Multi-Omics Profiling of Cigarette Smoke-Associated Changes in Cell Models of Human Liver, Intestine and Lung

Cigarette smoke is a complex mixture that affects toxicological and pharmacological mechanisms in multiple organs, including liver, intestine, and lung. Therefore, an integrated multi-omics approach was applied to characterize cigarette smoke extract (CSE)-induced effects across human in vitro models of liver, intestine and lung. Primary human hepatocytes, biopsy-derived intestinal organoids, alveolar A549 cells, primary bronchial and small airway epithelial cells were exposed to CSE and analyzed using RNA sequencing and untargeted proteomics. Across tissues and omics-layers, activation of aryl hydrocarbon receptor (AHR) signaling and strong induction of CYP1A1 and CYP1B1 was identified as cross-tissue response. CYP1A1 was the only overlapping molecule among deregulated proteins across all in vitro models. Consistent deregulation of G protein-coupled receptor-signaling was observed. Overall, tissue-specific adaptations were identified. Liver models showed upregulation of xenobiotic and metabolic pathways, intestine models displayed downregulation of cell cycle processes consistent with growth arrest. Lung models should be considered cautiously because of heterogeneity between cell models but demonstrated a shared response of CYP1A1 and CYP1B1 deregulation. Cross-omics comparisons of RNA sequencing and proteomics data revealed moderate correlations (ρ = 0.43-0.64) and limited overlap of individual molecules, highlighting the importance of post-transcriptional regulation. Network and upstream regulator analyses predicted a coordinated stress response accompanied by modulation of inflammatory signaling. These findings demonstrate that cigarette smoke induces shared pathway-level responses, alongside tissue-specific adaptations. This underscores the importance of considering multiple organ systems in toxicological and pharmacological assessments. This comprehensive dataset provides a resource that may support further hypothesis-driven analysis of cigarette smoke-related mechanisms.