Spatio-Temporal Multi-Omics Profiling of Mechanisms and Biomarkers in Inhaled Drug-Induced Lung Toxicity

Majumder, M. M.; Williams, E. C.; Lindvall, M. O.; Hamm, G.; Jarnuczak, A.; Setyo, L.; Di Poto, C.; Azim, A.; Chen, J.; Iannetta, A. A.; Touza, J. L.; Allman, E.; Miele, E.; Lindren, J.; Sand, E.; Anderberg, R. H.; Oag, S.; Franzen, L.; Costyson, A.; Keith, B. P.; Tan, J.; Jones, S.; Fitzpatrick, P.; Johansson, J.; Prasse, A.; Corkhill, D.; Borde, A.; Hess, S.; Terrilon, S.; Ostridge, K.; Stahl, P.; Aberg, P.; Hornberg, J.; Mohorianu, I.; Ollerstam, A.

doi:10.1101/2025.11.20.689571

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bioRxiv · 10.1101/2025.11.20.689571

Spatio-Temporal Multi-Omics Profiling of Mechanisms and Biomarkers in Inhaled Drug-Induced Lung Toxicity

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Abstract

Comprehensive understanding and early detection of drug-induced lung toxicity remain critical challenges in respiratory drug development. In this study, we propose a multi-omics framework that integrates spatial and temporal tissue-specific transcriptomic signatures with proteomics from minimally invasive biofluids to understand mechanisms and identify safety biomarkers associated with lung toxicity. Using this framework, we identified a panel of candidate biomarkers in bronchoalveolar lavage fluid and plasma, including LCN2/NGAL, RETNLA, SP-D, SPP1/osteopontin, and MMP7, that correlate with histopathological features (e.g., inflammation and epithelial remodeling). We confirmed that these molecular biomarkers were consistently dysregulated across a range of inhaled lung toxicants, human disease (IPF), and environmental exposures (smoke, Alternaria), demonstrating broad applicability across different toxic exposures and translatability. Collectively, this study establishes a robust workflow for mechanism-guided biomarker discovery and proposes a panel of candidates for monitoring drug-induced lung injury in humans.

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Majumder, M. M., Williams, E. C., Lindvall, M. O., Hamm, G., Jarnuczak, A., Setyo, L., Di Poto, C., Azim, A., Chen, J., Iannetta, A. A., Touza, J. L., Allman, E., Miele, E., Lindren, J., Sand, E., Anderberg, R. H., Oag, S., Franzen, L., Costyson, A., Keith, B. P., Tan, J., Jones, S., Fitzpatrick, P., Johansson, J., Prasse, A., Corkhill, D., Borde, A., Hess, S., Terrilon, S., Ostridge, K., Stahl, P., Aberg, P., Hornberg, J., Mohorianu, I., Ollerstam, A.. 2025-11-21. Spatio-Temporal Multi-Omics Profiling of Mechanisms and Biomarkers in Inhaled Drug-Induced Lung Toxicity. https://doi.org/10.1101/2025.11.20.689571

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