Ferroptosis and iron homeostasis in chronic obstructive pulmonary disease: Therapeutic opportunities of iron chelators

Abstract

Purpose

To review the role of ferroptosis, an iron-dependent form of regulated cell death, in chronic obstructive pulmonary disease (COPD), and to explore the therapeutic opportunities of iron chelators in mitigating ferroptosis-driven lung injury.

Methods

We performed a structured search of PubMed, Scopus, and Web of Science from inception to Dec 31, 2024, using the terms “ferroptosis,” “iron homeostasis,” “iron chelators,” “lipid peroxidation,” and “COPD.” Of the 86 records identified, 45 met the predefined criteria (relevance to pulmonary iron metabolism, ferroptotic mechanisms, and therapeutic interventions) and were included in the narrative synthesis.

Results

Dysregulated iron handling in COPD leads to increased labile iron pools in airway epithelial cells and alveolar macrophages, promoting Fenton chemistry, reactive oxygen species generation, and lipid peroxidation cascades, which trigger ferroptosis. Classical iron chelators, such as deferoxamine, deferiprone, and deferasirox, have shown efficacy in preclinical models by sequestering redox-active iron and preserving mitochondrial integrity. Novel synthetic chelators and nanoparticle-based delivery systems offer lung-specific iron removal with improved safety. The integration of trace-element biomarkers, including serum ferritin, hepcidin, transferrin saturation, and lipid peroxidation products, provides potential tools for patient stratification and therapy monitoring.

Conclusion

Targeting iron dysregulation and ferroptosis through advanced chelation strategies holds promise as a novel therapeutic approach for COPD. Combining mechanistic insights with precision delivery technologies may enhance treatment efficacy and improve clinical outcomes by mitigating iron-driven oxidative lung injuries.