Methylparaben promotes colorectal tumor growth through nuclear receptor-mediated transcriptional reprogramming and inflammatory signaling: Evidence from integrated transcriptomics and network toxicology.

Methylparaben (MP) is a widely used preservative with potential endocrine-disrupting activity, but its role in colorectal cancer (CRC) remains unclear. This study integrated in vitro and in vivo experiments with transcriptomics, network toxicology, and molecular simulations to investigate MP's effects on CRC progression. MP enhanced CRC cell proliferation, migration, and epithelial-mesenchymal transition while suppressing apoptosis in vitro. In CT26 tumor-bearing mice, dietary MP accelerated tumor growth and induced a pro-inflammatory microenvironment. Transcriptomic and network toxicology analyses implicated nuclear receptor signaling and inflammatory pathways. Among eight core targets identified, CD209 exhibited the most stable MP binding and was functionally validated in vivo: CD209a blockade significantly attenuated MP-driven tumor growth, reduced proliferation, and restored apoptosis. These findings demonstrate that MP promotes CRC through coordinated nuclear receptor and inflammatory signaling, with CD209 as a critical mediator, providing mechanistic insights for environmental risk assessment of chronic MP exposure.