德国科隆大学Gianmaria Liccardi课题组的一项最新研究探明了STING诱导ZBP1介导的坏死下垂不依赖于TNFR1和FADD。这一研究成果于2025年8月20日发表在国际顶尖学术期刊《自然》上。

该课题组研究人员发现Casp8缺失导致细胞质DNA的积累，负责激活环GMP-AMP合成酶(cGAS)/干扰素（IFN）基因刺激因子（STING）介导的转录程序。遗传和生化证据表明，STING上调Z-DNA结合蛋白1 （ZBP1）和混合谱系激酶结构域样（MLKL）。结合Casp8缺失和STING激活驱动的Z-核酸积累，激活ZBP1并触发独立于FADD-RIPK1-RIPK3复合物的ZBP1-RIPK1-RIPK3复合物的形成，从而导致坏死。

遗传学上，研究小组揭示了STING和ZBP1之间的功能重叠，独立于TNFR1作为致死性皮炎的驱动因素，揭示了坏死性炎症的新病因。由于婴儿期起病的人类STING腺苷型STING相关血管病变（SAVI）存在功能获得性突变，小组评估了STING诱导的坏死下垂在SAVI病因学中的作用。在N153S-SAVI临床前小鼠模型中，RIPK3共缺失显著地挽救了免疫细胞驱动的病理和致死性，这在患者体内的STING慢性激活协调了一个坏死性转录程序。这些发现证实了STING驱动的ZBP1介导的坏死性坏死是Casp8缺陷炎症和SAVI的主要致病机制，并表明靶向ZBP1-RIPK3-MLKL轴具有治疗以过度坏死性坏死为特征的干扰素病变的潜力。

研究人员表示，Caspase-8在表皮角质形成细胞（Casp8E-KO）致死性皮炎中的条件性缺失。

附：英文原文

Title: STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD

Author: Kelepouras, Konstantinos, Saggau, Julia, Bonasera, Debora, Kiefer, Christine, Locci, Federica, Rakhsh-Khorshid, Hassan, Grauvogel, Louisa, Varanda, Ana Beatriz, Peifer, Martin, Loricchio, Elena, Montinaro, Antonella, Croon, Marijana, Trifunovic, Aleksandra, Prencipe, Giusi, Insalaco, Antonella, De Benedetti, Fabrizio, Walczak, Henning, Liccardi, Gianmaria

Issue&Volume: 2025-08-20

Abstract: Conditional deletion of Caspase-8 in epidermal keratinocytes (Casp8E-KO) causes necroptosis-driven lethal dermatitis1-7. Here, we discover that Casp8 loss leads to accumulation of cytosolic DNA responsible for the activation of a cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) gene (STING)-mediated transcriptional program. Genetic and biochemical evidence indicate that STING upregulates both Z-DNA binding protein-1 (ZBP1), and mixed lineage kinase domain-like (MLKL). Combined Casp8-deficiency- and STING-activation-driven accumulation of Z-nuclei acids, activates ZBP1 and triggers formation of a ZBP1–RIPK1–RIPK3 complex independently of FADD-RIPK1-RIPK3 complex enabling necroptosis execution. Genetically, we reveal a functional overlap between STING and ZBP1 as drivers of lethal dermatitis independently of TNFR1, uncovering a novel aetiology of necroptotic inflammation. Since gain-of-function mutations in human STING cause STING-Associated Vasculopathy with onset in Infancy (SAVI), we assessed the role of STING-induced necroptosis in SAVI’s aetiology. Chronic activation of STING in patients orchestrates a necroptotic transcriptional program which is confirmed in the N153S-SAVI preclinical mouse model where immune cell–driven pathology and lethality are remarkably rescued by RIPK3 co-deletion. These findings establish STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism in both Casp8-deficient inflammation and SAVI and suggest that targeting the ZBP1-RIPK3-MLKL axis holds therapeutic potential for interferonopathies characterised by excessive necroptosis.

DOI: 10.1038/s41586-025-09536-4

Source: https://www.nature.com/articles/s41586-025-09536-4