{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:30:17Z","timestamp":1786354217002,"version":"build-2736575974"},"reference-count":43,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2024JJ5001, 2024JJ6002, 2024JJ9011"],"award-info":[{"award-number":["2024JJ5001, 2024JJ6002, 2024JJ9011"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Health Research Project of Hunan Provincial Health Commission","award":["20256129"],"award-info":[{"award-number":["20256129"]}]},{"name":"Xiangjiang Philanthropy Foundation","award":["KY25015"],"award-info":[{"award-number":["KY25015"]}]},{"name":"Science Research Foundation of Aier Eye Institute","award":["AEI202302ZD03"],"award-info":[{"award-number":["AEI202302ZD03"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["No. 82000871"],"award-info":[{"award-number":["No. 82000871"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Natural Science Foundation of Changsha","award":["No. kq2403202J03"],"award-info":[{"award-number":["No. kq2403202J03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Oxidative stress is central to keratoconus (KC) pathogenesis, and NRF2 is a key antioxidant regulator. However, an\n                    <jats:italic>in vivo<\/jats:italic>\n                    model linking NRF2 loss to KC has been lacking. We generated CRISPR\/Cas9\n                    <jats:italic>Nfe2l2<\/jats:italic>\n                    -knockout (KO) mice and assessed 4-month-old corneas by slit-lamp fluorescein staining, optical coherence tomography (OCT), histology\/immunofluorescence and transmission electron microscopy (TEM), reactive oxygen species (ROS) assays, \u03b2III-tubulin whole-mounts, and whole-cornea single-cell RNA-seq with Seurat\/CellChat.\n                    <jats:italic>Nfe2l2<\/jats:italic>\n                    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, \u03b1-SMA) and immune infiltration increased, mirroring clinical KC. The subbasal nerve plexus was markedly reduced and disorganized. Single-cell profiling revealed loss of extracellular matrix (ECM) -maintenance programs in keratocytes, epithelial-to-mesenchymal transition (EMT)-like epithelial changes, reduced limbal stemness, endothelial dysfunction, immune polarization, and remodeled intercellular signaling (attenuated FN1\/OCLN; augmented APP\/CALCR). Importantly, pharmacological activation of NRF2 with the activator RTA-408 in complementary\n                    <jats:italic>in vitro<\/jats:italic>\n                    rescue experiments partially reversed oxidative stress and inflammation. These data support a feed-forward axis in which NRF2 deficiency drives oxidative stress, inflammation, and extracellular-matrix degradation that extends to corneal innervation, while NRF2 supplementation partially mitigates these pathological changes. The\n                    <jats:italic>Nfe2l2-ko<\/jats:italic>\n                    mouse exhibits several pathological features similar to those observed in human keratoconus and provides a platform to investigate disease mechanisms and evaluate NRF2-targeted interventions.\n                  <\/jats:p>","DOI":"10.7717\/peerj.21613","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T08:43:18Z","timestamp":1786351398000},"page":"e21613","source":"Crossref","is-referenced-by-count":0,"title":["<i>Nfe2l2<\/i>\n                    -knockout mouse model exhibits oxidative stress-associated stromal degeneration and inflammatory activation resembling keratoconus pathology"],"prefix":"10.7717","volume":"14","author":[{"given":"Xiaoxue","family":"Li","sequence":"first","affiliation":[{"name":"Aier Academy of Ophthalmology, Central South University, Changsha, China"},{"name":"Changsha Aier Eye Hospital, Changsha, 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