Multiomics profiling reveals systemic biological responses to severe subacute exposure to heated tobacco products in rats.

Tobacco use is detrimental to human health and poses a high risk of various chronic lung diseases and lung cancers. Heated tobacco products (HTPs) are gaining attention on the market as potential reduced-risk alternatives to combustible cigarettes, but their potential health risks remain elusive. Here, we evaluated the global biological responses to HTP exposure in vivo via multiomics. In brief, the rats were subjected to subacute (4 weeks) exposure to combustible cigarette smoke (CS) as a positive control or HTP aerosols, and their lung and serum samples were assayed via clinical biochemical tests, histological examination, and multiomics (proteomics and metabolomics). HTP and CS exposure led to slight weight loss and lung lesions, such as a thickened alveolar interstitium and diminished alveolar space, whereas the severity of lung injury tended to be milder in the HTP group. Proteomic analyses revealed that HTP exposure induced several biological processes similar to those associated with CS exposure, such as redox perturbation, extracellular matrix production, metabolic alterations, and certain unique biological processes, such as proteolytic metabolism and negative immune regulation, in lung tissues. Integrated analysis of multiomics data revealed that HTP exposure perturbed several major metabolic pathways, such as energy metabolism (e.g., the citrate cycle and oxidative phosphorylation), amino acid metabolism (e.g., arginine), and fatty acid metabolism (e.g., arachidonic acid) pathways, in lung tissues. This study suggests that multiomics is a powerful means to evaluate the health risks of subacute tobacco exposure and that HTP exposure can induce biological processes and metabolic pathways related to lung inflammation and fibrosis.