B76-16 The Iron Grip of COPD: The Role of Ferroptosis in the Initiation of Early Stage COPD

Rationale COPD is a progressive condition marked by airflow obstruction and lung tissue destruction. Given the emerging role of ferroptosis in COPD pathogenesis, this study aims to elucidate the link between iron uptake and the regulation of ferroptotic cell death in epithelial cells. Understanding this connection may uncover novel targets to prevent ferroptosis and thereby offer new therapeutic strategies to slow or halt COPD progression. Methods We investigated single-cell transcriptomics of human lungs across various COPD stages and in mice to characterize ATII cell heterogeneity in relation to ferroptosis. Functional readouts and mechanistic analyses were performed using in-vivo and ex-vivo experiments combined with lipidomic analysis for the identification of crucial lipid species. Results We identified a distinct ATII subcluster with heightened ferroptosis sensitivity, indicated by elevated acyl-CoA synthetase long chain family member 4 (ACSL4) expression and an enhanced iron transporter profile. We also mechanistically delineated that iron influx regulates ACSL4 expression through mTOR and HIF-1α signaling. Finally, liproxstatin-1 reduced in-vivo disease features, suggesting ferroptosis inhibition as a potential promising therapeutic approach. Conclusions Our study reveals significant regulatory mechanisms linking iron metabolism with ACSL4-mediated ferroptosis in ATII cells. These findings offer new insights into COPD pathogenesis and identifying potential targets for future therapeutic strategies.