Wang Chao, Lin Junhao, Deng Jiewei, Li Xinyan, Zhai Junqiu, Yang Yunyun, Luan Tiangang
Guangdong Provincial Key Laboratory of Water Quality Improvement and Ecological Restoration for Watersheds, School of Ecology, Environment and Resources, Guangdong University of Technology, Guangzhou 510006, China; Guangdong Provincial Laboratory of Chemistry and Fine Chemical Engineering Jieyang Center, Jieyang 515200, China.
School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China; Guangdong Provincial Laboratory of Chemistry and Fine Chemical Engineering Jieyang Center, Jieyang 515200, China.
J Hazard Mater. 2025 Sep 5;495:139088. doi: 10.1016/j.jhazmat.2025.139088. Epub 2025 Jun 27.
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.
N-（1,3-二甲基丁基）-N'-苯基-对苯二胺（6PPD）是一种在轮胎橡胶中广泛使用的抗氧化剂。接触6PPD及其醌衍生物6PPDQ与环境污染和潜在健康风险的关联日益增加。鉴于环境污染物与肺癌发病率之间已确立的关联，尤其是非小细胞肺癌（NSCLC）作为主要恶性肿瘤的患病率，6PPD和6PPDQ对NSCLC进展的具体影响仍未得到探索。在此，我们证明6PPD和6PPDQ通过靶向PTEN-PI3K/AKT信号轴并诱导ARG2介导的代谢重编程，显著促进NSCLC细胞增殖和迁移。使用单细胞代谢组学，我们确定了暴露于6PPD/6PPDQ的NSCLC细胞中的共同代谢特征，包括氨基酸代谢、三羧酸（TCA）循环和核苷酸合成的破坏。从机制上讲，6PPD和6PPDQ与PTEN的C2结构域中的关键残基相互作用，降低其催化活性并导致PI3K/AKT途径的持续激活。PI3K/AKT途径的激活进一步增强了ARG2的表达，从而促进代谢重编程以支持NSCLC细胞的增殖和迁移。这些结果证实了PI3K/AKT途径在6PPD和6PPDQ诱导的NSCLC进展中的关键作用。我们的研究结果揭示了6PPD和6PPDQ驱动NSCLC进展的新分子机制，并证实了它们的致癌潜力以及在与污染相关的肺癌风险中的作用。此外，该研究强调了迫切需要进一步调查它们对健康的影响。
