Abstract
Epithelial cell damage-initiated chronic obstructive pulmonary disease (COPD) is implicated in regulated cell death (RCD) including ferroptosis triggered by complex gene-environment interactions. Our data showed that iron overload and ferroptosis are associated with COPD progression in COPD patients and in experimental COPD. Furthermore, we found that, in lung tissues of COPD patients, circSAV1 was associated with COPD progression by circRNA-seq screening. Knockdown of circSAV1 reversed cigarette smoke extract (CSE)-induced ferroptosis. Mechanistically, m6A-modified circSAV1 formed an RNA-protein ternary complex of circSAV1/YTHDF1/IREB2 to facilitate the translation of IREB2 mRNA. Elevated protein levels of IREB2 disrupted iron homeostasis, resulting in accumulation of a labile iron pool (LIP) and lipid peroxidation, which contribute to ferroptosis. Here we demonstrate, by use of an experimental COPD model induced by cigarette smoke (CS), that silencing of circSAV1 and the treatment with deferoxamine (DFO) blocked CS-induced ferroptosis of lung epithelial cells, which attenuated COPD progression in mice. Our results reveal that N6-methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2, indicating that circSAV1 is a mediator of ferroptosis and that circSAV1-dependent ferroptosis is a therapeutic target for COPD. In lung epithelial cell, m6A-modified circSAV1, via recruiting YTHDF1, induces the formation of a circSAV1/YTHDF1/IREB2 mRNA protein ternary complex, which promotes translation of IREB2 mRNA. Further, elevated IREB2 contributes to the accumulation of a labile iron pool (LIP) and lipid peroxidation, then triggers ferroptosis of lung epithelial cells. The ferroptosis of airway epithelial cells and alveolar epithelial cells induces airway remodeling and emphysema, respectively, which causes COPD.