Analysis of the effects of N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine Quinone on lung disorders using computational toxicology and molecular docking

Abstract This study aimed to investigate the potential molecular mechanisms by which N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine Quinone (6PPD-Q), the oxidative metabolite of a tire antioxidant, induces human pulmonary diseases. It focused on three representative lung disorders: lung cancer, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. A systematic analysis was conducted to identify key molecular pathways that 6PPD-Q potentially disrupts. Network toxicology and molecular docking approaches were employed. Disease-associated targets were screened using databases such as PubChem, SwissADME, and GeneCards. A protein–protein interaction network was constructed using the STRING database and Cytoscape to identify core targets. GO and KEGG enrichment analyses were performed using DAVID. Protein structural information was retrieved from UniProt and the PDB. Molecular docking simulations were carried out with AutoDock Vina to validate binding affinity. Results indicated that 6PPD-Q may induce lung cancer, COPD, and pulmonary fibrosis through synergistic effects involving multiple interconnected pathways. Specifically, it triggers oxidative stress and chronic inflammation, impairing innate immune function in the lung. It disrupts proteostasis, including protein synthesis and folding homeostasis. Additionally, it alters apoptosis and cellular proliferation, interferes with critical signal transduction pathways, and modulates cytoskeleton rearrangement. Molecular docking results validated the stable binding of 6PPD-Q to core targets, including ACTB and RPS27A. Moreover, this study revealed intrinsic molecular associations among the three diseases. Collectively, this work provided novel insights into the molecular mechanisms by which the environmental pollutant 6PPD-Q induces multiple pulmonary diseases and establishes inter-disease molecular connections. This establishes a theoretical foundation for the prevention and treatment of pulmonary diseases.