综合多组学解读脓毒症免疫失调：一种双途径靶向小分子治疗可提高生存率并改善多器官功能障碍
Integrated multi-omics deciphers sepsis immune dysregulation: a dual-pathway targeted small-molecule therapy improves survival and ameliorates multi-organ dysfunction.
摘要(中文译文)
脓毒症是一种危及生命的器官功能障碍综合征，由宿主免疫反应失调驱动，全球死亡率持续居高不下。现有的单靶点治疗无法同时解决过度炎症和组织修复受损的问题，导致临床疗效有限且转化研究反复失败。整合的多组学数据集（单细胞RNA测序、微小RNA测序、血液/肺RNA测序）描绘了脓毒症中免疫细胞动态变化和失调通路。在组学发现的指导下，我们设计了两组小分子联合方案（C1、C2），靶向所鉴定的通路。其疗效和机制在脓毒症模型中得到验证。脓毒症患者表现出标志性免疫重塑特征：促炎性髓系细胞（中性粒细胞、单核细胞）扩增，保护性淋巴系细胞（B细胞、NK细胞）耗竭。靶向炎症级联反应和Hippo/Wnt再生通路的双通路小分子联合方案C2发挥了显著的协同治疗效应。该方案强效再平衡了全身和器官特异性炎症（抑制，；升高，），改善了多器官损伤，并将脓毒症小鼠的7天生存率从20%（未治疗）提高至70%。单化合物对照实验证实，C2的增强疗效源于双通路协同作用，而非单一组分。本研究揭示了免疫失调是脓毒症的核心发病机制。C2联合方案同时减轻过度炎症并促进组织修复，为脓毒症管理提供了一种新型、机制驱动且具有临床转化潜力的联合策略。
Abstract
Sepsis is a life-threatening organ dysfunction syndrome with persistently high global mortality, driven by dysregulated host immune response. Existing single-target therapies fail to simultaneously address hyperinflammation and impaired tissue repair, leading to limited clinical efficacy and repeated translational failures. Integrated multi-omics datasets (scRNA-seq, miRNA-seq, blood/lung RNA-seq) delineated immune cell dynamics and dysregulated pathways in sepsis. Guided by omics findings, we designed two small-molecule combinations (C1, C2) targeting the identified pathways. Their efficacy and mechanism were validated in and sepsis models. Septic patients showed a hallmark immune remodeling signature: expansion of pro-inflammatory myeloid cells (neutrophils, monocytes) and depletion of protective lymphoid cells (B cells, NK cells). A dual-pathway small-molecule combination C2 targeting inflammatory cascades and Hippo/Wnt regenerative pathways, exerted significant synergistic therapeutic effects. It robustly rebalanced systemic and organ-specific inflammation (suppressed , , , ; elevated , , , ) and , ameliorated multi-organ injury, and improved 7-day survival in septic mice from 20% (untreated) to 70%. Single-compound control experiments confirmed that the enhanced efficacy of C2 stems from dual-pathway synergy, not individual components. This study revealed immune dysregulation as the core pathogenesis of sepsis. The C2 combination simultaneously mitigates hyperinflammation and promotes tissue repair, providing a novel, mechanism-driven, and clinically translatable combination strategy for sepsis management.
如何引用
AMA
Jiawen Duan, Lingyu Jiang, Kunlin Hu, Huirong Shi, Xinyu Chi, Weiting Feng, et al. Integrated multi-omics deciphers sepsis immune dysregulation: a dual-pathway targeted small-molecule therapy improves survival and ameliorates multi-organ dysfunction.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1809540.
APA
Jiawen Duan, Lingyu Jiang, Kunlin Hu, Huirong Shi, Xinyu Chi, Weiting Feng, et al (2026). Integrated multi-omics deciphers sepsis immune dysregulation: a dual-pathway targeted small-molecule therapy improves survival and ameliorates multi-organ dysfunction.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1809540
GB/T 7714
Jiawen Duan, Lingyu Jiang, Kunlin Hu, Huirong Shi, Xinyu Chi, Weiting Feng, et al. Integrated multi-omics deciphers sepsis immune dysregulation: a dual-pathway targeted small-molecule therapy improves survival and ameliorates multi-organ dysfunction.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1809540.
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