Precise prevention of DEHP induced hepatic fibrosis: Early identifying high-risk populations, revealing key factors, and applying targeted intervention.

Metabolic dysfunction-associated fatty liver disease (MAFLD) poses a serious threat to human health. Hepatic fibrosis is a decisive factor in the death of MAFLD patients. Di-2-ethylhexyl phthalate (DEHP) plays an indispensable role in MAFLD. However, there are still certain shortcomings in the systematic evaluation of its dose-response relationship, key toxic mechanisms, early identification of DEHP-induced hepatic fibrosis and the prevention of MAFLD in high-risk populations. Our present study successfully constructed an early identification model for high-risk individuals with DEHP-induced hepatic fibrosis via machine learning. We then conducted bioinformatics analysis and revealed a key molecule, peroxisome proliferator activated receptor alpha (PPARα), and its downstream signalling network involved in low-dose DEHP-induced hepatic fibrosis. Furthermore, we explored and analysed the protein structure of PPARα, cross-referenced these data with the traditional Chinese medicine (TCM) databases and innovatively discovered a small molecule, quercetin, in TCM that can target and inhibit the PPARα protein. Finally, we constructed an in vitro THLE2 cell model and an in vivo C57BL/6 J mouse model, and confirmed that targeted inhibition of PPARα by quercetin significantly blocked low-dose DEHP-dysregulated glucose and lipid metabolism and hepatic fibrosis. Our present study provides a new theoretical and practical basis for further elucidating the key toxic mechanism and early identification of DEHP-induced hepatic fibrosis, as well as the precise prevention and amelioration of this pathology in high-risk populations.