Abstract

Simple SummaryThis study provides compelling evidence that chronic exposure to TBPH acts as a potent environmental disruptor of hepatic homeostasis, driving the progression from simple steatosis to fibrotic steatohepatitis in zebrafish. We demonstrate that TBPH disrupts the critical balance between hepatic lipid acquisition and expenditure. Mechanistically, this imbalance is mediated by dysregulated lipid droplet biogenesis leading to the formation of enlarged lipid droplets, which has been validated in vitro. This unresolved lipid burden subsequently triggers a transition toward a chronic inflammatory state and fibrosis. Moreover, we identified the significant upregulation of key fibrotic drivers in the high-concentration exposure group. Collectively, these findings elucidate a distinct mechanism where long-term TBPH exposure exacerbates liver injury beyond the capacity of metabolic adaptation.Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is a widely used novel flame retardant and an emerging ubiquitous environmental contaminant. While acute exposure disrupts lipid signaling, the long-term consequences of TBPH exposure on the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly understood. This study aimed to elucidate the chronic hepatotoxic effects of TBPH and the underlying molecular mechanisms. Adult zebrafish were exposed to environmentally relevant concentrations of TBPH for 6 weeks. Hepatic damage was assessed using histological examination, biochemical assays, and integrated proteomic and transcriptomic profiling. In vitro assays using HepG2 cells were conducted to validate cellular mechanisms of lipid droplet (LD) dynamics. Chronic TBPH exposure induced severe macrovesicular steatosis and significant hepatic fibrosis in zebrafish. Transcriptional analysis revealed that TBPH activated both lipid synthesis and fatty acid oxidation. In vitro results confirmed that TBPH stimulated DGAT2-mediated triglyceride syn