Details

Autor(en) / Beteiligte

• Zeng, Zihang
• Li, Tiao
• Liu, Xiangming
• Ma, Yiming
• Luo, Lijuan
• Wang, ZuLi
• Zhao, Zhiqi
• Li, Herui
• He, Xue
• Zeng, Huihui
• Tao, Yongguang
• Chen, Yan

Titel

DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell

Ist Teil von

• Redox biology, 2023-11, Vol.67, p.102916-102916, Article 102916

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality currently. Long-term exposure of cigarette smoke (CS) inducing persistent inflammation, small airway remodeling and emphysematous lung are the distinguishing features of COPD. Ferroptosis, occurred in lung epithelial cells has recently been reported to be associated with COPD pathogenesis. DNA dioxygenase ten-eleven translocation 2 (TET2) is an important demethylase and its genetic mutation is associated with low forced expiratory volume in 1 s (FEV1) of lung function. However, its role in COPD remains elusive. Here, we found that TET2 regulates CS induced lipid peroxidation through demethylating glutathione peroxidase 4 (GPx4), thus alleviating airway epithelial cell ferroptosis in COPD. TET2 protein levels were mainly reduced in the airway epithelia of COPD patients, mouse models, and CS extract-treated bronchial epithelial cells. The deletion of TET2 triggered ferroptosis and further exaggerated CS-induced airway remodeling, inflammation, and emphysema in vivo. Moreover, we demonstrated that TET2 silencing intensified ferroptosis, while TET2 overexpression inhibited ferroptosis in airway epithelial cell treated with CSE. Mechanically, TET2 protected airway epithelial cells from CS-induced lipid peroxidation and ferroptosis through demethylating the promoter of glutathione peroxidase 4 (GPx4). Finally, co-administration of methylation inhibitor 5′-aza-2′-deoxycytidine (5-AZA) and the antioxidant N-acetyl-cysteine (NAC) have more protective effects on CS-induced COPD than either administration alone. Overall, our study reveals that TET2 is an essential modulator in the lipid peroxidation and ferroptosis of airway epithelial cell, and could act as a potential therapeutic target for CS-induced COPD. [Display omitted] •TET2 deficiency promotes the development of cigarette smoke induced COPD.•TET2 regulates cigarette smoke induced ferroptosis of airway epithelial cell by demethylating GPX4 gene promoter.•Co-administration of low-dose methylation inhibitor and antioxidants might be a potential therapeutic option for COPD treatment.