Di(2‐Ethylhexyl) Phthalate Exposure and Risk of Diabetic Kidney Disease: Epidemiological Association and Mechanistic Insights

Abstract

ABSTRACT Objective This study aims to explore the association between exposure to di‐(2‐ethylhexyl) phthalate (DEHP) and diabetic kidney disease (DKD), and to elucidate its potential molecular mechanisms. The study findings provide scientific evidence for the prevention and control of environmental risk factors related to DKD. Methods We utilised the United States National Health and Nutrition Examination Survey (NHANES) database to evaluate the correlations of DEHP exposure with DKD risk and renal function indices. Candidate targets were screened using network toxicology, and functional enrichment analysis was conducted. The binding ability of DEHP to the candidate mechanistic targets was verified through molecular docking. The toxicity and target effects of DEHP and its metabolites were verified using HK‐2 cells. Results The NHANES analysis demonstrated a positive correlation between DEHP exposure and the risk of DKD, with a significant dose‐response relationship observed. Network toxicology identified ALB, ESR1, and MMP9 as candidate mechanistic targets in DEHP‐induced DKD. In vitro experiments confirmed that DEHP and its metabolite MEHP reduced HK‐2 cell viability, induced lipid deposition, and altered the expression of candidate mechanistic targets. Conclusion DEHP is an important environmental risk factor for DKD. It may promote the development and progression of DKD by regulating key targets and interfering with lipid metabolism.