B76-13 Pharmacological Inhibition of Ferroptosis Attenuates Pulmonary Inflammation and Emphysema in Experimental Chronic Obstructive Pulmonary Disease (COPD)

Abstract Rationale Ferroptosis, an iron-dependent form of regulated necrosis driven by lipid peroxidation, contributes to oxidative stress and tissue injury. We previously reported altered ferroptosis markers and increased lipid peroxidation in lungs of patients with chronic obstructive pulmonary disease (COPD) (Geirnaert et al., ERJ Open Research 2025;11:TP213). In this study we investigated the therapeutic potential of ferroptosis inhibition using the novel inhibitor UAMC-3203 in experimental models of COPD. Methods C57BL/6 mice were exposed to air or cigarette smoke (CS) for 4 weeks to induce airway inflammation or subjected to oropharyngeal elastase instillation to model emphysema. Animals received daily intranasal administration of UAMC-3203 at increasing doses or vehicle control. Bronchoalveolar lavage (BAL) and lung tissue were analysed for inflammatory cells, gene expression, and emphysema. Results Pharmacological inhibition of ferroptosis with UAMC-3203 dose-dependently attenuated CS-induced pulmonary inflammation, as evidenced by reduced neutrophils, dendritic cells, and CD4+/CD8+ T lymphocytes in BAL. UAMC-3203 also significantly protected against elastase-induced emphysema. RT-PCR analysis revealed that UAMC-3203 normalized the CS-induced upregulation of MMP12 and CXCL1, while restoring the expression of the ferroptosis-inhibitor GPX4. Consistently, single-cell RNA sequencing of lung tissue from severe COPD patients and chronically CS-exposed mice confirmed reduced GPX4 expression in alveolar epithelial cells. Conclusion These findings identify ferroptosis as a key pathogenic mechanism in COPD and demonstrate that its pharmacological inhibition alleviates CS- and elastase-induced inflammation and emphysema. This abstract is funded by: None