Abstract
Ferroptosis is an iron-dependent form of cell death that contributes to the pathophysiology of chronic obstructive pulmonary disease (COPD). Ferroptosis-associated factors, including acyl-CoA synthetase long-chain family 4 (ACSL4), soluble transferrin receptor 1 (sTfR1), glutathione peroxidase 4 (GPX4), and apoptosis-inducing factor 2, (AIFM2) mediate intracellular iron metabolism, oxidative stress, and lipid peroxidation. Despite their potential clinical relevance, no studies have measured serum levels of these factors with respect to the manifestations of COPD. The study enrolled 179 stable, non-anemic outpatients diagnosed with COPD and 57 age- and sex-matched smokers who did not carry this diagnosis. Clinical characteristics were assessed together with baseline serum levels of the four ferroptosis-associated factors. Moderate and severe exacerbations of COPD were monitored over the following 12 months. Soluble TfR1 levels were higher and GPX4 levels were lower among those in the COPD group compared to smokers without COPD (p = 0.004 and p = 0.002, respectively). The sTfR1/GPX4 ratio was also higher among those in the COPD group (p = 0.001). Multivariate analysis identified low serum GPX4 (OR 5.475; p = 0.001), and high sTfR1/GPX4 (OR 4.293; p < 0.001) as independent predictors of poor performance on the six-minute walk distance test. Additionally, high sTfR1 (HR 1.850; p = 0.004), low GPX4 (HR 2.301; p = 0.001), and high sTfR1/GPX4 (HR 2.223; p < 0.001) were associated with increased risk of moderate exacerbation. High sTfR1 (HR 2.970; p = 0.014), low GPX4 (HR 3.753; p = 0.012), and high sTfR1/GPX4 (HR 3.668; p = 0.009) were also independent predictors of severe exacerbation. Serum levels of ferroptosis-associated factors were significantly different in patients diagnosed with COPD compared to smokers who had not been diagnosed with this disorder. Elevated sTfR1, low levels of GPX4, and higher sTfR1/GPX4 were associated with poor clinical outcomes, including reduced exercise capacity and an increased risk of moderate and severe exacerbations. These findings highlight the potential of ferroptosis-associated factors, particularly the calculated sTfR1/GPX4, in predicting COPD progression and the risk of exacerbation in stable, non-anemic outpatients.