Meng Xin, Zhao Wei, Yang Rui, Xu Shi-Qi, Wang Si-Yi, Li Meng-Meng, Jiang Yi-Kai, Hao Zhi-Chao, Guan Wei, Kuang Hai-Xue, Chen Qing-Shan, Yao Hong-Yan, Yan Jiu-Jiang, Yang Bing-You, Liu Yan
Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education Heilongjiang Touyan Innovation Team Program, Harbin, 150040, People's Republic of China.
College of Agriculture, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
J Ethnopharmacol. 2025 Feb 11;341:119335. doi: 10.1016/j.jep.2025.119335. Epub 2025 Jan 9.
Schisandra chinensis (Turcz.) Baill (S. chinensis), first recorded in Shennong's Classic of the Materia Medica, is described as a "top grade medicine". As a traditional Chinese medicine of tonifying the kidneys and the brain, S. chinensis is widely used to treat diseases such as amnesia and dementia. Alzheimer's disease (AD) is a neurodegenerative disease, and ferroptosis is one of the essential causes of AD. Although previous studies have suggested that the lignans of S. chinensis (SCL) have neuroprotective effects, it is unclear whether SCL can alleviate AD pathology by inhibiting ferroptosis.
To investigate the effect of SCL on AD caused by ferroptosis and its possible molecular mechanism.
This study was based on SAMR1/SAMP8 mouse models along with Erastin-induced HT22 cell lines to examine the influence of SCL on ferroptosis in AD. The S. chinensis was extracted via 75% EtOH-HO and identified by HPLC/UPLC-QTOF-MS. MWM assessed spatial learning, while HE staining, biochemical detection, IHC, and WB analyzed AD pathology and iron metabolism. Mitochondrial changes were evaluated by TEM, and confocal imaging post-SCL treatment analyzed ROS, MMP, and Fe levels in HT22 cells. IF determined the expression levels and localization of Nrf2 and FPN1. CETSA was deployed to study the interaction between SCL and Nrf2.
Treatment with SCL mitigated cognitive dysfunction and reduced p-Tau as well as neuronal loss in AD model mice. Additionally, the administration of SCL alleviated oxidative stress and maintained relatively intact mitochondrial ridges and membranes, decreased TFR and DMT1 protein expression, and upregulated FTH1. Consistent with the in vivo results, SCL inhibited Erastin-induced ferroptosis in HT22 cells. SCL promoted Nrf2 nuclear translocation and upregulated FPN1, SLC7A11, and GPX4 protein expressions while decreasing FACL4. The improvement of ferroptosis by SCL was associated with the regulation of the Nrf2/FPN1 signaling pathway.
The novel discoveries of this study suggest that SCL can suppress ferroptosis in the brains of AD model mice and exerts a partial protective effect against Erastin-induced ferroptosis in HT22 cells, in which the Nrf2/FPN1 signaling pathway plays a crucial role.
五味子最先记载于《神农本草经》，被列为“上品”。作为一种补肾健脑的传统中药，五味子被广泛用于治疗失忆和痴呆等疾病。阿尔茨海默病（AD）是一种神经退行性疾病，铁死亡是AD的重要病因之一。虽然先前的研究表明五味子木脂素（SCL）具有神经保护作用，但尚不清楚SCL是否能通过抑制铁死亡来减轻AD病理。
探讨SCL对铁死亡所致AD的影响及其可能的分子机制。
本研究基于SAMR1/SAMP8小鼠模型以及Erastin诱导的HT22细胞系，以研究SCL对AD中铁死亡的影响。五味子通过75%乙醇-水提取，并通过HPLC/UPLC-QTOF-MS进行鉴定。水迷宫试验评估空间学习能力，苏木精-伊红（HE）染色、生化检测、免疫组化（IHC）和蛋白质免疫印迹（WB）分析AD病理和铁代谢。通过透射电子显微镜（TEM）评估线粒体变化，SCL处理后的共聚焦成像分析HT22细胞中的活性氧（ROS）、线粒体膜电位（MMP）和铁水平。免疫荧光（IF）检测核因子E2相关因子2（Nrf2）和铁转运蛋白1（FPN1）的表达水平和定位。采用热蛋白质组分析（CETSA）研究SCL与Nrf2之间的相互作用。
SCL治疗减轻了AD模型小鼠的认知功能障碍，降低了磷酸化tau蛋白水平以及神经元损失。此外，给予SCL减轻了氧化应激，维持了线粒体嵴和膜相对完整，降低了转铁蛋白受体（TFR）和二价金属离子转运体1（DMT1）蛋白表达，并上调了铁蛋白重链1（FTH1）。与体内结果一致，SCL抑制了Erastin诱导的HT22细胞铁死亡。SCL促进Nrf2核转位，上调FPN1、溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）蛋白表达，同时降低脂肪酸辅酶A连接酶4（FACL4）。SCL对铁死亡的改善与Nrf2/FPN1信号通路的调节有关。
本研究的新发现表明，SCL可抑制AD模型小鼠大脑中的铁死亡，并对Erastin诱导的HT22细胞铁死亡发挥部分保护作用，其中Nrf2/FPN1信号通路起关键作用。
