Harpagide Confers Protection Against Acute Lung Injury Through Multi-Omics Dissection of Immune–Microenvironmental Crosstalk and Convergent Therapeutic Mechanisms

作者：Hong Wang, Jicheng Yang, Yusheng Zhang, Jie Wang, Shaoqi Song, Long‐Hui Gao, Mei Liu, Zhiliang Chen, Xianyu Li · 发表于：Pharmaceuticals · 年份：2025 · DOI：10.3390/ph18101494 · 被引用次数：3 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Hydrogen's biological and therapeutic effects、Extracellular vesicles in disease

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality, yet no targeted pharmacological therapy is available. Excessive neutrophil and macrophage infiltration drives reactive oxygen species (ROS) production and cytokine release, leading to alveolar–capillary barrier disruption and fatal respiratory failure. Methods: We applied an integrative multi-omics strategy combining single-cell transcriptomics, peripheral blood proteomics, and lung tissue proteomics in a lipopolysaccharide (LPS, 10 mg/kg)-induced mouse ALI model to identify key signaling pathways. Harpagide, an iridoid glycoside identified from our natural compound screen, was evaluated in vivo (40 and 80 mg/kg) and in vitro (0.1–1 mg/mL). Histopathology, oxidative stress markers (SOD, GSH, and MDA), cytokine levels (IL-6 and IL-1β), and signaling proteins (HIF-1α, p-PI3K, p-AKT, Nrf2, and HO-1) were quantitatively assessed. Direct target engagement was probed using surface plasmon resonance (SPR), the cellular thermal shift assay (CETSA), and 100 ns molecular dynamics (MD) simulations. Results: Multi-omics profiling revealed robust activation of HIF-1, PI3K/AKT, and glutathione-metabolism pathways following the LPS challenge, with HIF-1α, VEGFA, and AKT as core regulators. Harpagide treatment significantly reduced lung injury scores by ~45% (p < 0.01), collagen deposition by ~50%, and ROS accumulation by >60% relative to ...