{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:53:43Z","timestamp":1791572023694,"version":"4.3.4"},"reference-count":76,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2021R1A2C2010523"],"award-info":[{"award-number":["2021R1A2C2010523"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuroinflammation and oxidative stress are key drivers of various ocular diseases. Experimental hypoxia, modeled using cobalt chloride (CoCl2), induces hypoxia-inducible factor 1-alpha (HIF-1\u03b1) stabilization, mitochondrial dysfunction, and excessive reactive oxygen species (ROS) production, primarily via the NADPH oxidase 2 (Nox2)\u2013voltage-gated proton channel Hv1 axis. Although Botulinum neurotoxin type A (BoNT\/A) is classically recognized for SNAP-25 cleavage, recent studies suggest broader anti-inflammatory and neuroprotective effects. We evaluated BoNT\/A in R28 retinal precursor cells and ex vivo retinal explants subjected to CoCl2-induced hypoxic stress. BoNT\/A pretreatment attenuated CoCl2-induced upregulation of HIF-1\u03b1, Hv1, Nox2, NOD-like receptor protein 3 (NLRP3), COX2, and nuclear factor kappa B (NF-\u03baB), while enhancing protective mediators including suppressor of cytokine signaling 3 (SOCS3), Growth Associated Protein 43 (Gap43), and Syntaxin12. Brn3a expression and retinal architecture were preserved, apoptotic cell death reduced, and glial activation suppressed. Moreover, BoNT\/A decreased mitochondrial ROS accumulation, restored voltage-dependent anion channel 1 (VDAC1) distribution, and partially stabilized intracellular pH. These findings indicate that BoNT\/A mitigates oxidative stress and inflammation in hypoxia-driven retinal injury, at least in part, via modulation of the Nox2\u2013Hv1\u2013ROS axis, and support its potential as a therapeutic candidate for ocular disorders associated with hypoxia and neuroinflammation.<\/jats:p>","DOI":"10.3390\/ijms262110806","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T17:51:43Z","timestamp":1762451503000},"page":"10806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Therapeutic Modulation of the Nox2\u2013Hv1\u2013ROS Axis by Botulinum Neurotoxin A Confers Protection Against CoCl2-Induced Retinal Hypoxic Injury"],"prefix":"10.3390","volume":"26","author":[{"given":"Hey Jin","family":"Lee","sequence":"first","affiliation":[{"name":"CHA R&D Institute, CHA University, Seongnam 13496, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Bundang CHA Medical Center, CHA University, Seongnam 13496, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Ah","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13496, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0121-3000","authenticated-orcid":false,"given":"Helen","family":"Lew","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Bundang CHA Medical Center, CHA University, Seongnam 13496, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"ref_1","first-page":"e213","article-title":"Trends in the Prevalence of Blindness and Correlation with Health Status in Korean Adults: A 10-Year Nationwide Population-Based Study","volume":"38","author":"Na","year":"2023","journal-title":"Int. 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