O-GlcNAc-mediated FTH1 degradation is involved in smoking-induced emphysema through iron ion disorder in alveolar epithelial cells

Emphysema is a pathological mechanism of chronic obstructive pulmonary disease (COPD); however, its specific mechanism is unknown. Iron disorders are linked to ferroptosis, but the specific mechanism underlying iron homeostasis imbalance in alveolar epithelial cells in smoke-stimulated COPD emphysema is unclear. The present study investigated ferroptosis markers, lipid peroxidation, and Fe²⁺ levels in patients with COPD, smoke-exposed mice, and A549 cells. Techniques included H&E staining and lung function tests, western blotting/immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)/FerroOrange staining, and C11-BODIPY. Bioinformatics and in vitro experiments explored FTH1's role in COPD emphysema. We used AAV5-FTH1 plasmids to increase FTH1 expression in mice, CS exposed for 6 months, and assessed emphysema and ferroptosis-related indicators in mice. Co-immunoprecipitation was used to detect the binding of FTH1 with O-GlcNAcase (OGA), O-GlcNAc, and nuclear receptor coactivator 4. TMG, FTH1, and SLC40A1 plasmids were added in A549 cells, exposed in 5 % CSE, and indicators of ferroptosis were detected. Ferroptosis and ion disorders were major causes of COPD emphysema in vitro and in vivo. We determined that FTH1 plays a key role in the steady-state imbalance of iron ions and ferroptosis in A549 cells exposed to cigarette smoke (CS). FTH1 expression was high in human lung tissue. In A549 cells, O-GlcNAc, which can bind with FTH1, decreased. The addition of TMG reversed the ferroptosis. Finally, FTH1 prevents COPD formation in mice. CS increases OGA expression in alveolar epithelial cells and causes iron metabolism disorders, which leads to ferroptosis and may facilitate the formation of COPD emphysema.