Combined exposure of nano‐titanium dioxide and polystyrene nanoplastics exacerbate oxidative stress‐induced liver injury in mice by regulating the <i>Keap‐1</i> / <i>Nrf2</i> / <i>ARE</i> pathway

It is well known that polystyrene nanoplastics (PS-NaP) and nano-titanium dioxide (TiO₂ NPs) are frequently co-appeared in daily life and can cause liver injury when they accumulate in the liver. Nonetheless, the combined toxicological impacts and potential molecular mechanisms of PS-NaP and TiO₂ NPs in the hepatic system have not been revealed. Thus, we conducted experiments on C57BL/6 mice exposed to PS-NaP or/and TiO₂ NPs for 4 weeks. The findings suggested that PS-NaP and TiO₂ NPs co-exposed significantly altered the hepatic function parameters, levels of antioxidant-related enzymes and genes expression of Keap-1/Nrf2/ARE signaling pathway, as well as significantly increased the hepatic Ti contents, aggravated hepatic pathological and oxidative stress (OS) damage compared with individual exposure to PS-NaP or TiO₂ NPs. Using N-Acetyl-L-cysteine (NAC), an OS inhibitor, we further demonstrated that OS played a pivotal role in coexposure-induced liver injury. NAC reduced the levels of OS in mice, which mitigated co-exposure-induced liver injury. Taken together, we proposed that PS-NaP and TiO₂ NPs co-exposed activated the Keap-1, then inhibited the recognition of Nrf2 and ARE, consequently exacerbated liver injury. These findings shed light on the co-toxicity and potential mechanism of nanoplastics and nanoparticles, which informed the risk assessment of human exposure to environmental pollutants.