DEHA-induced hepatotoxicity identified from screening food packaging non-phthalate plasticizers: An integrative...

Non-phthalate plasticizers (NPPs) are replacing phthalate esters in food packaging, but their comparative hepatotoxicity profiles remain poorly characterized. Here we established an integrated computational framework to evaluate five common food-packaging NPPs, identifying bis(2-ethylhexyl) adipate (DEHA) as the compound with the highest hepatotoxicity risk through multi-model validation. Network toxicology analysis of 127 DEHA-associated hepatotoxicity targets revealed significant enrichment in the PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, TNF signaling, and key pathological processes of liver diseases. Topology centrality analyses further identified ALB, AKT1, and EGFR as hub targets. Two-sample Mendelian randomization confirmed causal associations between genetic predispositions to ALB, AKT1, and EGFR expression levels and liver disease susceptibility, while molecular docking demonstrated stable DEHA-target binding conformations (binding energy below -5.0 kcal/mol). Disease progression analyses showed significantly decreased ALB and EGFR expression in advanced liver disease stages, whereas AKT1 exhibited elevated expression. Single-cell transcriptomic profiling revealed predominant ALB expression in hepatocytes and pan-cellular distribution of AKT1/EGFR across liver cell types. Virtual knockout simulations indicated acute-phase response disruption following hepatocyte-specific deletions of ALB, AKT1, or EGFR. Finally, in vitro and in vivo exposure models validated DEHA-induced hepatotoxicity, demonstrating dysregulation of hepatic Alb, Akt1, and Egfr post-exposure. We propose a mechanistic hypothesis that DEHA compromises hepatic functions by disrupting the ALB-AKT1-EGFR regulatory axis. Collectively, this work provides a computational framework for NPP toxicity risk assessment and nominates ALB, AKT1, and EGFR as potential therapeutic targets for mitigating DEHA-induced hepatotoxicity.