Nonylphenol Promotes Colorectal Cancer Progression via the ERK–FosB Signaling Pathway

Purpose Nonylphenol (NP) is a pervasive environmental endocrine disruptor, yet its mechanistic role in colorectal cancer (CRC) progression remains poorly defined. This study aimed to elucidate the molecular pathways through which NP influences CRC pathogenesis. Methods Human CRC cell lines HCT-116 and HT29 were treated with environmentally relevant NP concentrations. Functional assays assessed proliferation, apoptosis, cell cycle, migration, and invasion. RNA sequencing identified transcriptional changes, followed by validation via qPCR and western blot. Stable FosB knockdown and pharmacological MEK/ERK inhibition were employed to interrogate pathway necessity. A BALB/c nude mouse xenograft model was used for in vivo validation. Results Low-dose NP (100 nM) significantly enhanced proliferation, S-phase entry, migration, and invasion in CRC cells. Transcriptomic analysis revealed activation of the MAPK signaling pathway and marked upregulation of the AP-1 transcription factor FOSB. NP induced rapid ERK1/2 phosphorylation and FosB expression. Genetic knockdown of FOSB or pharmacological inhibition of MEK/ERK completely abolished NP-driven malignant phenotypes in vitro. In xenograft models, NP significantly accelerated tumor growth; this effect was abrogated by FOSB silencing, which also reversed NP-induced proliferation and suppressed apoptosis in vivo. Conclusion NP promotes CRC progression via the ERK1/2–FosB signaling axis. This pathway represents a critical mechanistic link between environmental NP exposure and aggressive CRC phenotypes, identifying FosB as a potential therapeutic target.