Exacerbated Hepatotoxicity in Non-alcoholic Fatty Liver by Copper Sulfide Nanoparticles

Abstract

Background Copper sulfide nanoparticles represent a promising photothermal agent with significant commercial potential. Despite these advantages, the safety assessment of copper sulfide NPs, particularly for tumor patients with liver diseases, remains insufficient. Non-alcoholic fatty liver (NAFL) is a condition characterized by the accumulation of excess fat in the liver, potentially leading to increased sensitivity to foreign substances and progression to more severe liver disease. Results To explore the differential hepatotoxicity of copper sulfide NPs in NAFL conditions, we synthesized and characterized large-sized (LNPs, 15.1 nm) and small-sized (SNPs, 3.5 nm) BSA@Cu_2 − xS NPs. A NAFL rat model fed with high fat diet (HFD) was successfully established for a 14-day subacute toxicity study by daily repeated administration of BSA@Cu_2 − xS NPs. Our findings from serum biochemistry and histopathological examinations revealed that copper sulfide at both sizes NPs induced more pronounced liver damage in NAFL rats compared to rats fed with normal diet. Additionally, LNPs exhibited significantly higher intrahepatic accumulation than SNPs, leading to more severe hepatotoxicity. Transcriptome sequencing analysis showed that LNPs activated inflammation and DNA damage repair pathways in the livers of NAFL rats, while SNPs displayed minimal inflammation. In vitro 3D NAFL spheroids experiments demonstrated that LNPs, but not SNPs, triggered a distinct release of inflammatory factors and increased reactive oxygen species through Kupffer cells. Conclusions These results highlight that NAFL condition exacerbated the hepatotoxicity of BSA@Cu_2 − xS NPs, with SNPs emerging as relatively safer photothermal agents compared to LNPs, suggesting superior potential for clinical applications.