DsbA-L deficiency promotes cigarette smoke-induced bronchial epithelial cells ferroptosis by inhibiting catalase in COPD

Abstract

Background

Ferroptosis, characterized by iron-dependent programmed cell death, has been implicated in chronic obstructive pulmonary disease (COPD). Recent studies have shown that the disulfide-bond A oxidoreductase-like protein (DsbA-L) is associated with various diseases. However, the involvement of DsbA-L in COPD remains unclear.

Methods

To establish a COPD model, 8-week-old male mice were exposed to cigarette smoke (CS) for 6 months. BEAS-2B cells were cultured with cigarette smoke extract (CSE) in vitro. DsbA-L siRNA, DsbA-L plasmid, or catalase siRNA were used to elucidate the underlying mechanisms. Lung function; lung histopathology; Fe²⁺ concentration; glutathione (GSH), reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) levels; and protein expression of DsbA-L, xCT, glutathione peroxidase-4 (GPX4), and catalase were measured.

Results

DsbA-L expression was significantly decreased in the lung tissues of COPD mice and CSE-treated BEAS-2B cells. DsbA-L knockout exacerbated COPD progression by increasing ferroptosis, as confirmed by reduced GSH, xCT, and GPX4 levels and elevated Fe²⁺, ROS, 4-HNE and MDA levels. Catalase expression was also attenuated in the lung tissues of COPD mice and CSE-treated BEAS-2B cells. DsbA-L overexpression ameliorated ferroptosis by upregulating catalase expression in BEAS-2B cells, whereas catalase knockdown abolished the effects of DsbA-L overexpression on ferroptosis.

Conclusion

DsbA-L deficiency exacerbated COPD progression by promoting ferroptosis in bronchial epithelial cells through catalase inhibition. These findings indicate that DsbA-L may be an underlying therapeutic strategy for COPD.