{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:22:04Z","timestamp":1792815724770,"version":"4.5.0"},"reference-count":98,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UNMC funding"},{"DOI":"10.13039\/100000053","name":"National Eye Institute, NIH","doi-asserted-by":"publisher","award":["EY36404"],"award-info":[{"award-number":["EY36404"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Deregulated Nlrp3 (NOD-like receptor pyrin 3) inflammasome activation is strongly associated with age-related blinding diseases, including cataract. Previously, we demonstrated that loss of peroxiredoxin6 (Prdx6) promotes reactive oxygen species (ROS) amplification and aberrant activation of Klf9 and Nlrp3 inflammasome activity\u2013driven pyroptosis. In this study, using aging mouse(m)\/human(h) lenses and lens epithelial cells (LECs), we reveal a critical link between Nlrp3 and thioredoxin (TRX)-interacting protein (TXNIP), which increases during aging and oxidative stress conditions. We found that aging lenses exhibiting opacity showed elevated ROS levels, increased TXNIP expression, along with upregulation of Nlrp3 inflammasome components, including caspase-1, ASC, IL-1\u03b2, IL-18, and gasderminD (GSDMD), with significantly reduced TRX1. mLECs overexpressing TXNIP were more susceptible to hydrogen peroxide (H2O2), Lipopolysaccharide (LPS), ultraviolet B (UVB)-induced oxidative stress, displaying increased ROS accumulation, reduced cell viability, and enhanced activation of Nlrp3 inflammasome and its downstream inflammatory mediators, hallmarks of pyroptotic cell death. Conversely, TXNIP knockdown suppressed Nlrp3 inflammasome activation, decreased ROS production, and significantly improved cell survival, indicating a protective effect against oxidative injury. Ex vivo, TAT-HA-Prdx6 delivery inhibited H2O2-induced Nlrp3 activation and preserved lens transparency, demonstrating its potent antioxidant and anti-inflammatory effects. Collectively, these findings identify TXNIP as a key regulator of Nlrp3 inflammasome signaling and thereby highlight the therapeutic potential of TXNIP silencing (ShTXNIP) or TAT-HA-Prdx6 delivery to halt Nlrp3-mediated pyroptosis during aging or oxidative stress conditions.<\/jats:p>","DOI":"10.3390\/antiox15020170","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:48:04Z","timestamp":1769590084000},"page":"170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TXNIP-Deficiency and Prdx6 Delivery Inhibit Aging\/Oxidative Stress\u2013Driven TXNIP-Nlrp3 Inflammasome Activation and Mitigate Pyroptosis in Lens Epithelial Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9613-8765","authenticated-orcid":false,"given":"Bhavana","family":"Chhunchha","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68186, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6789-9311","authenticated-orcid":false,"given":"Eri","family":"Kubo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kanazawa Medical University, Kanazawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renuka R.","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68186, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68186, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3311-2191","authenticated-orcid":false,"given":"Dhirendra P.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68186, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1002\/1873-3468.13156","article-title":"Enhanced expression of thioredoxin-interacting-protein regulates oxidative DNA damage and aging","volume":"592","author":"Oberacker","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/2046-2395-3-6","article-title":"Mitochondrial oxidative stress in aging and healthspan","volume":"3","author":"Dai","year":"2014","journal-title":"Longev. 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