Bis(2-Ethylhexyl)-2,3,4,5-Tetrabromophthalate Promotes NASH Progression through Disrupting Endoplasmic Reticulum-Mitochondria Contacts

Growing evidence has established potential associations between environmental pollutants and the progression of chronic liver diseases. Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), a widely used novel brominated flame retardant, has raised concerns due to its widespread detection in human tissues. However, its role in chronic liver diseases remains poorly understood. In this study, we established both mouse and liver Organoid (LO) models to investigate the impact of TBPH exposure on the progression of nonalcoholic steatohepatitis (NASH) and the underlying mechanisms. In a diet-induced NASH mouse model, TBPH exposure significantly enhanced hepatic steatosis, inflammation, and fibrosis. Lipidomic analysis revealed that TBPH induced dysregulation of phospholipid metabolism, particularly reduced levels of cardiolipin (CL) and phosphatidylserine (PS). Mechanistically, TBPH decreased Mitofusin2 (MFN2) expression, leading to impaired endoplasmic reticulum-mitochondria (ER-Mito) contacts, disrupted phospholipid transfer, and subsequent mitochondrial dysfunction. These alterations triggered both mitochondrial unfolded protein response (UPR^mt) and ER stress. Importantly, the activation of MFN2 with the agonist M1 in LOs alleviated TBPH-induced NASH phenotypes by restoring ER-Mito contacts and cellular bioenergetics. Our findings identify TBPH as an environmental risk factor for NASH progression, providing novel insights into the MFN2-mediated ER-Mito contacts in lipid metabolic homeostasis and new perspectives for the health risk evaluation of brominated flame retardants.

ER-Mito contacts; bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate; liver organoid; mitochondria-associated membranes; nonalcoholic steatohepatitis.