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.

中文翻译：

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丙二酸脑病1在贫铀诱导的人类胚胎肾293细胞中引起过度自噬

肾脏是贫铀（DU）急性毒性的靶标。但是，DU诱导细胞毒性的机制尚不清楚。该研究旨在证明自噬在DU诱导的细胞毒性中的作用，并确定潜在的机制。我们证实，在DU暴露4小时后，人胚肾293细胞（HEK293）中的自噬泡和自噬标记轻链3-II增加，并且通过使用自噬抑制剂消除过度自噬而降低了细胞毒性。我们还发现在DU处理的HEK293细胞中p53核的激活和mTOR通路的抑制。同时，随着自噬通量的增加，乙二醛脑病1（ETHE1）随着DU暴露剂量的增加而降低。我们建议通过减少ETHE1，激活p53途径并抑制mTOR途径，DU可能会诱导过度自噬，从而影响细胞毒性。这项研究将为DU诱导的细胞毒性治疗提供新的治疗靶点。