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Resveratrol Alleviates Chronic Intermittent Hypoxia-Induced Lung Injury by Inhibiting Ferroptosis via SIRT1-Dependent
Fan Wei1,2, Jia Chen1,2, Xiaoyu Deng1,2
1Department of Respiratory and Critical Care Medicine, Respiratory Disease Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Aims:
Obstructive sleep apnea (OSA)-associated chronic intermittent hypoxia (CIH) induces lung injury, partly through ferroptosis. Although resveratrol (Res) exhibits antioxidant activity, its mechanism in mitigating ferroptosis under CIH remains unclear. This study aimed to determine whether Res attenuates CIH-induced lung injury by suppressing ferroptosis and to elucidate the role of Sirtuin 1 (SIRT1)-dependent modulation of the early growth response factor 1 (EGR1)/glutaminase 2 (GLS2) axis.
Results:
CIH models were established using Sprague-Dawley rats and human bronchial epithelial BEAS-2B cells, treated with optimal doses of Res. In vivo, Res treatment significantly attenuated alveolar structural damage, enhanced glutathione (GSH) biosynthesis, and upregulated the expression of glutathione peroxidase 4 (GPX4). In vitro, Res reversed CIH-induced ferroptotic phenotypes and restored mitochondrial morphological integrity in BEAS-2B cells. Mechanistically, Res activated SIRT1. Integrated analysis of RNA sequencing and the FerrDb database identified EGR1 as a pivotal downstream effector of SIRT1-mediated ferroptosis regulation. Rescue experiments demonstrated that EGR1 knockdown abrogated the anti-ferroptotic effects conferred by both Res treatment and SIRT1 overexpression, indicating that SIRT1 suppresses ferroptosis via EGR1 upregulation. Furthermore, bioinformatics prediction and dual-luciferase reporter assays confirmed that EGR1 directly binds to and transcriptionally activates the promoter of GLS2. Consequently, GLS2 knockdown attenuated the protective effects of Res, whereas GLS2 overexpression augmented GSH production and suppressed ferroptosis.
Innovation And Conclusion:
Res alleviates CIH-induced lung injury by inhibiting ferroptosis via SIRT1-dependent modulation of the EGR1/GLS2 axis. These findings reveal a novel mechanism in OSA pathophysiology and highlight Res as a promising therapeutic candidate for CIH-induced lung injury. Antioxid. Redox Signal. 00, 000-000.