Nuclear factor erythroid 2-related factor 2 alleviates lung endothelial cells injury by inhibition of ferroptosis.

Background: In recent years, the survival rate of preterm infants has significantly improved due to the application of pulmonary surfactant (PS) and advancements in lung-protective mechanical ventilation strategies. However, this has been accompanied by an increased incidence of complications, particularly lung diseases triggered by elevated reactive oxygen species (ROS) induced by hyperoxia. The primary mechanism of hyperoxic lung injury (HLI) involves the excessive production of ROS within cells and the aggregation of inflammatory cells. Currently, no effective prevention or treatment methods are available. Ferroptosis, a newly identified form of cell death, is closely linked to ROS accumulation and is likely involved in HLI. Nuclear factor erythroid 2-related factor 2 () regulates both HLI and ferroptosis, and targeting to inhibit ferroptosis may represent a key therapeutic approach for treating HLI. This study aimed to investigate the involvement of ferroptosis in HLI and to elucidate the regulatory role of .

Methods: We employed the human pulmonary microvascular endothelial cell (HPMEC) model of hyperoxia exposure and corresponding intervention groups. Mitochondrial morphological alterations within HPMECs exposed to hyperoxia and various control groups were examined using transmission electron microscopy (TEM). Cell viability was assessed via the Cell Counting Kit-8 (CCK-8) assay, whereas intracellular ROS levels were quantified using the dichlorodihydrofluorescein diacetate (DCFH-DA) probe. Furthermore, the expression levels of and were analyzed through quantitative polymerase chain reaction (qPCR) and western blot techniques.

Results: Relative to the control group, the HPMECs subjected to hyperoxic conditions exhibited diminished viability, heightened ROS levels, decreased expression, and increased expression. These cells also demonstrated mitochondrial morphological alterations characteristic of ferroptosis, including reduced mitochondrial cristae and shrinkage. The application of a ferroptosis inhibitor mitigated cellular damage, lipid peroxidation, and the morphological manifestations of mitochondrial ferroptosis, whereas inhibitor ML385 reversed this effect.

Conclusions: Ferroptosis appears to contribute to the pathogenesis of HLI, with serving a protective function by mitigating ferroptosis.