Sub-chronic exposure to lanthanum chloride induces hepatic steatosis via AMPK-dependent lipophagic defects in male zebrafish.

Lanthanum (La), one of the most widely used rare earth elements (REEs), is inevitably released into the environment, raising concerns about its potential health risks. Epidemiological evidence has linked La exposure to liver injury, but the mechanisms underlying chronic hepatotoxicity remain poorly understood. Here, zebrafish were exposed to environmentally relevant concentrations of LaCl3 (0.1 and 1 μM) from 2 hours post-fertilization (hpf) to 120 days post-fertilization (dpf), and integrated histological, biochemical, metabolomic, and transcriptomic analyses to examine LaCl3-induced hepatic responses. We found that chronic LaCl3 exposure caused marked hepatic steatosis and liver injury in male zebrafish, and these effects persisted after a 30-day depuration period. Multi-omics analyses revealed that LaCl3 drives glycolysis-dependent metabolic reprogramming, which subsequently suppresses the AMPK-ULK1-LC3B axis, thereby impairing lipophagy and leading to abnormal lipid droplet accumulation. In HepG2 cells, pharmacological inhibition of glycolysis with 2-DG or activation of AMPK with AICAR effectively restored AMPK-ULK1-LC3B signaling and attenuated LaCl3-induced lipid accumulation. Collectively, our findings provide a previously underrecognized mechanism underlying LaCl3-disrupted hepatic lipid homeostasis, offering novel insights into REEs-related hepatotoxicity and supporting environmental health risk assessment.