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<p>This study investigated the role of ferroptosis in acute depleted uranium (DU)-induced nephrotoxicity. Using Sprague–Dawley rats and HK-2 cells to establish models of acute DU exposure (rats: 10&#xa0;mg/kg; cells: 500&#xa0;μM for 24&#xa0;h), we found that DU exposure caused mitochondrial dysfunction, lipid peroxidation, and iron accumulation, all hallmarks of ferroptosis, which were inhibited by ferrostatin-1 (Fer-1). We identified mitochondrial ethylmalonic encephalopathy 1 (ETHE1) as a key DU target. ETHE1 downregulation exacerbated DU-induced reactive oxygen species (ROS), ferrous ions (Fe<sup>2+</sup>) overload and ferroptosis, while exogenous ETHE1 protein alleviated them. Furthermore, DU-triggered ROS activated the p38 mitogen-activated protein kinase (P38-MAPK) pathway, an effect enhanced by ETHE1 knockdown. Inhibiting P38-MAPK with adezmapimod (SB203580) suppressed ferroptosis and autophagy, and reduced the expression of nuclear receptor coactivator 4 (NCOA4), a mediator of ferritinophagy. Knockdown of NCOA4 also attenuated ferroptosis. In conclusion, acute DU exposure downregulates ETHE1, promoting mitochondrial ROS that activates P38-MAPK signaling. This pathway induces NCOA4-mediated ferritinophagy, ultimately leading to renal cell ferroptosis. These findings elucidate a novel mechanism for DU-induced kidney injury.</p>

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Depleted uranium exposure induced ferroptosis in renal cells via the ETHE1/P38-MAPK pathway

  • 期刊论文

  • 发表日期：

    2025年11月7日

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  • Feng Huang,
  • Wenrun Li,
  • Juan Li,
  • Yonghong Ran,
  • Shiyan Fu,
  • Li Shen,
  • Qi Li,
  • Xiaoyu Yang,
  • Yazhen Zhao,
  • Yuhui Hao

摘要

This study investigated the role of ferroptosis in acute depleted uranium (DU)-induced nephrotoxicity. Using Sprague–Dawley rats and HK-2 cells to establish models of acute DU exposure (rats: 10 mg/kg; cells: 500 μM for 24 h), we found that DU exposure caused mitochondrial dysfunction, lipid peroxidation, and iron accumulation, all hallmarks of ferroptosis, which were inhibited by ferrostatin-1 (Fer-1). We identified mitochondrial ethylmalonic encephalopathy 1 (ETHE1) as a key DU target. ETHE1 downregulation exacerbated DU-induced reactive oxygen species (ROS), ferrous ions (Fe2+) overload and ferroptosis, while exogenous ETHE1 protein alleviated them. Furthermore, DU-triggered ROS activated the p38 mitogen-activated protein kinase (P38-MAPK) pathway, an effect enhanced by ETHE1 knockdown. Inhibiting P38-MAPK with adezmapimod (SB203580) suppressed ferroptosis and autophagy, and reduced the expression of nuclear receptor coactivator 4 (NCOA4), a mediator of ferritinophagy. Knockdown of NCOA4 also attenuated ferroptosis. In conclusion, acute DU exposure downregulates ETHE1, promoting mitochondrial ROS that activates P38-MAPK signaling. This pathway induces NCOA4-mediated ferritinophagy, ultimately leading to renal cell ferroptosis. These findings elucidate a novel mechanism for DU-induced kidney injury.