The impacts of polystyrene nanoplastics on colorectal cancer: Evidence from integrated network toxicity and in vitro approaches

Environmental ingestion of polystyrene nanoplastics (PNPLs) raises critical public health concerns, yet their impacts on colorectal cancer (CRC) remain obscure. In this study, network toxicology, and in vitro validation were integrated to evaluate the molecular mechanisms linking PNPLs to CRC. We identified 154 overlapping targets by integrating GEO-derived differentially expressed genes with PNPLs-predicted targets and CRC-associated genes, which are enriched in pathways associated with cancer signaling, apoptosis, oxidative stress, and inflammation. Using protein-protein interaction network, along with two machine learning algorithms (LASSO and Random Forest), we identified seven hub genes in which the expression of these genes was corroborated by the CRC database of TCGA, the CRC dataset of GEO, and the RT-qPCR analysis on HCT-116 cells. Molecular docking demonstrated the significant binding affinities between PNPLs and six hub targets. In vitro experiments with HCT-116 cells revealed PNPLs dose- and time-dependent cytotoxicity. Additionally, PNPLs induced oxidative stress by significant reactive oxygen species (ROS) accumulation, collapse of mitochondrial membrane potential, and decrease of SOD, GPx and CAT activity. Furthermore, PNPLs caused apoptosis while concurrently pronounced pro-inflammatory responses by exciting the release of pro-inflammatory cytokines and mediators, including IL-6, IL-1β, TNF-α, NO, and PGE2. This study suggests the complex toxicity effects of PNPLs on CRC and supports the need for further research into nanoplastics as a potential environmental risk factor for CRC.