The kidney is the target of the acute toxicity of depleted uranium (DU). However, the mechanism of DU‐induced cytotoxicity is not clear. The study was to demonstrate the role of autophagy in DU‐induced cytotoxicity and to determine the potential mechanism. We confirmed that after a 4‐h exposure to DU, the autophagic vacuoles and the autophagy marker light chain 3‐II in the human embryonic kidney 293 cells (HEK293) increased, and cytotoxicity decreased by abrogation of excessive autophagy using autophagy inhibitor. We also found activation of nucleus p53 and inhibiting mTOR pathways in DU‐treated HEK293 cells. Meanwhile, ethylmalonic encephalopathy 1 (ETHE1) decreased as the exposure dose of DU increased, with increasing autophagy flux. We suggested that by reducing ETHE1, activation of the p53 pathway, and inhibiting mTOR pathways, DU might induce overactive autophagy, which affected the cytotoxicity. This study will provide a novel therapeutic target for the treatment of DU‐induced cytotoxicity.
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