NRF2 loss to KC has been lacking. We generated CRISPR/Cas9 Nfe2l2-knockout (KO) mice and assessed 4-month-old corneas by slit-lamp fluorescein staining, OCT, histology/immunofluorescence and TEM, ROS assays, βIII-tubulin whole-mounts, and whole-cornea single-cell RNA-seq with Seurat/CellChat. Nfe2l2 loss caused central corneal thinning, increased fluorescein uptake, and disrupted epithelial tight junctions; the stroma exhibited reduced keratocyte density, disorganized collagen, and depleted proteoglycans. ROS accumulated while antioxidant effectors (HMOX1, ALDH3A1) declined; inflammatory/fibrotic markers (ICAM1, iNOS, α-SMA) and immune infiltration increased, mirroring clinical KC. The subbasal nerve plexus was markedly reduced and disorganized. Single-cell profiling revealed loss of ECM-maintenance programs in keratocytes, EMT-like epithelial changes, reduced limbal stemness, endothelial dysfunction, immune polarization, and remodeled intercellular signaling (attenuated FN1/OCLN; augmented APP/CALCR). These data support a feed-forward axis in which NRF2 deficiency drives oxidative stress, inflammation, and extracellular-matrix degradation that extends to corneal innervation. The Nfe2l2-KO mouse reproduces cardinal KC pathologies and furnishes a relevant platform to dissect mechanisms and test NRF2-directed therapies.
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