Ferroptosis and neuroinflammation contribute to the development of Alzheimer's disease (AD). Isoforsythiaside (IFY) is a phenylethanoid glycoside isolated from the dried fruit of Forsythia suspensa (Thunb.) Vahl that has been confirmed to improve the memory and cognitive abilities of APP/PS1 mice in our previous study. The purpose of this study was to explore the anti-ferroptosis and anti-neuroinflammatory properties of IFY-mediated neuroprotection. In APP/PS1 mice, erastin-damaged HT22 cells, and LPS-exposed BV2 cells, the neuroprotective effects against ferroptosis and neuroinflammation were investigated using immunohistochemistry, label-free proteomics, western blot, ELISA, MTT, fluorescence, and TEM. IFY alleviated the expression levels of NO, IL-6, and IL-1β in LPS-exposed BV2 cells and improved the morphology of mitochondria in erastin-damaged HT22 cells. Additionally, IFY upregulated the expression levels of GPX4, FTH, FTL, p-GSK-3β, Nrf2, and NQO1, and downregulated the expression of TFR1, DMT1, p-Fyn, GFAP, p-IKKα+β, p-IκBα, p-NF-κB, and pro-inflammatory factors in the brains of APP/PS1 mice and erastin-damaged HT22 cells. In conclusion, IFY inhibits ferroptosis and neuroinflammation in erastin-damaged HT22 cells and APP/PS1 mice, at least partially by regulating the activation of Nrf2 and NF-κB signaling. IFY may prevent ferroptosis and neuroinflammation in AD and provide a new treatment strategy for AD.

铁死亡和神经炎症导致阿尔茨海默病 (AD) 的发展。Isoforsythiaside (IFY) 是一种苯乙醇苷，从连翘的干果中分离出来(Thunb.) Vahl 在我们之前的研究中已被证实可以改善 APP/PS1 小鼠的记忆和认知能力。本研究的目的是探索 IFY 介导的神经保护作用的抗铁死亡和抗神经炎症特性。在 APP/PS1 小鼠、erastin 损伤的 HT22 细胞和 LPS 暴露的 BV2 细胞中，使用免疫组织化学、无标记蛋白质组学、蛋白质印迹、ELISA、MTT、荧光和 TEM 研究了对铁死亡和神经炎症的神经保护作用。IFY 减轻了 LPS 暴露的 BV2 细胞中 NO、IL-6 和 IL-1β 的表达水平，并改善了 erastin 损伤的 HT22 细胞中线粒体的形态。此外，IFY 上调 GPX4、FTH、FTL、p-GSK-3β、Nrf2 和 NQO1 的表达水平，下调 TFR1、DMT1、p-Fyn、GFAP、p-IKKα+β、p-IκBα、p-NF-κB，以及 APP/PS1 小鼠和 erastin 损伤的 HT22 细胞大脑中的促炎因子。总之，IFY 抑制 erastin 损伤的 HT22 细胞和 APP/PS1 小鼠的铁死亡和神经炎症，至少部分是通过调节 Nrf2 和 NF-κB 信号的激活。IFY可以预防AD中的铁死亡和神经炎症，为AD提供新的治疗策略。