Triphenyl phosphate accelerates collagen-rich ECM remodeling and proliferation in gastric cancer via partially TGFβ/NOTCH-dependent transcription Programs

Organophosphate esters are increasingly used as replacements for legacy halogenated flame retardants, yet their tumor-promoting potential remains poorly defined. Here, we identify triphenyl phosphate (TPP) as a potent environmental driver of extracellular-matrix (ECM) remodeling and growth in gastric cancer (GC). Chemical–gene signatures for phosphate flame retardants (PFRs) from the Comparative Toxicogenomics Database were projected onto TCGA-STAD using single-sample GSEA and compared with a curated proliferation signature, nominating TPP as the top correlate. In AGS cell line, TPP increased viability and expanded CD133⁺ fractions. RNA-seq revealed a collagen-dominant program enriched for ECM organization, collagen fibrillogenesis, EMT regulation, and TGFβ production; qPCR, immunofluorescence, and ELISA confirmed upregulation and secretion of fibrillar collagens. Promoter-reporter assays and 4sU-qPCR demonstrated promoter-level activation and accelerated nascent transcription of ECM genes. Pharmacologic inhibition of TGFβ receptors preferentially suppressed SERPINE1 and collagens, while γ-secretase/NOTCH blockade strongly reduced HEY1 and partially reduced collagens; neither alone fully abrogated responses, indicating partial TGFβ/NOTCH dependence. In xenograft models, TPP accelerated tumor growth. Collectively, these data position TPP as an environmental accelerator of ECM-mechanics-proliferation circuitry in GC and highlight druggable nodes of therapeutic and regulatory relevance. • Triphenyl phosphate (TPP) is identified as a potent environmental driver of gastric cancer proliferation and collagen remodeling. • TPP accelerates nascent transcription of ECM genes via AHR/PXR-mediated activation of TGFβ and NOTCH signaling. • Dual blockade of TGFβ and NOTCH signaling effectively attenuates TPP-driven tumorigenesis and fibrosis in vivo.