Diethyl phthalate exposure promotes colon cancer progression through ALDOC mediated proliferation, epithelial-mesenchymal transition, and ferroptosis resistance.

Abstract

Colon cancer is a global health threat characterized by marked heterogeneity and therapeutic resistance. Although environmental pollutants may contribute to tumor progression, the role of diethyl phthalate (DEP), a widely used plasticizer and endocrine disruptor, remains unclear. By integrating clinical cohort data, bioinformatics, and in vitro and in vivo models, we investigated the oncogenic effects and mechanisms of DEP in colon cancer. Elevated serum DEP was independently associated with shorter overall survival, and DEP exposure accelerated subcutaneous tumor growth in vivo. In vitro, DEP enhanced cell migration and epithelial-mesenchymal transition (EMT), while suppressing ferroptosis by reducing intracellular iron accumulation and lipid peroxidation. LASSO regression and tumor immune microenvironment profiling further established a DEP-related prognostic signature associated with an immune-cold phenotype, characterized by reduced CD4+ and CD8+ memory T cells and increased M2 macrophage infiltration. ALDOC was identified as a key downstream mediator of DEP-induced malignancy. DEP markedly upregulated ALDOC, whereas ALDOC knockdown reversed EMT activation, restored ferroptosis sensitivity, and inhibited cell migration. These findings demonstrate that DEP promotes colon cancer progression through the ALDOC/EMT axis and ferroptosis evasion, highlighting ALDOC as a potential therapeutic target.