Triphenyl phosphate promotes gastric cancer progression via LDHA deubiquitination-induced lactate production and H3K18 lactylation

Triphenyl phosphate (TPP) is an organophosphate flame retardant widely detected in environmental matrices and human tissues. Although its endocrine-disrupting effects are well-documented, the role of TPP in gastric cancer (GC) progression remains to be elucidated. The effects of TPP on the proliferation, migration, and invasion of MKN-28 and MKN-45 cells were evaluated. A nude mouse xenograft model was employed to assess the tumor-promoting effects of TPP in vivo. Ubiquitination assays and cycloheximide (CHX) chase assays were performed to examine LDHA protein stability. Furthermore, integrated RNA-seq and CUT&Tag analyses were utilized to identify downstream transcriptional programs and signaling pathways. TPP exposure significantly promoted the proliferation, migration, and invasion of GC cells in vitro and accelerated tumor growth in vivo. Mechanistically, TPP treatment increased LDHA protein levels through suppressed protein degradation rather than enhanced transcription. The reduction in LDHA ubiquitination induced by TPP was associated with altered expression of APOL3 and NDRG1, suggesting that these regulators may mediate the effect of TPP. The accompanying lactate accumulation was associated with a significant increase in histone H3K18la levels. Integrated epigenomic and transcriptomic analyses suggested that H3K18la enrichment is linked to the activation of oncogenic programs, including the WNT/β-catenin, Notch, and hypoxia signaling pathways. The present study suggests that TPP exposure contributes to malignant phenotypes in GC, likely via an APOL3/NDRG1-LDHA regulatory pathway that promotes lactate accumulation and H3K18la-associated transcriptional reprogramming. These findings implicate TPP as a potential environmental risk factor for GC and provide experimental evidence supporting further investigation of this metabolic-epigenetic axis in cancer intervention.