Multiomics Profiling of Lung Tissues Reveals an Inflammation–Metabolism Axis Response to High-Temperature and Ozone Exposure

Abstract Environmental stressors associated with heatwaves and ozone (O3) pollution are increasingly recognized as important contributors to metabolic and immune dysfunction, yet the underlying mechanisms remain incompletely understood. Using a newly developed “Temperature–Humidity–Ozone” Exposure System (THOES), the multiomics strategy was systematically applied to examine pulmonary responses due to O3 and high-temperature exposure in male mice and Apoe–/– mice. Microbial 16S rRNA sequencing analysis revealed that high temperature and ozone (HO) exposure and Apoe–/– caused gut microbiota dysbiosis and alterations in metabolic pathways, findings that were further supported by marked changes in lipid- and amino acid–related metabolites. Apoe–/– exacerbated disturbances in lipid-related metabolites linked to oxidative stress and fatty acid β-oxidation. Lipidomics identified remodeling of pulmonary lipid composition across major lipid classes, accompanied by a significant reduction in unsaturated lipid species following HO exposure and Apoe–/–. Complementary proteomic analysis revealed induction of acute-phase proteins and immune-related factors, alongside dysregulation of lipid transport proteins and mitochondrial respiratory components, highlighting activation of innate immune and defense-related pathways. These findings demonstrate that HO exposure induces coordinated immune, metabolic, and lipidomic alterations in the lung, with Apoe–/– conferring heightened susceptibility to disruption of metabolic and lipid homeostasis.