Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice.

The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl 3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl 3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc⁻ axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl 3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y³⁺ and its underlying mechanisms. • Yttrium chloride can induce iron accumulation in mice cardiomyocytes. • Yttrium chloride can trigger ferroptosis through GPX4/GSH/system Xc⁻ axis via the inhibition of Nrf2 signaling pathway. • Yttrium chloride can cause subacute cardiac injury and dysfunction in mice. • Ferroptosis can be a viable target for protecting against YCl 3 -induced cardiotoxicity. [ABSTRACT FROM AUTHOR]