Exposure to environmental cadmium (Cd) is known to cause neuronal death and cognitive decline in humans. Ferroptosis, a novel iron-dependent type of regulated cell death, is involved in various neurological disorders. In the present study, Cd exposure triggered ferroptosis in the mouse hippocampus and in the HT22 murine hippocampal neuronal cell line, as indicated by significant increases in ferroptotic marker expression, intracellular iron levels, and lipid peroxidation. Interestingly, ferroptosis of hippocampal neurons in response to Cd exposure relied on the induction of autophagy since the suppression of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) substantially ameliorated Cd-induced ferroptosis. Furthermore, nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin was required for the Cd-induced ferroptosis of hippocampal neurons, demonstrating that NCOA4 knockdown decreased intracellular iron levels and lipid peroxidation and increased cell survival, following Cd exposure. Moreover, Cd-induced mitochondrial reactive oxygen species (mtROS) generation was essential for the ferritinophagy-mediated ferroptosis of hippocampal neurons. Importantly, pretreatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated Cd-induced hippocampal neuronal death and cognitive impairment in mice. Taken together, these findings indicate that ferroptosis is a novel mechanism underlying Cd-induced neurotoxicity and cognitive impairment and that the mtROS-ferritinophagy axis modulates Cd-induced neuronal ferroptosis.

中文翻译：

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镉暴露通过 mtROS-铁蛋白自噬途径诱导神经元铁死亡和认知缺陷

众所周知，暴露于环境镉 (Cd) 会导致人类神经元死亡和认知能力下降。铁死亡是一种新型的铁依赖性调节细胞死亡类型，与多种神经系统疾病有关。在本研究中，镉暴露引发了小鼠海马和 HT22 小鼠海马神经元细胞系的铁死亡，铁死亡标记物表达、细胞内铁水平和脂质过氧化显着增加表明了这一点。有趣的是，Cd 暴露引起的海马神经元铁死亡依赖于自噬的诱导，因为 3-甲基腺嘌呤 (3-MA) 和氯喹 (CQ) 抑制自噬可显着改善 Cd 诱导的铁死亡。此外，Cd 诱导的海马神经元铁死亡需要核受体共激活剂 4 (NCOA4) 介导的铁蛋白降解，这表明在 Cd 暴露后，NCOA4 敲低可降低细胞内铁水平和脂质过氧化，并增加细胞存活率。此外，镉诱导的线粒体活性氧（mtROS）的产生对于铁蛋白吞噬介导的海马神经元铁死亡至关重要。重要的是，用铁死亡抑制剂铁他汀-1 (Fer-1) 进行预处理可有效减轻镉诱导的小鼠海马神经元死亡和认知障碍。综上所述，这些发现表明铁死亡是镉诱导的神经毒性和认知障碍的一种新机制，并且 mtROS-铁蛋白自噬轴调节镉诱导的神经元铁死亡。