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  3. 6PPD and 6PPDQ exposure promote the proliferation and migration of non-small cell lung cancer cells through PTEN dysfunction and ARG2-mediated metabolic reprogramming

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

  • J Hazard Mater. 2025 Jun 27:495:139088. doi: 10.1016/j.jhazmat.2025.139088.
Chao Wang 1,  Junhao Lin 2,  Jiewei Deng 3,  Xinyan Li 2,  Junqiu Zhai 4,  Yunyun Yang 5,  Tiangang Luan 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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. Electronic address: jwdeng@gdut.edu.cn.
  • 4 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 5 Guangdong Provincial Key Laboratory of Chemical Measurement and Emergency Test Technology, Guangdong Provincial Engineering Research Center for Ambient Mass Spectrometry, Institute of Analysis, Guangdong Academy of Sciences (China National Analytical Center, Guangzhou), Guangzhou 510070, China.
  • 6 School of Environmental and Chemical Engineering, Wuyi University, Jiangmen 529020, China. Electronic address: cesltg@mail.sysu.edu.cn.
PMID: 40602111 DOI: 10.1016/j.jhazmat.2025.139088
Abstract

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.

Keywords

6PPD; 6PPDQ; Metabolic reprogramming; NSCLC; PTEN-PI3K/AKT pathway.

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