Adverse outcome pathway (AOP) framework for predicting toxic mechanisms in E-cigarette-induced lung injury.

This study establishes an Adverse Outcome Pathway (AOP) framework to decode pulmonary injury mechanisms induced by E-cigarette constituents, emphasizing the structural properties of propylene glycol (PG), vegetable glycerin (VG), and nicotine in driving oxidative-inflammatory cascades. Computational toxicogenomics leveraging the Comparative Toxicogenomics Database (CTD) identified 1214 chemical-gene interactions specific to PG/VG pyrolysis byproducts (formaldehyde, acrolein) and nicotine, with 83.7 % overlap with lung injury-associated genes from public repositories. Furthermore, analysis revealed Hippo pathway inhibition in lung tissues harvested from patients with lung cancer attributable to long-term smoking. Similarly, in vitro experiments revealed that exposure of bronchial epithelial cells to E-cigarette components suppressed of Hippo pathway kinases. This suppression induced the nuclear translocation of YAP/TAZ and consequently led to the hypersecretion of pro-inflammatory cytokines, including IL-6 and TNF-α. Moreover, a murine model subjected to chronic E-cigarette aerosol exposure manifested oxidative lung injury and neutrophilic infiltration. These findings collectively imply that E-cigarette exposure can induce lung injury, and upon prolonged exposure, may be associated with an increased risk of cancer development. Quantitative weight-of-evidence (QWOE) modeling delineated the following cascade: 1) PG/VG thermal degradation generates reactive carbonyls (KE1: oxidative stress), 2) nicotine synergistically amplifies inflammation (KE2: chronic inflammation), and 3) Hippo/YAP axis suppression (KE3) drives genomic instability via impaired DNA repair fidelity. This AOP framework establishes a predictive paradigm linking structural properties of nicotine delivery systems to signaling perturbations, advancing toxicity assessment for next-generation tobacco products.