对乙酰氨基酚通过调节谷胱甘肽过氧化物酶 4 和铁死亡抑制蛋白 1 通路损害脓毒症小鼠海马中的铁死亡。

BACKGROUND: Neuronal ferroptosis is a major cause of cognitive impairment and mortality in patients with sepsis-associated encephalopathy (SAE). A low dose of acetaminophen (APAP) in septic mice can prevent ferroptosis in the hippocampal tissue; however, the underlying mechanism is unknown. This study aimed to investigate the mechanism by which APAP reduces ferroptosis in the hippocampal tissues of septic mice. METHODS: A mouse model of SAE was established, and the ferroptosis pathway inhibitors RSL3 and iFSP1+RSL3 were used in addition to APAP for the interventions, respectively. The 7-day survival rate of the mice was recorded, and cognitive function was examined using the Morris water maze test. Hematoxylin and eosin staining was performed to observe hippocampal tissue damage. Hippocampal iron and malondialdehyde (MDA) were measured using chemical colorimetric methods. Immunofluorescence was used to detect the reactive oxygen species (ROS) content in hippocampal tissues. RESULTS: RSL3 reversed the efficacy of APAP on improving cognitive dysfunction in septic mice but did not obviously reverse the survival rate of mice enhanced by APAP. RSL3 aggravated APAP-induced hippocampal tissue damage in mice attenuated by APAP. RSL3 inhibited glutathione peroxidase 4 (GPX4) expression and increased ferroptosis suppressor protein 1 (FSP1) and 4-hydroxy-2-nonenal (4-HNE) expression. RSL3 also reversed the effects of APAP in reducing iron, MDA, and ROS levels in the hippocampal tissues of septic mice. iFSP1+RSL3 further reversed the effect of APAP on ameliorating cognitive dysfunction in septic mice and successfully reversed the survival rate of mice enhanced by APAP. iFSP1+RSL3 aggravated APAP-induced cerebral hippocampal damage. iFSP1+RSL3 inhibited both GPX4 and FSP1, further reversing the effect of APAP on the reduction in iron, 4-HNE, ROS, and MDA levels in the cerebral hippocampus of mice with sepsis. CONCLUSION: These data suggest that APAP inhibits ferroptosis in the cerebral hippocampus of septic mice through the GPX4 and FSP1 pathways.

背景：神经元铁死亡是脓毒症相关脑病（SAE）患者认知障碍和死亡的主要原因。小剂量对乙酰氨基酚（APAP）可预防脓毒症小鼠海马组织铁死亡；然而，其潜在机制尚不清楚。本研究旨在探讨 APAP 降低脓毒症小鼠海马组织铁死亡的机制。

方法：建立 SAE 小鼠模型，分别采用铁死亡途径抑制剂 RSL3 和 iFSP1+RSL3 以及 APAP 进行干预。记录小鼠 7 天存活率，采用 Morris 水迷宫试验检测认知功能。采用苏木精-伊红染色观察海马组织损伤。采用化学比色法检测海马铁和丙二醛（MDA）含量。免疫荧光法检测海马组织中活性氧（ROS）含量。

结果：RSL3 逆转了 APAP 改善脓毒症小鼠认知功能障碍的作用，但对 APAP 增强的小鼠存活率无明显逆转作用。RSL3 加重了 APAP 减轻的脓毒症小鼠海马组织损伤。RSL3 抑制谷胱甘肽过氧化物酶 4（GPX4）表达，增加铁死亡抑制蛋白 1（FSP1）和 4-羟基-2-壬烯醛（4-HNE）表达。RSL3 还逆转了 APAP 降低脓毒症小鼠海马组织铁、MDA 和 ROS 水平的作用。iFSP1+RSL3 进一步逆转了 APAP 改善脓毒症小鼠认知功能障碍的作用，并成功逆转了 APAP 增强的小鼠存活率。iFSP1+RSL3 加重了 APAP 引起的脓毒症小鼠脑海马损伤。iFSP1+RSL3 抑制了 GPX4 和 FSP1，进一步逆转了 APAP 降低脓毒症小鼠脑海马铁、4-HNE、ROS 和 MDA 水平的作用。

结论：这些数据表明，APAP 通过 GPX4 和 FSP1 途径抑制脓毒症小鼠脑海马铁死亡。