Polystyrene nanoplastics trigger ferroptosis-dependent liver injury caused by ACSL4 overaccumulation.

Abstract

Nanoplastics (NPs) are persistent environmental pollutants that can accumulate in the liver, but the mechanisms of their hepatotoxicity remain poorly understood. Here, using AML12 cells and a mouse model, we investigated how polystyrene nanoplastics (PS-NPs) cause liver injury. Exposure to PS-NPs induced dose-dependent cytotoxicity and ferroptosis, evidenced by elevated Fe²⁺ and reactive oxygen species (ROS) levels, enhanced lipid peroxidation, glutathione peroxidase 4 (GPX4) downregulation, and acyl-CoA synthetase long chain family member 4 (ACSL4) upregulation. PS-NPs exposure increased hepatic pathological injury scores and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in vivo. Treatment with ferrostatin-1 (Fer-1) markedly attenuated these changes. Mechanistically, PS-NPs exposure disrupted lysosomal function, as shown by reduced expression of lysosome-associated membrane proteins and increased lysosomal pH. This lysosomal impairment hindered degradative capacity and led to ACSL4 accumulation. Restoring lysosomal function with NKH477 reduced ACSL4 levels. Together, these findings suggest that PS-NPs promote hepatocyte ferroptosis through lysosomal dysfunction and subsequent ACSL4 accumulation. This study provides new insight into the mechanisms of PS-NPs-induced liver toxicity and highlights potential targets for intervention.