Multiomics Reveals Mitochondrial and Metabolic Perturbations Underlying Cyclotriphosphazene-Induced Lung Injury

Cyclotriphosphazenes (CTPs), widely used as flame-retardant electrolyte additives in lithium batteries, have raised significant environmental and health concerns due to their potential release and human exposure. However, the toxicological effects of CTPs, particularly on pulmonary health, remain poorly understood. This study investigates the impact of long-term CTPs exposure at environmentally relevant doses on lung cells and animal models. In vitro experiments revealed that CTPs exposure impaired mitochondrial function in BEAS-2B cells in a time-dependent manner. Proteomic analysis demonstrated significant alterations in oxidative phosphorylation-related proteins, disrupting the electron transport chain (ETC). Untargeted metabolomics further revealed disruptions in the tricarboxylic acid (TCA) cycle, glutathione metabolism, and purine metabolism, with notably decreased levels of key metabolites. Multiomics integration suggested potential associations between high-dose CTPs exposure and diseases including lipoyltransferase 1 deficiency, Alzheimer's disease, and schizophrenia. In vivo studies confirmed pathological lung damage in mice, including alveolar destruction and pulmonary fibrosis. Additionally, downregulation of <i>N</i>-lauroylsphingosine (NLDP) was identified as a potential metabolic biomarker for CTPs-induced lung injury, offering novel insights for mitigating CTPs' adverse effects. These findings highlight the pulmonary toxicity of CTPs and provide a foundation for future risk assessment and preventive strategies.