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

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.