The researchers first applied toxicological prediction models, which indicated high model-predicted probabilities that 6PPD-quinone would activate stress-response endpoints including SR-MMP and SR-ARE. By integrating multiple databases, they identified 59 molecular targets shared between the compound and disc degeneration. Protein–protein interaction analysis narrowed these to five hub genes: PTGS2, MMP2, SMAD3, RELA, and GSK3B.

Functional enrichment analysis suggested these targets participate mainly in AGE-RAGE, PI3K-Akt, MAPK, TNF, and IL-17 signaling pathways, which collectively point toward oxidative stress, inflammation, and apoptosis. These processes are relevant to degeneration of avascular disc tissue, where the compound’s potential toxicological effects were previously unclear.

Molecular docking predicted favorable binding between 6PPD-quinone and all five hub proteins, with the strongest predicted affinity for RELA, at a docking score of −8.82 kcal/mol. A subsequent 100-nanosecond molecular dynamics simulation of the 6PPD-quinone–RELA complex showed relatively stable RMSD, radius of gyration, and solvent-accessible surface area profiles, along with a concentrated low-energy conformational basin, supporting the complex’s dynamic stability under the simulated conditions. These predictions describe model-estimated behavior and do not establish toxicity in living organisms.

The authors state that the results provide hypotheses for subsequent experimental validation rather than clinical conclusions. The link between the modeled protein interactions and actual degeneration in human discs remains to be demonstrated, and the findings should be interpreted as a testable framework for future laboratory work rather than evidence of harm.

Subject of Research: Computational analysis of potential molecular mechanisms linking 6PPD-quinone exposure to intervertebral disc degeneration

Article Title: Investigating potential molecular mechanisms linking 6PPD-quinone exposure to Intervertebral Disc Degeneration: A network toxicology, molecular docking, and molecular dynamics simulation study

Article References: Yang, B., Wang, X., Zhuo, L., Chen, Y., & He, Q. (2026). Investigating potential molecular mechanisms linking 6PPD-quinone exposure to Intervertebral Disc Degeneration: A network toxicology, molecular docking, and molecular dynamics simulation study. PLOS One, 21(10), e0359621. https://doi.org/10.1371/journal.pone.0359621

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0359621

Keywords: 6PPD-quinone, tire rubber pollutant, intervertebral disc degeneration, network toxicology, molecular docking, molecular dynamics simulation, RELA, oxidative stress, inflammation, emerging pollutants, Investigating, potential