Lactate aggravates myocardial Ischemia-Reperfusion injury through SLC39A14-mediated ferroptosis

Abstract Ferroptosis, a new form of iron-dependent regulated cell death, is driven by lipid peroxidation, playing a role in various pathogenic processes. Although the role of ferroptosis in myocardial ischemia-reperfusion injury (MIRI) has been intensively studied, the underlying molecular mechanisms remained largely unclear. Here, we showed that lactate participated in ferroptosis induced by hypoxia/reoxygenation in H9C2 cell. Importantly, hypoxia/reoxygenation induced apoptosis through aggravating ferroptosis by targeting NRF2/system Xc-/GPX4 axis, which reduced ROS scavenging. In addition, lactate promoted SLC39A14 expression followed by elevation of Fe²⁺ uptake, which generated superfluous ROS via the Fenton reaction. The excessive ROS could finally induce lipid peroxidation, thereby leading to ferroptosis characterized by cell apoptosis. Together, our findings suggest that lactate plays a crucial role as a novel regulator of ferroptosis, and reducing lactate levels might potentially offer a promising therapeutic strategy for managing myocardial ischemia-reperfusion injury.