Microplastics as a Cross‐Disease Driving Risk Factor in Lung Pathogenesis: An Integrative Study Combining In Silico Analysis and Experimental Validation Using Polystyrene Nanoplastics

Microplastics (MPs), as environmental pollutants, have garnered widespread attention. Growing evidence suggests a close association between MP exposure and lung diseases. However, the molecular mechanisms through which MP exposure influences the onset and progression of lung diseases remain unclear. This study positions MP exposure as a cross-disease driving risk factor and employs integrated computational toxicology and bioinformatics approaches to explore potential key targets underlying the impact of MP exposure on the development of lung diseases (COPD, IPF, and LUAD). Common differentially expressed genes (cDEGs) and shared common DEGs (scDEGs) associated with MP exposure and COPD, IPF, and LUAD were identified through database screening and intersection analysis. A protein-protein interaction (PPI) network was constructed using the STRING database, followed by enrichment analysis. The expression patterns and cellular localization of key targets among the shared common differentially expressed genes were validated using single-cell datasets of COPD, IPF, and LUAD. Finally, experimental validation was conducted based on the cell types identified through analysis. MP exposure may influence the occurrence and progression of COPD, IPF, and LUAD through mechanisms involving the cell cycle, mitosis, and DNA repair. Potential key targets identified include CDK1, BRCA1, and CCND1. Validation via database and single-cell analyses suggests that MP exposure may increase the risk of COPD, IPF, and LUAD by upregulating CDK1 expression in pulmonary fibroblasts. Experimental validation in human pulmonary fibroblasts demonstrated that PS-NPs significantly upregulated CDK1 mRNA and protein levels in a dose-dependent manner. CDK1 inhibition experiments confirmed that PS-NP exposure promotes fibrosis in human pulmonary fibroblasts by upregulating CDK1. This study defines MP exposure as a cross-disease driving risk factor and identifies CDK1 as a potential key target mediating the development of MPs-driven lung diseases. This finding offers a new perspective for understanding MPs-related lung diseases and establishes a novel paradigm for exploring the intrinsic connections between pollutant exposure and disease pathogenesis.