6PPD-quinone exposure impairs erectile function through dysregulation of the HIF-1α/eNOS/NO axis: multi-omics and in vivo evidence
- 1Department of Urology, Beijing Anzhen Nanchong Hospital of Capital Medical University & Nanchong Central Hospital
- 2Department of Andrology, Nanjing Drum Tower Hospital, Affiliated hospital of Nanjing University Medical School
- 3Department of Urology, Affiliated Hospital of Southwest Medical University
Abstract
Background: 6PPD-quinone (6PPD-Q), a transformation product of the tire antioxidant 6PPD, has emerged as an environmental contaminant with potential reproductive toxicity. However, its role in erectile dysfunction (ED) and the underlying mechanisms remain unclear.
Methods: This study integrated network toxicology, transcriptomics, single-cell RNA sequencing, machine learning, Mendelian randomization, molecular docking, molecular dynamics simulation, and animal experiments to investigate the potential mechanisms linking 6PPD-Q exposure to ED.
Results: A total of 134 genes were identified at the intersection of the 6PPD-Q- and ED-related gene sets. Integration of bulk and single-cell transcriptomic data, followed by LASSO and SVM-RFE analyses, prioritized ACO1, HIF1A, PDK4, and PTPN11. Among these genes, only HIF1A showed a significant association with ED risk in the Mendelian randomization analysis. Molecular docking and a 100-ns molecular dynamics simulation supported the structural plausibility of an interaction between 6PPD-Q and HIF-1α. In rats, 6PPD-Q exposure reduced the ICPmax/MAP ratio and cavernosal NO levels without affecting testosterone. These changes were accompanied by increased HIF-1α and decreased p-eNOS, eNOS, and p-eNOS/eNOS levels in the corpus cavernosum. PX-478 partially restored eNOS/NO signaling and erectile function.
Conclusion: These findings suggest that 6PPD-Q may contribute to ED by activating HIF1A-related stress responses and impairing eNOS/NO-mediated endothelial relaxation.
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BibTeX
@article{meng20266ppdquinone,
title = {{6PPD-quinone exposure impairs erectile function through dysregulation of the HIF-1α/eNOS/NO axis: multi-omics and in vivo evidence}},
author = {Chunyang Meng and Yuqi Li and Xinyao Zhu and Yifan Li and Yuelin Du and Zhongyou Xia},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1912092},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1912092/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - 6PPD-quinone exposure impairs erectile function through dysregulation of the HIF-1α/eNOS/NO axis: multi-omics and in vivo evidence
AU - Chunyang Meng
AU - Yuqi Li
AU - Xinyao Zhu
AU - Yifan Li
AU - Yuelin Du
AU - Zhongyou Xia
PY - 2026
DA - 2026/10/16
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1912092
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1912092/full
AB - Background: 6PPD-quinone (6PPD-Q), a transformation product of the tire antioxidant 6PPD, has emerged as an environmental contaminant with potential reproductive toxicity. However, its role in erectile dysfunction (ED) and the underlying mechanisms remain unclear. Methods: This study integrated network toxicology, transcriptomics, single-cell RNA sequencing, machine learning, Mendelian randomization, molecular docking, molecular dynamics simulation, and animal experiments to investigate the potential mechanisms linking 6PPD-Q exposure to ED. Results: A total of 134 genes were identified at the intersection of the 6PPD-Q- and ED-related gene sets. Integration of bulk and single-cell transcriptomic data, followed by LASSO and SVM-RFE analyses, prioritized ACO1, HIF1A, PDK4, and PTPN11. Among these genes, only HIF1A showed a significant association with ED risk in the Mendelian randomization analysis. Molecular docking and a 100-ns molecular dynamics simulation supported the structural plausibility of an interaction between 6PPD-Q and HIF-1α. In rats, 6PPD-Q exposure reduced the ICPmax/MAP ratio and cavernosal NO levels without affecting testosterone. These changes were accompanied by increased HIF-1α and decreased p-eNOS, eNOS, and p-eNOS/eNOS levels in the corpus cavernosum. PX-478 partially restored eNOS/NO signaling and erectile function. Conclusion: These findings suggest that 6PPD-Q may contribute to ED by activating HIF1A-related stress responses and impairing eNOS/NO-mediated endothelial relaxation.
SN - 1664-2392
ER -