6PPDQ promotes the malignant progression of colorectal cancer via enhancing EGF/EGFR signaling

6PPD-quinone (6PPDQ), a transformation product of the rubber antioxidant 6PPD, is a newly identified pollutant found globally. Originating mainly from tire wear particles, it contaminates water bodies, the atmosphere, and the food chain, leading to continuous exposure risks. However, the impact of 6PPDQ on the progression of colorectal cancer remains largely unknown, representing an urgent scientific question to be addressed. This research explored the toxicological impact and molecular mechanisms of 6PPDQ on colorectal cancer. In vitro experiments showed that environmentally relevant concentrations of 6PPDQ significantly promoted proliferation, colony formation, and invasiveness in human colorectal cancer cell lines HCT116 and HT-29, while inducing glycolysis-associated changes marked by elevated lactate production and glucose uptake. Further mechanistic studies indicated that 6PPDQ increased epidermal growth factor receptor (EGFR) expression by stabilizing the transcription factor c-Jun, which activated the EGFR/ERK/AKT signaling pathway; this activation was reversible with the EGFR inhibitor gefitinib. In vivo experiments demonstrated that 6PPDQ exposure accelerated xenograft tumor growth in nude mice and increased EGF/EGFR pathway activity. This study reveals that 6PPDQ promotes colorectal cancer progression via regulating EGF/EGFR signaling, offering new experimental evidence for its environmental health risk assessment. Our research indicates that pollutants from traffic could be environmental risk factors for colorectal cancer, highlighting significant public health and cancer prevention implications.