Molecular mechanisms of environmental risk factors for interstitial lung disease

PURPOSE OF REVIEW: Interstitial lung disease (ILD) comprises a diverse group of conditions characterized by lung inflammation and fibrosis. Cumulative lifetime exposures (i.e. the exposome) contribute to ILD onset and progression by interacting with genetic susceptibility and influencing multiple molecular pathways. This review summarizes current evidence evaluating how environmental exposures interact across the genome, epigenome, transcriptome, proteome, metabolome, and microbiome to drive ILD pathogenesis. RECENT FINDINGS: Environmental exposures, including air pollution, influence ILD risk through interactions with genetic factors that modify disease susceptibility. Epigenetic mechanisms, particularly DNA methylation, reflect key pathways through which exposures may contribute to ILD onset and progression and serve as sensitive biomarkers of environmental injury. Exposure-associated molecular alterations can be detected across multiple omic layers, including transcriptomic, proteomic, and metabolomic profiles. In parallel, exposures like cigarette smoking, silica, and air pollution influence the respiratory microbiome, with potential downstream effects on immune responses and fibrogenesis. Integrating these findings highlights environmentally-sensitive pathways that may represent novel targets for therapeutic modulation. SUMMARY: Integration of exposomic and multiomic molecular frameworks offers new opportunities to improve ILD risk stratification, prognostication, and precision therapeutic development, while also strengthening our mechanistic understanding of environmentally-mediated disease.