Investigating potential molecular mechanisms linking 6PPD-quinone exposure to Intervertebral Disc Degeneration: A network toxicology, molecular docking, and molecular dynamics simulation study
- 1Bayi Orthopedic Hospital, China RongTong Medical Healthcare Group Co., Ltd., Chengdu, China.
- 2Department of Orthopedics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- 3School of Sports Medicine and Health, Chengdu Sports University, Chengdu, China.
Abstract
As an emerging pollutant derived from tire rubber, 6PPD-quinone (6PPD-Q) has raised public health concerns due to widespread environmental exposure; however, its potential toxicological effects on avascular tissues such as intervertebral discs remain unclear. This study integrated network toxicology, molecular docking, and molecular dynamics (MD) simulation to investigate the potential mechanisms linking 6PPD-Q exposure to intervertebral disc degeneration (IVDD). ADMET toxicological predictions indicated high model-predicted probabilities for SR-MMP and SR-ARE activation. Through multidimensional database integration, 59 common targets potentially associated with 6PPD-Q and IVDD were identified. Protein–protein interaction network analysis further identified five hub genes: PTGS2, MMP2, SMAD3, RELA, and GSK3B. Functional enrichment analysis suggested that these targets were mainly involved in AGE-RAGE, PI3K-Akt, MAPK, TNF, and IL-17 signaling pathways, collectively implicating oxidative stress, inflammation, and apoptosis. Molecular docking showed favorable predicted binding between 6PPD-Q and the five hub proteins, with RELA exhibiting the most favorable docking score (−8.82 kcal/mol). A subsequent 100-ns MD simulation of the 6PPD-Q–RELA complex showed relatively stable RMSD, Rg, and SASA profiles and a concentrated low-energy conformational basin, supporting its dynamic stability under the simulated conditions. Collectively, these computational findings suggest potential molecular links between 6PPD-Q exposure and IVDD and provide hypotheses for subsequent experimental validation.
Related
- M6A demethylation of IRF9 by ALKBH5 promotes intervertebral disc degeneration via nucleus pulposus cell necroptosis
- Extracellular vesicles reprogram cytokine signaling and the immune microenvironment in intervertebral disc degeneration
- Integrated transcriptomic, machine learning, and network pharmacology analyses reveal shared inflammatory biomarkers between intervertebral disc degeneration and osteoporosis
- Aquaporin 9 drives macrophage M1 polarization and intervertebral disc degeneration by stabilizing p65 to activate NF-κB signaling
- Molecular Mechanisms of 6PPD and 6PPD-Q Toxicity in Neurodegenerative Diseases: A Network Toxicology and Experimental Validation Study
BibTeX
@article{yang2026investigating,
title = {{Investigating potential molecular mechanisms linking 6PPD-quinone exposure to Intervertebral Disc Degeneration: A network toxicology, molecular docking, and molecular dynamics simulation study}},
author = {Bin Yang and Xiangjin Wang and Li Zhuo and Yutong Chen and Qiansong He},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0359621},
url = {https://doi.org/10.1371/journal.pone.0359621},
note = {CC BY},
}
RIS
TY - JOUR
TI - Investigating potential molecular mechanisms linking 6PPD-quinone exposure to Intervertebral Disc Degeneration: A network toxicology, molecular docking, and molecular dynamics simulation study
AU - Bin Yang
AU - Xiangjin Wang
AU - Li Zhuo
AU - Yutong Chen
AU - Qiansong He
PY - 2026
DA - 2026/10/22
JO - PLOS One
DO - 10.1371/journal.pone.0359621
UR - https://doi.org/10.1371/journal.pone.0359621
AB - As an emerging pollutant derived from tire rubber, 6PPD-quinone (6PPD-Q) has raised public health concerns due to widespread environmental exposure; however, its potential toxicological effects on avascular tissues such as intervertebral discs remain unclear. This study integrated network toxicology, molecular docking, and molecular dynamics (MD) simulation to investigate the potential mechanisms linking 6PPD-Q exposure to intervertebral disc degeneration (IVDD). ADMET toxicological predictions indicated high model-predicted probabilities for SR-MMP and SR-ARE activation. Through multidimensional database integration, 59 common targets potentially associated with 6PPD-Q and IVDD were identified. Protein–protein interaction network analysis further identified five hub genes: PTGS2, MMP2, SMAD3, RELA, and GSK3B. Functional enrichment analysis suggested that these targets were mainly involved in AGE-RAGE, PI3K-Akt, MAPK, TNF, and IL-17 signaling pathways, collectively implicating oxidative stress, inflammation, and apoptosis. Molecular docking showed favorable predicted binding between 6PPD-Q and the five hub proteins, with RELA exhibiting the most favorable docking score (−8.82 kcal/mol). A subsequent 100-ns MD simulation of the 6PPD-Q–RELA complex showed relatively stable RMSD, Rg, and SASA profiles and a concentrated low-energy conformational basin, supporting its dynamic stability under the simulated conditions. Collectively, these computational findings suggest potential molecular links between 6PPD-Q exposure and IVDD and provide hypotheses for subsequent experimental validation.
SN - 1932-6203
ER -