DEHP induces hepatic fibrosis through STAT3-SLC7A11-ROS axis

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is a pervasive environmental contaminant commonly found in daily life, and numerous studies have linked it to the progression of liver diseases and organ fibrosis. However, the precise molecular mechanisms by which DEHP induces liver fibrosis remain incompletely understood. This study aimed to investigate the effects of DEHP on liver fibrosis and its underlying mechanisms. We observed that 100 μM DEHP and 6 days of exposure significantly induced activated human hepatic stellate cells (HSCs) and upregulated the fibrosis marker α-smooth muscle actin (α-SMA). By integrating DEHP and liver fibrosis-related target information from various databases, followed by an assessment of the protein-protein interactome (PPI) network and corresponding functional pathway mapping, we predicted that DEHP-induced liver fibrosis is closely associated with the accumulation of reactive oxygen species (ROS). Molecular docking experiments revealed that DEHP spontaneously binds to STAT3, with GLU-638 identified as a critical amino acid residue for this interaction. Further functional experiments confirmed that DEHP promotes ROS accumulation by downregulating SLC7A11 expression, a process mediated by STAT3. In summary, DEHP facilitates intracellular ROS accumulation by mediating the STAT3-SLC7A11-ROS signaling axis, thereby triggering the formation of liver fibrosis. This research provides novel molecular targets and therapeutic strategies for the future prevention and treatment of liver fibrosis.