Involvement of ductal reaction in Di-(2-ethylhexyl)-phthalate-caused hepatic fibrosis: Molecular mechanisms and potential intervention strategies

Di-(2-ethylhexyl)-phthalate (DEHP) is a persistent environmental endocrine toxicant present in many products, and liver is the main target organ for DEHP metabolism. Long-term exposure to DEHP induces hepatic fibrosis, which is reversible in the early stages, while progresses to cirrhosis without timely intervention. Ductular reaction (DR) is a characteristic pathological change in hepatobiliary diseases, however, the involvement of DR in DEHP-caused hepatic fibrosis, the underlying molecular mechanisms, remail largely uninvestigated. Here, we found that the DEHP exposure is positively correlated with hepatic fibrosis index in male population, revealing a sex-specific disparity. A low dose of DEHP chronic exposure induced the development of DR in male C57BL/6J mice and in cholangiocytes. Through high-throughput screening and bioinformatics analysis, we identified a potential key molecule, squalene epoxidase (SQLE). For the molecular mechanisms, DEHP elevated the expression of SQLE, which in-turn induced the epithelial to mesenchymal transition (EMT) process in reactive-appearing duct-like cells (RDCs), leading to acquire the functional properties of mesenchymal cells, and promote DR amplification. These processes promoted the DEHP-caused hepatic fibrosis. Furthermore, via drug screening and functional analysis, we identified a traditional Chinese medicine monomer, luteolin, targeting inhibited the SQLE protein. Finally, we found that, targeted intervention of SQLE by luteolin prevented the DEHP induced EMT, DR, and hepatic fibrosis. Our present study offered new insights into environmental toxin-induced hepatobiliary diseases and suggested a potential key intervention target/approach for the prevention of hepatic fibrosis.