Multi-scale systems toxicology defines a KLF5-centered adverse outcome pathway linking DEHP exposure to pancreatic cancer progression and signaling programs relevant to therapy tolerance.

ABSTRACT: Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous plasticizer implicated in pancreatic carcinogenesis, yet the molecular initiating events and adverse outcome pathways (AOPs) linking exposure to disease mechanisms remain poorly resolved. In this study, we integrated a multi-scale systems toxicology framework-combining heterogeneous ensemble machine learning, Mendelian randomization (MR), molecular docking and molecular dynamics (MD), single-cell transcriptomics, and in vitro assays-to delineate a candidate mechanistic trajectory. A Tabular Prior-Data Fitted Network (TabPFN)-enhanced ensemble identified a six-gene pancreatic ductal adenocarcinoma (PDAC) signature (AUC = 0.946). Within this signature, MR provided suggestive evidence for a modest association between genetically predict

SUBMITTER: Chen J 

PROVIDER: S-EPMC12917211 | biostudies-literature | 2026

REPOSITORIES: biostudies-literature