Elucidating the Mechanisms of DEHP‐Induced Insulin Resistance: A Comprehensive Network Toxicology and In Vitro Approach

ABSTRACT Di (2‐ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor that can induce insulin resistance (IR), a risk factor for type 2 diabetes. This study explored the molecular mechanism of DEHP‐induced IR by network toxicology and cellular experiments. We identified eight core targets (CASP3, CTNNB1, TNF, ITGB1, PRKCA, ACE2, EGFR, NCOR2), and AGE‐RAGE signaling pathway, insulin resistance, lipid and atherosclerosis, cell adhesion, PI3K‐Akt and other key signaling pathways related to IR. We demonstrated the binding ability of DEHP and the core targets by molecular docking, and verified the effects of DEHP on the core target expression and transcription by Western‐blot and RT‐PCR. We found that DEHP can interfere with the normal function and activity of the core targets, leading to IR. Our results provide new evidence and insights for the toxicological evaluation and intervention of DEHP, and the pathogenesis and therapeutic targets of IR.