Di(2-ethylhexyl) phthalate and Mono(2-ethylhexyl) phthalate upregulate PPARG and induce metabolic reprogramming in hepatocellular carcinoma cells: a pan-cancer and metabolomics study.
TL;DR
Findings support a functional contribution of PPARG to DEHP/MEHP-associated lipid accumulation, potentially involving a DGAT2/PLIN2-related lipid-storage program, and provide mechanistic clues to phthalate-associated metabolic dysregulation in liver cancer cells.
Abstract
Di(2-ethylhexyl) phthalate (DEHP) and its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) have been implicated in metabolic dysregulation and carcinogenesis, but their potential links to hepatocellular carcinoma (HCC) remain unclear. Using network toxicology and pan-cancer analyses, we identified PPARG as a candidate shared target of DEHP and MEHP. PPARG was upregulated in HCC tissues, and higher expression was associated with poorer overall survival in the TCGA-LIHC cohort. Molecular docking and dynamics simulations predicted a more favorable and stable interaction between MEHP and PPARG than between DEHP and PPARG. In HepG2 cells, both compounds increased lipid accumulation and PPARG expression. Rosiglitazone promoted lipid accumulation and upregulated the lipid-storage genes DGAT2 and PLIN2, whereas GW9662 attenuated DEHP/MEHP-induced lipid accumulation and related transcriptional responses. Untargeted LC-MS metabolomics revealed relative alterations in phosphatidylcholine and phosphatidylethanolamine features and suggested perturbations in fatty acid-, bile acid-, arachidonic acid-, and nucleotide-related pathways. Collectively, these findings support a functional contribution of PPARG to DEHP/MEHP-associated lipid accumulation, potentially involving a DGAT2/PLIN2-related lipid-storage program, and provide mechanistic clues to phthalate-associated metabolic dysregulation in liver cancer cells.