Yttrium nitrate induces vascular toxicity via ferroptosis: Mechanistic insights into iron dysregulation and lipid peroxidation

The environmental accumulation of yttrium (Y), driven by its increasing industrial applications, has raised concerns regarding its potential health and safety risks. Epidemiological evidence suggests a correlation between chronic environmental Y exposure and an increased risk of hypertension, yet the mechanisms underlying its vascular toxicity remain unclear. Herein, we investigated the subchronic effects of yttrium nitrate (Y(NO 3 ) 3 ) on aortic health using a murine model. After 90 days of Y(NO 3 ) 3 exposure (100 mg/kg·bw), we observed significant reduction in weight gain, elevated systolic blood pressure (SBP), and histopathological signs of vascular remodeling. Using an integrated approach combining lipidomics, biochemical assays, and transcriptomics, we elucidate the mechanism by which Y(NO 3 ) 3 disrupts iron homeostasis, inducing iron overload and triggering extensive lipid peroxidation in aortic tissues. Dysregulation of the xCT/GPX4 axis was found to mediate Y-induced endothelial damage via ferroptosis, as confirmed in both in vitro and in vivo models. Notably, rescuing Y-exposed human umbilical vein endothelial cells with the ferroptosis-specific inhibitor deferoxamine provides direct interventional validation of our findings. Collectively, these findings highlight ferroptosis as a critical pathway linking Y exposure to cardiovascular damage and underscore the potential public health risks posed by rare earth elements. • Ferroptosis as the pivotal mechanism driving Y-induced vascular toxicity. • The xCT/GPX4 axis emerges as a potential therapeutic target for mitigating Y-induced toxicity. • Ferroptosis inhibitor can ameliorate Y-induced vascular injury.