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Ferroptosis, an iron\u2010dependent form of cell death driven by lipid peroxidation, has been identified as a critical downstream mechanism of oxidative damage in DED. However, its precise regulatory mechanisms remain unclear. In this study, we demonstrate that hyperosmotic stress promotes ferroptosis in corneal epithelial cells by downregulating the NAD\u2010dependent deacetylase sirtuin 1 (SIRT1). SIRT1 positively regulates\u00a0GPX4, a pivotal mediator of ferroptosis. Pharmacological activation of SIRT1 using SRT1720 alleviated oxidative damage and suppressed ferroptosis in corneal epithelial cells both in vitro and in vivo. Mechanistically, we further observed that SIRT1 deacetylates the HIF1\u03b1, stabilizing it via the ubiquitin\u2010proteasome pathway. The SIRT1\u2013HIF1\u03b1 axis positively regulates GPX4 levels, thereby inhibiting ferroptosis activation. These results reveal a previously unrecognized pathway of ferroptosis regulation in DED and suggest a potential therapeutic strategy for reducing oxidative damage in corneal epithelium.<\/jats:p>","DOI":"10.1002\/advs.202522806","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:21:32Z","timestamp":1773030092000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["SIRT1 Prevents Ferroptosis in Corneal Epithelial Cells by Enhancing HIF1\u03b1 Protein Stability in Dry Eye Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Lili","family":"Lian","sequence":"first","affiliation":[{"name":"Eye Hospital and School of Ophthalmology and Optometry Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenmin","family":"Le","sequence":"additional","affiliation":[{"name":"Ningde Municipal Hospital Ningde 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