Integrated Network Toxicology and Multiomics Analyses Reveal the Potential Hepatocarcinogenic Effect of BDE 47 and Its Underlying Mechanism

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-associated hepatocellular carcinoma (HCC) is a growing global concern, with environmental pollutants implicated in its progression. 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) exhibits hepatotoxic potential, but its role in MASLD-to-HCC progression remains unclear. Here, we investigated the association between BDE 47 and MASLD using data from the National Health and Nutrition Examination Survey and explored the potential mechanisms through network toxicology and multiomics analyses. Individuals with higher serum BDE 47 levels showed positive associations with MASLD and advanced fibrosis. Network toxicology predicted that BDE 47 perturbed lipid metabolism, inflammation, and oxidative stress, thereby contributing to malignant progression. <i>In vitro</i>, integrated lipidomic and transcriptomic analyses revealed that BDE 47 disrupted lysosome, sphingolipid, and cholesterol metabolism, leading to lipid accumulation. Additionally, BDE 47 exposure enhanced inflammatory response, oxidative stress, and the development of immunosuppressive environment, which may facilitate MASLD-to-HCC progression. Pharmacological experiments further demonstrated that increased sphingolipid synthesis and impaired cholesterol efflux played important roles in BDE 47-induced lipid accumulation. Notably, only the parent BDE 47 compound was detected in exposed cells. Collectively, these findings provide mechanistic evidence of the carcinogenic potential of BDE 47 and its role in liver disease progression.