6PPD and 6PPDQ exposure promote the proliferation and migration of non-small cell lung cancer cells through PTEN dysfunction and ARG2-mediated metabolic reprogramming.

N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a widely used antioxidant in tire rubber. Exposure to 6PPD and its quinone derivative, 6PPDQ, has increasingly been linked to environmental pollution and potential health risks. Given the established association between environmental contaminants and the incidence of lung cancer-particularly the prevalence of non-small cell lung cancer (NSCLC) as a major malignancy-the specific effects of 6PPD and 6PPDQ on NSCLC progression remain unexplored. Here, we demonstrate that 6PPD and 6PPDQ significantly promote NSCLC cell proliferation and migration by targeting the PTEN-PI3K/AKT signaling axis and inducing ARG2-mediated metabolic reprogramming. Using single-cell metabolomics, we identified shared metabolic characteristics in NSCLC cells exposed to 6PPD/6PPDQ, including disruptions in amino acid metabolism, tricarboxylic acid (TCA) cycle, and nucleotide synthesis. Mechanistically, 6PPD and 6PPDQ interacted with key residues in the C2 domain of PTEN, reducing its catalytic activity and leading to sustained activation of the PI3K/AKT pathway. Activation of the PI3K/AKT pathway further enhanced ARG2 expression, thereby promoting metabolic reprogramming to support NSCLC cell proliferation and migration. These results confirmed the pivotal role of the PI3K/AKT pathway in 6PPD and 6PPDQ-induced NSCLC progression. Our findings revealed novel molecular mechanisms by which 6PPD and 6PPDQ drove NSCLC progression, and confirmed their carcinogenic potential and role in pollution-related lung cancer risk. Moreover, the study highlighted the urgent need for further investigation into their health impacts.