Du Lixia, Wu You, Jia Qi, Li Jin, Li Yi, Ma Hongwei, Fan Zhongmin, Guo Xiaofeng, Li Ling, Peng Yuliang, Li Jing, Fang Zongping, Zhang Xijing
Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
College of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China.
Cell Mol Neurobiol. 2023 Oct;43(7):3605-3622. doi: 10.1007/s10571-023-01370-4. Epub 2023 Jun 21.
Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that is characterized by long-term cognitive impairment, which imposes a heavy burden on families and society. However, its pathological mechanism has not been elucidated. Ferroptosis is a novel form of programmed cell death that is involved in multiple neurodegenerative diseases. In the current study, we found that ferroptosis also participated in the pathological process of cognitive dysfunction in SAE, while Liproxstatin-1 (Lip-1) effectively inhibited ferroptosis and alleviated cognitive impairment. Additionally, since an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis, we further proved the essential role of autophagy in this process and demonstrated the key molecular mechanism of the autophagy-ferroptosis interaction. Currently, we showed that autophagy in the hippocampus was downregulated within 3 days of lipopolysaccharide injection into the lateral ventricle. Moreover, enhancing autophagy ameliorated cognitive dysfunction. Importantly, we found that autophagy suppressed ferroptosis by downregulating transferrin receptor 1 (TFR1) in the hippocampus, thereby alleviating cognitive impairment in mice with SAE. In conclusion, our findings indicated that hippocampal neuronal ferroptosis is associated with cognitive impairment. In addition, enhancing autophagy can inhibit ferroptosis via degradation of TFR1 to ameliorate cognitive impairment in SAE, which shed new light on the prevention and therapy for SAE.
脓毒症相关性脑病（SAE）是脓毒症的一种严重并发症，其特征为长期认知障碍，给家庭和社会带来沉重负担。然而，其病理机制尚未阐明。铁死亡是一种新型程序性细胞死亡形式，与多种神经退行性疾病有关。在本研究中，我们发现铁死亡也参与了SAE认知功能障碍的病理过程，而Liproxstatin-1（Lip-1）可有效抑制铁死亡并减轻认知障碍。此外，由于越来越多的研究表明自噬与铁死亡之间存在相互作用，我们进一步证实了自噬在此过程中的重要作用，并揭示了自噬-铁死亡相互作用的关键分子机制。目前，我们发现向侧脑室内注射脂多糖后3天内，海马体中的自噬下调。此外，增强自噬可改善认知功能障碍。重要的是，我们发现自噬通过下调海马体中的转铁蛋白受体1（TFR1）来抑制铁死亡，从而减轻SAE小鼠的认知障碍。总之，我们的研究结果表明海马神经元铁死亡与认知障碍有关。此外，增强自噬可通过降解TFR1抑制铁死亡，从而改善SAE的认知障碍，这为SAE的预防和治疗提供了新的思路。
