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

作者：Yue Gu, Shurui Cao, Lizhen Zhu, G. Lu, Xuan Tao, Yu Ding, Rong You, Qin Chu, Shumin Feng, Tao Bian · 发表于：Ecotoxicology and Environmental Safety · 年份：2025 · DOI：10.1016/j.ecoenv.2025.118999 · 被引用次数：5 · 研究领域：Peptidase Inhibition and Analysis、Lung Cancer Research Studies、Glycosylation and Glycoproteins Research

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...