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.