ZBP1-RIPK1轴对Z-核酸的先天免疫感知驱动阿尔茨海默病的神经炎症，这一成果由中国科学院上海有机化学研究所许代超课题组经过不懈努力而取得。该项研究成果发表在2025年9月2日出版的《免疫学》上。

该研究团队发现ZBP1在AD小胶质细胞中被扩增，通过感应Z型线粒体DNA （mtDNA）驱动先天免疫反应和神经炎症。该研究组发现，由淀粉样蛋白-β (Aβ)诱导的氧化应激产生的氧化mtDNA被分裂并释放到细胞质中，形成Z-DNA。Z-DNA激活的ZBP1参与受体相互作用蛋白激酶1 (RIPK1)，促进其激酶活化并诱导促炎分子和炎症信号介质的转录。Zbp1基因缺失或RIPK1基因抑制可减轻阿尔茨海默病模型中的神经炎症、Aβ病理和行为缺陷。他们的研究结果表明，氧化诱导mtDNA中的Z构象，并建立ZBP1-RIPK1轴作为AD神经炎症的关键驱动因素，为AD发病机制的免疫机制提供了见解，并确定了潜在的治疗靶点。

据悉，神经炎症驱动阿尔茨海默病（AD）的发病机制。Z-DNA是一种非规范的左旋DNA结构，通过Z-DNA结合蛋白1（ZBP1）激活先天免疫信号。然而，ZBP1介导的Z-DNA检测在AD中的功能意义尚不明确。

附：英文原文

Title: Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer’s disease

Author: Ziwen Song, Xingxing Xie, Yulu Chen, Boxin Zhang, Xingyan Li, Yuanxin Yang, Wei Mo, Jian Zhang, Daichao Xu

Issue&Volume: 2025-09-02

Abstract: Neuroinflammation drives Alzheimer's disease (AD) pathogenesis. Z-DNA, a non-canonical left-handed DNA structure, activates innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated Z-DNA detection in AD remains undefined. Here, we found that ZBP1 is amplified in AD microglia, driving innate immune responses and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that oxidized mtDNA, generated by amyloid-β (Aβ)-induced oxidative stress, was fragmented and released into the cytoplasm, forming Z-DNA. Z-DNA-activated ZBP1 engaged receptor-interacting protein kinase 1 (RIPK1), promoting its kinase activation and inducing transcription of pro-inflammatory molecules and inflammatory signaling mediators. Genetic deletion of Zbp1 or inhibition of RIPK1 attenuated neuroinflammation, Aβ pathology, and behavioral deficits in an AD mouse model. Our findings reveal that oxidation induces the Z conformer in mtDNA and establish the ZBP1-RIPK1 axis as a key driver of AD neuroinflammation, providing insights into the immune mechanisms underlying AD pathogenesis and identifying a potential therapeutic target.

DOI: 10.1016/j.immuni.2025.07.024

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00333-4