Nanoplastics Mitigate 6PPD-Induced Zebrafish Cardiac Ferroptosis Mediated by the GRK5/p53/SLC7A11 Pathway

Abstract

6PPD, as an antioxidant in tire rubber, constitutes an emerging pollutant together with nanoplastics (NPs) widely present in the environment. This study explored the potential combined toxicity risk of 6PPD and 50 nm polystyrene nanoplastics (PS-NPs) to aquatic ecosystems. The study found that the presence of PS-NPs altered the physicochemical behavior of 6PPD and was associated with reduced cardiac accumulation of 6PPD and its oxidation product 6PPD-Q. The experiment showed that 6PPD activated the p53 signaling pathway by upregulating the expression of GRK5, thereby inhibiting the expression of SLC7A11 and GPX4, leading to increased ROS, iron overload, lipid peroxidation, and mitochondrial damage in zebrafish heart and rat cardiomyocytes (H9C2), thereby triggering ferroptosis. After coexposure of PS-NPs and 6PPD, physicochemical interactions between PS-NPs and 6PPD altered the colloidal state and environmental behavior of the mixture, while the cardiac levels of both 6PPD and 6PPD-Q were reduced, accompanied by weakened ferroptosis-related responses. This study revealed the cardiotoxic mechanism of 6PPD and the mitigation effect of PS-NPs after coexposure, providing a basis for environmental pollution risk assessment.