Polystyrene Nanoplastics Exacerbate CCl4-Induced Liver Fibrosis by Aggravating Stretch-Induced Mechanical Stress in Hepatic Stellate Cells

Abstract

Although studies on the potential hepatotoxicity of nanoplastic depositions are being conducted, there remains a lack of research on the association between nanoplastic depositions and chronic liver disease. Therefore, this research aimed to explore the influence of polystyrene nanoparticles (PS-NPs) on the progression of liver fibrosis and the mechanisms involved in the hepatic stellate cells (HSCs) activation. Chronic exposure to PS-NPs aggravated CCl4-induced liver fibrosis, as evidenced by enhanced collagen accumulation and elevated alpha-smooth muscle actin (alpha-SMA) expression. Most PS-NPs were accumulated in non-parenchymal liver cells, with Kupffer cells exhibiting the highest uptake. This accumulation was associated with enhanced recruitment of CD68-positive macrophages. However, PS-NPs were not associated with TGF-beta expression in CD68-positive cells. Additionally, CD68-positive cells treated with PS-NPs did not affect alpha-SMA expression in HSCs. Further in vitro experiments revealed that alpha-SMA and pSmad2/3 were directly promoted by PS-NPs in both LX-2 HSCs and primary isolated HSCs, indicating a direct stimulatory effect on HSC activation. PS-NPs enhanced pTGFBR1 expression of HSCs by promoting stretch-induced mechanical stress, suggesting a novel pathway through which nanoplastics may exacerbate fibrogenesis. Our findings provide the first evidence that PS-NPs, as xenobiotic particles, can directly promote HSC activation and exacerbate liver fibrosis, indicating potential health risks associated with chronic nanoplastic exposure.