Acute ozone exposure induced lung impairments in aged mice: multi-omics evidence.

Acute ozone (O3) exposure poses significant health risks to the elderly, yet its molecular mechanisms remain poorly defined. Here, we established an aged murine model (16-month C57BL/6J male mice) subjected to ozone (1.0 ppm, 6 h) and integrated lung histopathology, respiratory function, serum/lung metabolomics, and gut microbiota analysis at 7 days after exposure to explore underlying metabolic- microbiota response and possible mechanisms. Our data demonstrated that acute exposure to ozone triggered transient ventilatory dysfunction and residual histological alterations, including alveoli destruction and inflammation. In parallel, metabolic disturbances in pulmonary amino acid biosynthesis/metabolism and serum glycerophospholipid metabolism occurred, predominantly affecting autophagy and ferroptosis. Crucially, the potential involvement of the gut-lung axis was supported by ozone-induced gut microbiota dysbiosis (e.g., depletion of Muribaculaceae, Parasutterella) and its strong correlations with lung damage and metabolic disorders. Mechanistically, our data indicated that ozone activated HIF-1α signaling, contributing to lipid peroxidation and ferroptosis. Overall, these data suggested that HIF-1α-associated ferroptosis, along with systemic metabolic perturbations and gut microbiota alterations, may serve as a regulator for ozone-induced pulmonary injury in aging populations.