SIRT1 Prevents Ferroptosis in Corneal Epithelial Cells by Enhancing HIF1α Protein Stability in Dry Eye Disease

Abstract

Hyperosmotic stress induced by tear film instability significantly exacerbates oxidative damage in corneal epithelial cells, contributing to the pathogenesis of dry eye disease (DED). Ferroptosis, an iron-dependent 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-dependent deacetylase sirtuin 1 (SIRT1). SIRT1 positively regulates GPX4, 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 HIF1α, stabilizing it via the ubiquitin-proteasome pathway. The SIRT1-HIF1α 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.

Keywords: GPX4; SIRT1; corneal epithelial cells; dry eye disease; ferroptosis.