Protective role of DsbA-L in COPD: Alleviating ER stress-induced apoptosis through AMPK activation

Chronic obstructive pulmonary disease (COPD) is associated with apoptosis and endoplasmic reticulum (ER) stress; however, the role of disulfide-bond A oxidoreductase-like protein (DsbA-L) in COPD pathophysiology remains unclear. In this study, we established COPD models in mice exposed to cigarette smoke and BEAS-2B cells treated with cigarette smoke extract (CSE). DsbA-L expression and markers of apoptosis and ER stress were evaluated. The function of DsbA-L was investigated using DsbA-L knockout mice and BEAS-2B cells with DsbA-L knockdown or overexpression. Our results indicate that DsbA-L expression was downregulated in the airway epithelium of COPD models. DsbA-L deletion accelerated COPD progression, increasing the expression of apoptosis- and ER stress-related proteins mainly through PERK phosphorylation. Conversely, DsbA-L overexpression reduced CSE-induced apoptosis and ER stress in BEAS-2B cells, an effect reversed by the ER stress inducer thapsigargin. Mechanistically, adenosine monophosphate-activated protein kinase (AMPK) inhibition abolished the protective effects of DsbA-L. In conclusion, DsbA-L attenuates ER stress-induced apoptosis primarily via the AMPK signaling axis, highlighting its potential as a therapeutic target in COPD management.