Glutathione peroxidase 4 alleviates chronic obstructive pulmonary disease by inhibition of ferroptosis.

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by persistent inflammation, oxidative stress, and lung function decline. Ferroptosis, an iron-dependent regulated cell death, has emerged as a key contributor to COPD pathogenesis. Glutathione peroxidase 4 (GPX4) is a core suppressor of ferroptosis, but its role in COPD remains unclear. This study aimed to investigate whether GPX4 alleviates COPD by inhibiting ferroptosis. A mouse model of COPD was established by cigarette smoke (CS) exposure. Lung epithelial cells were treated with cigarette smoke extract (CSE) to mimic COPD in vitro. Morphological changes were observed in lung tissue and lung epithelial cells by HE, Masson, and transmission electron microscope, respectively. The expression of GPX4 in lung tissues and BEAS-2B cells was detected by qRT-PCR and Western blot. Iron content, oxidative stress markers (SOD, MDA, GSH), inflammatory cytokines (IL-6, IL-1β, and TNF-α), and cell viability were measured. Our results showed that CS exposure significantly induced lung inflammation (elevated IL-6, IL-1β, and TNF-α), iron overload, and oxidative stress (increased MDA and decreased GSH and SOD) in mice. GPX4 mRNA and protein levels were markedly downregulated in lung tissues of CS-induced COPD mice and CSE-treated BEAS-2B cells. Overexpression of GPX4 in COPD mice significantly restored mitochondrial morphology, reduced iron content and MDA levels, increased GSH and SOD content, and suppressed IL-6, IL-1β, and TNF-α levels, with similar protective effects to Fer-1 (ferroptosis inhibitor). In vitro, GPX4 overexpression improved CSE-induced lung epithelial cell viability reduction, inhibited ferroptosis (decreased iron and lipid peroxidation), and attenuated inflammatory response. In conclusion, GPX4 is downregulated in COPD, and its overexpression alleviates CS/CSE-induced lung injury by inhibiting ferroptosis and inflammation. GPX4 may serve as a potential therapeutic target for COPD.