Integrated network toxicology and multi-omics analysis reveals the role of tobacco-specific carcinogen NNK in idiopathic pulmonary fibrosis pathogenesis.

[UNLABELLED] 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific nitrosamine that has been widely recognized as a major carcinogen contributing to smoking-related lung diseases. Although its involvement in lung cancer has been extensively studied, the underlying pathogenic mechanisms by which NNK contributes to the development of idiopathic pulmonary fibrosis (IPF) remain unclear. In this study, potential IPF-related targets of NNK were identified through integrating multiple public databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to uncover key biological processes associated with NNK-induced IPF. Weighted gene co-expression network analysis (WGCNA) combined with machine learning approaches was employed to screen for core regulatory genes. Furthermore, molecular docking and 100-nanosecond molecular dynamics simulations were utilized to assess the binding interactions between NNK and candidate target proteins. Single-cell RNA sequencing (scRNA-seq) and immune infiltration analyses were also performed to validate gene expression patterns and characterize the immune microenvironment. A total of 204 overlapping targets associated with both NNK exposure and IPF were identified, which were predominantly enriched in the biological processes of oxidative stress, cell cycle regulation, and the FoxO signaling pathway. Six hub genes (BCHE, CD38, MMP7, PLA2G2A, ST6GAL1, and TIMP1) were identified as potential key diagnostic biomarkers. This study suggests that NNK may contribute to IPF progression through multiple mechanisms, including disrupting redox homeostasis, activating fibrotic signaling pathways, and modulating the immune microenvironment. The identified core genes and associated pathways provide novel insights into the molecular mechanisms underlying smoking-related IPF and offer promising targets for future therapeutic strategies.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12931-026-03586-6.