Dexmedetomidine Blocks NCOA4‐Dependent Ferritinophagy to Confer Ferroptosis Resistance in Lung Ischemia Reperfusion Injury via Targeting NRF2

ABSTRACT Lung ischemia reperfusion injury (LIRI) represents an evitable but significant pathologic complication post pulmonary transplantation. Dexmedetomidine (Dex) that is extensively applied as an anesthetic adjuvant in the intensive care setting has increasingly presented outstandingly protective effect on LIRI. This article concerns the elaborate role of Dex in ferroptosis after LIRI and the correlative downstream mechanism. Upon hypoxia/reoxygenation (H/R) in human (A549) and mouse (MLE‐12) alveolar epithelial cells, reverse transcription‐quantitative PCR and western blot analysis tested nuclear receptor coactivator 4 (NCOA4) expression. CCK‐8 kit determined cell viability. Western blot analysis and immunofluorescence assay estimated ferritinophagy. C11‐BODIPY 581/591 staining, western blot analysis, assay kits and ferro‐orange staining appraised ferroptosis. Molecular docking technology investigated the binding affinity between Dex and nuclear factor erythroid 2‐related factor 2 (NRF2). Cell viability was eliminated and ferritinophagy was aggravated in A549 and MLE‐12 cells in response to H/R. Disturbance of NCOA4 or treatment with Dex suppressed the ferroptosis in H/R‐stimulated cells. Also, Dex docked with NRF2 and upregulated NRF2 to concentration‐dependently obstruct NCOA4‐mediated ferritinophagy and ferroptosis in H/R‐challenged cells. Collectively, Dex might protect against NCOA4‐mediated ferritinophagy through targeting NRF2, thereby alleviating ferroptosis during LIRI.