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

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 CCl-induced liver fibrosis, as evidenced by enhanced collagen accumulation and elevated -smooth muscle actin (-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- expression in CD68-positive cells.Additionally, CD68positive cells treated with PS-NPs did not affect -SMA expression in HSCs.Further in vitro experiments revealed that -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.