Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lung, mainly caused by cigarette smoke (CS) and characterized by bronchiolitis and emphysema. Ferroptosis, an iron-dependent form of regulated necrosis, is characterized by lipid peroxidation that leads to oxidative stress and cell death.

This study aimed to evaluate the presence of ferroptosis markers in lungs of COPD patients and investigate the therapeutic potential of inhibiting ferroptosis in two experimental COPD models using the ferroptosis inhibitor UAMC-3203.

mRNA expression and protein levels of the key ferroptosis regulator glutathione peroxidase 4 (GPX4) were quantified in lung tissue from individuals with and without COPD using RT-PCR and immunohistochemistry. Lipid peroxidation in lung macrophages was evaluated through E06 staining. C57BL/6 mice were either exposed to air or CS for 4 weeks to examine pulmonary inflammation or subjected to oropharyngeal elastase instillation to model the development of pulmonary emphysema. The animals were treated daily with increasing doses of UAMC-3203 or placebo via intranasal instillation.

Results showed that GPX4 mRNA expression in lung tissue and GPX4 protein levels in airway epithelium were significantly higher in patients with severe COPD. E06 staining revealed significantly higher lipid peroxidation in lung macrophages of current smokers both with and without COPD. Pharmacological inhibition of ferroptosis using UAMC-3203 dose-dependently attenuated inflammation in bronchoalveolar lavage in CS-exposed mice and significantly protected against elastase-induced emphysema.

These findings suggest that ferroptosis is increased in lungs of COPD patients and contributes to the pathogenesis of the disease.