6PPDQ exposure enhances susceptibility to ulcerative colitis by disturbing MMP9, PTGS2, and PPARG homeostasis: an integrative network toxicology and in vivo study.

The tire-derived contaminant 6PPD-quinone (6PPDQ) is widespread in the environment and exhibits intestinal toxicity, yet its role in ulcerative colitis (UC) remains unclear. This study integrated network toxicology, bioinformatics, molecular docking, and in vivo experiments to investigate whether 6PPDQ exposure increases the risk of UC, despite its lack of direct colonic damage. Network toxicology identified 233 common targets between 6PPDQ and UC. Multi-index topological screening combined with validation across independent GEO datasets yielded three hub targets (MMP9, PTGS2, and PPARG), all of which displayed strong binding affinity to 6PPDQ and showed dose-dependent expression alterations in mouse colon following 6PPDQ exposure, without causing colonic injury. However, upon dextran sulfate sodium (DSS) induction, mice exposed to 6PPDQ developed more severe colitis than vehicle controls, as reflected by dose-dependent body weight loss, elevated disease activity index (DAI) scores, colon shortening, increased colonic MPO and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and suppressed anti-inflammatory IL-10. Collectively, our results suggest that 6PPDQ exposure may exacerbate DSS-induced colitis by disrupting the homeostasis of MMP9, PTGS2, and PPARG, indicating that this tire-derived quinone may act as an emerging environmental pollutant that enhances UC susceptibility.