Di-(2-ethylhexyl) phthalate (DEHP) and its metabolite promote multiple myeloma progression and bortezomib resistance.

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in consumer and medical products, readily leaches into the environment and is metabolized into its bioactive derivative mono-(2-ethylhexyl) phthalate (MEHP). Emerging evidence links DEHP/MEHP exposure to tumor progression and drug resistance in multiple cancers. While environmental factors are hypothesized to contribute to the pathogenesis of multiple myeloma (MM)-a currently incurable plasma cell malignancy-the specific role of DEHP and MEHP in MM remains unexplored. This study aimed to investigate the effects of prolonged DEHP exposure on MM progression and drug resistance. Comparative analysis of MM cells with and without DEHP exposure demonstrated that DEHP promotes tumorigenesis and induces resistance to bortezomib, a frontline MM therapy. Mechanistically, DEHP activates the Wnt/β-catenin and NF-κB signaling pathways, and MEHP recapitulates these pro-tumorigenic effects. Our findings not only identify DEHP/MEHP as potential environmental risk factors for MM but also implicate Wnt/β-catenin and NF-κB as actionable targets for therapeutic intervention. These results underscore the need to reevaluate DEHP exposure risks in clinical settings and public health policies.