综合分析确定了系统性红斑狼疮中具有上下文依赖作用的cGAS STING通路驱动特征
Integrative Analyses Identify a cGAS-STING Pathway-Driven Signature With Context-Dependent Roles in Systemic Lupus Erythematosus.
摘要(中文译文)
cGAS-STING通路正逐渐被认为是系统性红斑狼疮（SLE）的重要驱动因素。本研究通过整合大规模转录组学、基于细胞的实验以及两种狼疮样小鼠模型，刻画了cGAS-STING通路的关键特征及其在SLE中的作用。我们鉴定出一个依赖于STING的基因特征，命名为M7core，可用于定量评估SLE中cGAS-STING通路的活性。M7core揭示了在3，180份SLE样本中有70.4%存在广泛的cGAS-STING通路激活，并可预测74.1%的患者对STING拮抗剂的治疗反应，活性越高提示敏感性越强。在十个独立队列中，M7core优于干扰素刺激基因特征（平均AUROC = 0.876），并与疾病活动度、抗dsDNA抗体、淋巴细胞减少及狼疮肾炎相关。羟氯喹治疗可降低M7core表达及其临床相关性。重要的是，在cGAS-STING通路驱动的狼疮样小鼠中，给予STING拮抗剂可改善多器官病理，并抑制参与促进炎症、I型干扰素及细胞死亡的M7core基因，其中包括ZBP1——一个已被确认的cGAS-STING通路促进因子。值得注意的是，ZBP1缺陷可模拟阻断cGAS-STING通路介导的自身免疫病理加重，在降植烷诱导的狼疮样小鼠中表现一致，凸显了其在狼疮发病机制中具有情境依赖性的作用。总之，这些发现确立了M7core作为一种稳健的诊断和机制性生物标志物，并强调了在SLE中启动STING靶向治疗前评估通路活性的必要性。
Abstract
The cGAS-STING pathway is emerging as an essential driver in systemic lupus erythematosus (SLE). Here, we characterize the key signature of cGAS-STING pathway and its roles in SLE by leveraging large-scale transcriptomics, cell-based assays, and two lupus-like mouse models. We identify a STING-dependent gene signature termed M7core, enabling quantitative assessment of cGAS-STING pathway activity in SLE. M7core reveals widespread cGAS-STING pathway activation in 70.4% of 3,180 SLE samples and predicts therapeutic response to STING antagonists in 74.1% of patients, with higher activity indicating greater sensitivity. Across ten independent cohorts, M7core outperforms interferon-stimulated gene signatures (mean AUROC = 0.876) and correlates with disease activity, anti-dsDNA antibodies, lymphopenia, and lupus nephritis. Hydroxychloroquine treatment reduces M7core expression and its clinical associations. Importantly, in cGAS-STING pathway-driven lupus-like mice, STING antagonist administration ameliorates multiorgan pathology and suppresses M7core genes participating in promoting inflammation, type I interferon, and cell death, including ZBP1-an established cGAS-STING pathway facilitator. Notably, ZBP1 deficiency phenocopies blocking cGAS-STING pathway-mediated autoimmune pathology exacerbation in pristane-induced lupus-like mice, underscoring its context-dependent roles in lupus pathogenesis. Together, these findings define M7core as a robust diagnostic and mechanistic biomarker and highlight the necessity of assessing pathway activity before initiating STING-targeted therapy in SLE.
如何引用
AMA
Lele Zhang, Ming-Ju Amy Lyu, Ze Hong, Jing Sun, Lan Guo, Jiameng Hu, et al. Integrative Analyses Identify a cGAS-STING Pathway-Driven Signature With Context-Dependent Roles in Systemic Lupus Erythematosus.. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2026; doi:10.1002/advs.202521560.
APA
Lele Zhang, Ming-Ju Amy Lyu, Ze Hong, Jing Sun, Lan Guo, Jiameng Hu, et al (2026). Integrative Analyses Identify a cGAS-STING Pathway-Driven Signature With Context-Dependent Roles in Systemic Lupus Erythematosus.. Advanced science (Weinheim, Baden-Wurttemberg, Germany). https://doi.org/10.1002/advs.202521560
GB/T 7714
Lele Zhang, Ming-Ju Amy Lyu, Ze Hong, Jing Sun, Lan Guo, Jiameng Hu, et al. Integrative Analyses Identify a cGAS-STING Pathway-Driven Signature With Context-Dependent Roles in Systemic Lupus Erythematosus.[J]. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026 doi:10.1002/advs.202521560.
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