Glucocorticoid triggers endothelial cell ferroptosis via NOX4-mediated reactive oxygen species and lipid peroxidation
Year: 2025
Type: article
Abstract: Background Glucocorticoids (GCs) are widely used in acute and critical illnesses, but long-term and high-dose use of GCs can cause several vascular side effects. However, the underlying mechanisms are not well-understood. Ferroptosis, a novel form of reactive oxygen species (ROS)-dependent cell death, is characterized by intracellular iron accumulation and lipid peroxidation. NADPH oxidase 4 (NOX4) is a major source of ROS. The roles of ferroptosis and NOX4 in GC-induced endothelial injury remain unknown. Methods Human umbilical vein endothelial cells (HUVECs) were exposed to varying concentrations of dexamethasone (DEX) to evaluate ferroptosis and NOX4 expression. Further mechanistic studies were conducted using NOX4-overexpressing adenovirus (Ad-NOX4), NOX4 small interfering RNA (siRNA), ferrostatin-1 (FER-1), and erastin. Results Our findings demonstrate that DEX induces ferroptosis in HUVECs. Inhibition of ferroptosis with FER-1 prevents DEX-induced reduction in HUVEC viability. Furthermore, DEX treatment increases NOX4 expression in HUVECs, and NOX4 overexpression with Ad-NOX4 promotes ferroptosis. NOX4 knockdown with siRNA suppresses DEX-induced ROS production, lipid peroxidation, and ferroptosis, thereby improving the viability, angiogenesis, and migration capacity of DEX-treated HUVECs. However, the protective effect of NOX4 knockdown is negated by the reactivation of ferroptosis with erastin. Conclusion GC-induced endothelial cell ferroptosis occurs through NOX4-mediated ROS production and lipid peroxidation, leading to cell death, impaired angiogenesis, and migration dysfunction. Inhibition of ferroptosis and NOX4 knockdown ameliorate GC-induced endothelial damage and dysfunction.
Authors: Lijun Fang, Jiazheng Chen, Wenqiang Li, Linmao Lyu
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4408964247