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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

6PPDQ Promotes Cutaneous Squamous Cell Carcinoma Growth with PI3K-Akt/MMP9 Activation: Evidence from Integrated Network Toxicology and Experimental Investigation

  • Dekun Song1,2,3
  • Yulu Chen1,2,3
  • Yue Wu4
  • Yuhao Wu1,2,3
  • Lunhui Chang1,2,3
  • Xuan Liu1,2,3
  • Xiaoxiang Xu2,5
  • Guorong Yan1,2,3
  • Guolong Zhang1,2,3
5 affiliations
  1. 1Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
  2. 2Skin Cancer Center, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
  3. 3Institute of Photomedicine, School of Medicine, Tongji University, Shanghai 200443, China
  4. 4School of Astronomy and Space Science, Nanjing University, Nanjing 210023, China
  5. 5Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
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Abstract

N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD) and its transformation product 6PPD-quinone (6PPDQ) are emerging tire-derived environmental contaminants, showing a potential tumor-promoting effect. However, their relevance to cutaneous squamous cell carcinoma (cSCC) remains unclear. Here, we used network toxicology and experimental validation to investigate their potential involvement in cSCC progression. A total of 91 candidate genes were identified, and enrichment analysis revealed their participation in oxidative stress response, epithelial proliferation, extracellular matrix degradation, and oncogenic pathways, including PI3K-Akt, MAPK, and IL-17 pathways. Machine learning identified six hub genes: MMP1, MMP9, RECK, LGALS3, GSTP1, and FOXM1. Immune profiling and single-cell RNA-sequencing analysis linked hub-gene expression patterns and tumor microenvironment features, with an emphasis on macrophages, T cells, and keratinocytes. Molecular docking prioritized MMP9 among the six candidate proteins, and molecular dynamics simulations characterized predicted MMP9-ligand complexes. Furthermore, 6PPDQ was found to promote cSCC cell proliferation and tumor growth in both in vitro and in vivo experiments. At the molecular level, 6PPDQ exposure was accompanied by increased PI3K p110α expression, elevated p-AKT/AKT ratio, and MMP9 upregulation, consistent with the computational predictions. Pharmacological AKT inhibition attenuated MMP9 upregulation and the 6PPDQ-associated growth response, while MMP9 silencing reduced 6PPDQ-enhanced invasion and wound closure. Overall, this bioinformatics-led exploratory study suggests that 6PPDQ has tumor-promoting potential in experimental cSCC models and proposes PI3K-Akt/MMP9 activation as a preliminary mechanistic hypothesis. These findings provide candidate targets for future mechanistic and environmental risk studies.

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Cite

BibTeXRIS
BibTeX
@article{song20266ppdq,
  title = {{6PPDQ Promotes Cutaneous Squamous Cell Carcinoma Growth with PI3K-Akt/MMP9 Activation: Evidence from Integrated Network Toxicology and Experimental Investigation}},
  author = {Dekun Song and Yulu Chen and Yue Wu and Yuhao Wu and Lunhui Chang and Xuan Liu and Xiaoxiang Xu and Guorong Yan and Guolong Zhang},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = sep,
  doi = {10.3390/ijms27188304},
  url = {https://www.mdpi.com/1422-0067/27/18/8304},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - 6PPDQ Promotes Cutaneous Squamous Cell Carcinoma Growth with PI3K-Akt/MMP9 Activation: Evidence from Integrated Network Toxicology and Experimental Investigation
AU  - Dekun Song
AU  - Yulu Chen
AU  - Yue Wu
AU  - Yuhao Wu
AU  - Lunhui Chang
AU  - Xuan Liu
AU  - Xiaoxiang Xu
AU  - Guorong Yan
AU  - Guolong Zhang
PY  - 2026
DA  - 2026/09/18
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27188304
UR  - https://www.mdpi.com/1422-0067/27/18/8304
AB  - N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD) and its transformation product 6PPD-quinone (6PPDQ) are emerging tire-derived environmental contaminants, showing a potential tumor-promoting effect. However, their relevance to cutaneous squamous cell carcinoma (cSCC) remains unclear. Here, we used network toxicology and experimental validation to investigate their potential involvement in cSCC progression. A total of 91 candidate genes were identified, and enrichment analysis revealed their participation in oxidative stress response, epithelial proliferation, extracellular matrix degradation, and oncogenic pathways, including PI3K-Akt, MAPK, and IL-17 pathways. Machine learning identified six hub genes: MMP1, MMP9, RECK, LGALS3, GSTP1, and FOXM1. Immune profiling and single-cell RNA-sequencing analysis linked hub-gene expression patterns and tumor microenvironment features, with an emphasis on macrophages, T cells, and keratinocytes. Molecular docking prioritized MMP9 among the six candidate proteins, and molecular dynamics simulations characterized predicted MMP9-ligand complexes. Furthermore, 6PPDQ was found to promote cSCC cell proliferation and tumor growth in both in vitro and in vivo experiments. At the molecular level, 6PPDQ exposure was accompanied by increased PI3K p110α expression, elevated p-AKT/AKT ratio, and MMP9 upregulation, consistent with the computational predictions. Pharmacological AKT inhibition attenuated MMP9 upregulation and the 6PPDQ-associated growth response, while MMP9 silencing reduced 6PPDQ-enhanced invasion and wound closure. Overall, this bioinformatics-led exploratory study suggests that 6PPDQ has tumor-promoting potential in experimental cSCC models and proposes PI3K-Akt/MMP9 activation as a preliminary mechanistic hypothesis. These findings provide candidate targets for future mechanistic and environmental risk studies.
SN  - 1422-0067
ER  -