Mechanistic investigation of DDT/DDE in MASLD/MASH pathogenesis: An integrated network toxicology and transcriptomics approach

  • Ecotoxicol Environ Saf. 2025 Nov 15:307:119390. doi: 10.1016/j.ecoenv.2025.119390.
Yicheng Jiang  1 ,  Yuancheng Shao  1 ,  Jiaming Xue  1 ,  Zhigang Chen  1 ,  Qi Liu  1 ,  Shuai Chen  1 ,  Xihan Gu  1 ,  Shufan Zhang  1 ,  Liming Tang  2
Affiliations
  • 1. Department of Gastrointestinal Surgery, Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, PR China.
  • 2. Department of Gastrointestinal Surgery, Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, PR China. Electronic address: [email protected].
PMID: 41232492 DOI: 10.1016/j.ecoenv.2025.119390
Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) pose significant public health challenges, yet the role of environmental pollutants remains inadequately characterized. Here, we systematically dissect the hepatotoxic mechanisms of DDT and its metabolite DDE through a multi-platform strategy. Network toxicology and PPI analysis pinpointed IL-6, ALB, Akt1, TNF, and TP53 as central mediators, with molecular docking validating DDT's high-affinity binding. Transcriptomic and KEGG pathway analyses uncovered broad dysregulation of inflammatory and metabolic processes, which were experimentally confirmed through Western blotting, mitochondrial superoxide assays, and ELISA. Together, these results delineate a coherent mechanistic pathway from DDT/DDE exposure to transcriptional dysregulation, protein-level perturbations, oxidative stress, and inflammation-key hallmarks of MASLD/MASH progression. This study provides a foundational framework for understanding pollutant-driven metabolic liver disease and developing targeted countermeasures.

Keywords
DDE; DDT; MASH; MASLD; Network Toxicology.
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