Nanoplastics as Hepatic Toxicant Vectors: Interactions with Environmental Chemicals, Organelle Dysfunction, and Regulated Cell Death

The environmental accumulation of nanoplastics (NPs) raises concerns regarding their potential effects on hepatic function. Experimental studies suggest that NP exposure can be related with altered mitochondrial electron transport chain activity, reduced ATP availability, changes in Keap1/Nrf2-mediated antioxidant responses, and impaired mitophagy. NPs have also been linked to cytoskeletal alterations, disrupted autophagic flux, and metabolic disturbances that can contribute to processes relevant to metabolic dysfunction-associated steatotic liver disease (MASLD). This review critically evaluates regulated cell death pathways correlated with NP exposure, containing intrinsic apoptosis, RIPK1/RIPK3/MLKL-mediated necroptosis, and NLRP3/cGAS-STING-associated pyroptosis. The available evidence implicates oxidative stress, mitochondrial and lysosomal dysfunction, altered autophagy, metabolic reprogramming, and regulated cell death in nanoplastic-associated hepatic effects. However, mechanistic evidence varies in strength, and observed responses depend on particle composition, surface characteristics, exposure conditions, and experimental models. Particular attention is given to distinguishing associative findings from experimentally supported causal mechanisms and to the limitations of extrapolating results from polystyrene nanoparticle models to other nanoplastics. By integrating evidence on mitochondrial quality control, microRNA-mediated metabolic regulation, and modulated cell death, this review identifies main knowledge gaps relevant to future mechanistic studies and toxicological risk assessment.