Integrative analysis of NHANES, network toxicology, molecular docking, molecular dynamics, and in vitro experiments to elucidate the molecular mechanisms linking BPA to NAFLD.
TL;DR
These findings integrate population-level, computational, and hepatocyte evidence, suggesting that matrix remodeling, inflammation, and lipid metabolism may underlie the link between BPA exposure and NAFLD.
Abstract
Bisphenol A (BPA), a ubiquitous plasticizer, has been implicated in lipid metabolic imbalance, yet its contribution to nonalcoholic fatty liver disease (NAFLD) remains incompletely understood. Here, we combined NHANES data analysis, network toxicology, microarray profiling, molecular docking and dynamics simulations, and LO2 hepatocyte experiments to investigate the association between BPA exposure and NAFLD and its underlying mechanisms. Epidemiologically, urinary BPA levels were positively associated with NAFLD prevalence. In vitro, low-dose BPA induced hepatocellular triglyceride and cholesterol accumulation and impaired cell function. Mechanistic investigations highlighted inflammatory, steroidogenic, and lipid metabolic pathways. Network pharmacology and gene expression profiling pinpointed MMP9, PTGS2, MMP2, NOS3, and PLAU as key BPA-responsive genes, and experimental validation confirmed upregulation of MMP9, PTGS2, and PLAU transcripts and proteins alongside increased MMP2 protein. These findings integrate population-level, computational, and hepatocyte evidence, suggesting that matrix remodeling, inflammation, and lipid metabolism may underlie the link between BPA exposure and NAFLD.