F-53B exposure accelerates progression from preexisting fatty liver to non-alcoholic steatohepatitis and hepatic fibrosis.

6:2 Chlorinated polyfluoroalkyl ether sulfonate (F-53B) is prevalent in the environment, yet its effect on pre-existing metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Using adult male zebrafish with high-fat diet-induced MASLD, we investigated the hepatotoxicity of F-53B. Following exposure, F-53B exacerbated hepatic damage in MASLD zebrafish, accelerating progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Notably, environmentally relevant concentrations altered lipid metabolism and MASH/fibrosis markers only in MASLD fish, while high concentrations were required to affect normal-diet fish. This heightened susceptibility stemmed from increased hepatic F-53B accumulation in diseased livers. Mechanistically, liver-type fatty acid-binding protein (L-FABP) knockdown in HepG2 cells reduced lipid accumulation, inflammatory and fibrotic responses, identifying L-FABP as a key F-53B transporter. These findings demonstrate that metabolic dysfunction increases vulnerability to F-53B hepatotoxicity, highlighting the need to consider pre-existing conditions in environmental pollutant risk assessment.