Triphenyl phosphate exacerbates lung cancer metastasis by activating NF-κB signaling pathway.

Triphenyl phosphate (TPP) is a widely utilized organophosphorus flame retardant that has drawn increasing attention due to its persistence in the environment and potential toxicity. However, its involvement in cancer progression has not been fully explored. This study investigated the potential influence of environmentally relevant low-dose exposure to TPP on the progression of lung adenocarcinoma. Bioinformatics analyses revealed strong associations among TPP-related genes, lung cancer, and inflammatory signaling pathways. Plasma TPP concentrations were significantly higher in lung adenocarcinoma patients than in non-tumor controls and were positively associated with distant metastasis. In patient tumor tissues, higher plasma TPP levels were also associated with lower E-cadherin expression and higher Vimentin expression, supporting a link between TPP exposure and an EMT-related phenotype. Although exposure to low-dose TPP (≤1 μM) did not affect the proliferation of lung adenocarcinoma cells, it significantly enhanced their migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Transcriptomic and protein analyses confirmed activation of the NF-κB signaling pathway, and these effects were mitigated by pharmacologically inhibiting NF-κB. In vivo, TPP exposure promoted lung metastasis, which was partially blocked by NF-κB inhibition. These findings demonstrate that low-dose TPP exposure promotes lung cancer metastasis through NF-κB-driven EMT, underscoring the carcinogenic risk associated with environmental TPP exposure.