Wang, Y., Ren, K., Jin, L., Xia, P., Xie, B., Tian, J., Zhang, K., Li, L., Wei, T. (2026). F-53B triggers sleep disorders via very long-chain ceramide accumulation in Drosophila neurons.  Ecotoxicol. Environ. Saf. 313(): 119980.

FBrf0264914

Research paper

Per- and polyfluoroalkyl substances (PFAS) disrupt sleep homeostasis, but the underlying mechanisms remain poorly understood. Here we demonstrate that chronic exposure to environmentally relevant concentrations (0.8 μM) of chlorinated polyfluoroalkyl ether sulfonate (F-53B) induces sleep disorders in Drosophila melanogaster, a model with conserved sleep-regulatory pathways. F-53B-exposed flies exhibited reduced total sleep duration, fragmented sleep architecture, and disrupted circadian rhythms. Mechanistically, molecular docking and dynamics simulations identified F-53B as a direct inhibitor of the alkaline ceramidase Dacer (binding energy: -10.34 kcal/mol), thereby suppressing ceramide hydrolysis and triggering neuronal accumulation of very long-chain ceramides, such as Cer(d36:2). Integrated multi-omics analysis revealed that these ceramides activate sterol regulatory element-binding protein (SREBP)-dependent lipogenesis (e.g., DGAT1B upregulation). These lipid perturbations led to neuronal mitochondrial oxidative stress and cytosolic calcium overload, as validated by mitochondrial redox sensor MitoTimer and calcium indicator GCaMP5G. Our findings establish F-53B as a sleep-disrupting environmental toxicant and uncover a conserved lipid-mitochondrial axis underlying pollutant-induced sleep disorders. Very long-chain ceramides, particularly Cer(d36:2), emerge as candidate diagnostic biomarkers for F-53B neurotoxicity. This work highlights lipid metabolic reprogramming as a novel target for mitigating the impact of emerging environmental contaminants on sleep homeostasis.