Exploring the Mechanism of DEHP Promoting Hepatic Fibrosis Based on Network Toxicology by Triggering Lipophagy-Dependent Hepatic Stellate Cell Activation

Abstract Di(2-ethylhexyl)phthalate (DEHP), a common environmental endocrine disruptor and agricultural organic pollutant, has drawn wide concern for its hepatotoxicity. However, the molecular mechanisms underlying DEHP-induced hepatic fibrosis remain unclear. Through network toxicology analysis, lipid metabolism and autophagy pathways are involved in DEHP-related hepatic fibrosis. Subchronic DEHP exposure (50–500 mg/kg) induced dose-dependent hepatic fibrosis in mice, while its metabolite MEHP synergized with TGF-β1 to promote LX2 cell activation in vitro. Crucially, MEHP activates lipophagy by targeting Beclin1, thereby mobilizing energy for the activation of hepatic stellate cells (HSCs). Attenuating autophagy with 3-Methyladenine (3-MA) or Chloroquine (CQ), or via Beclin1 knockdown, all rescued the activation phenotype induced by MEHP. These results suggest that DEHP acts as a trigger for fibrosis, promoting this process by inducing the activation of HSCs. This work identifies the lipophagy pathway as a crucial mechanistic link between environmental toxin exposure and HSC-mediated hepatic fibrosis progression.