Ferroptosis inhibition by ferrostatin-1 attenuates nanoplastic-induced angiogenesis impairment in zebrafish larvae and human microvascular endothelial cells

Nanoplastics (NPs) induce ferroptosis in endothelial cells and zebrafish. • NPs disrupt unsaturated fatty acid metabolism in zebrafish. • NPs downregulate GPX4 and induce lipid peroxidation in vitro and in vivo. • Targeting ferroptosis mitigates NPs-related cardiovascular injury. Nanoplastics (NPs) are widespread environmental pollutants, and their potential cardiovascular toxicity has raised growing concern. This study aimed to investigate whether NPs impair angiogenesis through ferroptosis induction. Zebrafish larvae were exposed to NPs (10-1000 μg/L) or erastin (5 μM) for 48 h. Rescue experiments were performed by co-treatment with ferrostatin-1 (Fer-1, 1 μM). Human microvascular endothelial cell line-1 were treated with NPs at 100 μg/mL for 24 h, with or without Fer-1 (1 μM). NPs exposure resulted in reduced body length, impaired intersegmental vessel formation, and downregulated expression of key angiogenesis-related genes in zebrafish larvae. Additionally, NPs inhibited tube formation, migration, and vascular endothelial growth factor A expression in HMEC-1 cells. Transcriptomic and metabolomic analyses revealed that NPs exposure disrupted unsaturated fatty acid metabolism. NPs induced lipid peroxidation, reactive oxygen species accumulation, elevated malondialdehyde levels, and downregulation of glutathione peroxidase 4 expression, all of which were reversed by treatment with the ferroptosis inhibitor Fer-1. Intervention with Fer-1 not only rescued NPs-induced intersegmental vessel defects but also upregulated the expression of angiogenesis-related genes, thereby effectively ameliorating NPs-induced vascular damage. These findings indicate that ferroptosis is a key mechanism underlying NPs-mediated vascular dysfunction.