Dexmedetomidine suppresses ferritinophagy-mediated ferroptosis in myocardial ischemia/reperfusion injury via the YAP1/NCOA4 pathway.

The present study aimed to investigate the mechanism by which dexmedetomidine (Dex) mitigates myocardial ischemia/reperfusion injury (MIRI) through the regulation of ferritinophagy-mediated ferroptosis. In vivo, a rat MIRI model was established by surgical ligation of the coronary artery to evaluate the infarct area and histopathological changes. In vitro, H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) treatment to assess cell viability, lipid peroxidation levels, intracellular Fe2+ levels, and mitochondrial and autophagosome morphology using transmission electron microscopy (TEM). Yes-associated protein 1 (YAP1) and nuclear receptor coactivator 4 (NCOA4) mRNA levels were quantified using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), while Western blotting was employed to assess protein levels related to ferritinophagy and associated signaling pathways. Our findings demonstrate that Dex pretreatment significantly reduced infarct size and histopathological damage in MIRI rats. In H/R-injured H9c2 cells, Dex markedly improved cell viability, reduced Fe2+ accumulation and lipid peroxidation, inhibited ferroptosis, and suppressed the expression of ferritinophagy-related markers. Furthermore, Dex significantly upregulated YAP1 expression; however, YAP1 inhibition attenuated Dex's protective effects. Silencing NCOA4 via siRNA further confirmed that NCOA4 acts downstream of YAP1 to mediate Dex's regulation of ferritinophagy and ferroptosis. In conclusion, Dex protects against MIRI by inhibiting ferritinophagy-mediated ferroptosis through the YAP1/NCOA4 signaling pathway.