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<p>Acute lung injury (ALI) is a life-threatening inflammatory disorder with limited therapeutic options. This study evaluated the anti-inflammatory activity of ZLWH-38, a novel harmine derivative, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and a murine ALI model. ZLWH-38 showed low cytotoxicity and effectively inhibited the production of nitric oxide and pro-inflammatory cytokines. In macrophages, it dose-dependently reduced the expression of TNF-α, IL-6, IL-1β and iNOS, and intracellular ROS levels. Mechanistic investigations indicated that ZLWH-38 interacted with glycogen synthase kinase-3β (GSK3β) and suppressed downstream NF-κB signaling. In female C57BL/6 mice subjected to LPS-induced lung injury, prophylactic administration of ZLWH-38 markedly attenuated histopathological damage, lowered the lung wet/dry weight ratio, and decreased neutrophil infiltration and cytokine levels in bronchoalveolar lavage fluid and lung tissue. These findings suggest that ZLWH-38 ameliorates ALI by blocking GSK3β and thereby repressing downstream NF-κB signaling to curtail inflammation, offering a novel rationale and mechanistic foundation for ALI therapeutics.</p>

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Harmine Derivatives Alleviate LPS-Induced Acute Lung Injury via Targeting GSK3β

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月24日

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  • Xinhui Ye,
  • Junjie Lin,
  • Tianqi Zhang,
  • Huanhua Chen,
  • Hui Huang,
  • Lingyu Cui,
  • Jiacheng Zhuang,
  • Mingzuo Zhang,
  • Wenwu Liu,
  • Wenjie Liu,
  • Limeng Wu,
  • Bolin Du,
  • Ying Chen,
  • Qiong Wu,
  • Zihua Xu,
  • Xi Zeng,
  • Qingchun Zhao

摘要

Acute lung injury (ALI) is a life-threatening inflammatory disorder with limited therapeutic options. This study evaluated the anti-inflammatory activity of ZLWH-38, a novel harmine derivative, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and a murine ALI model. ZLWH-38 showed low cytotoxicity and effectively inhibited the production of nitric oxide and pro-inflammatory cytokines. In macrophages, it dose-dependently reduced the expression of TNF-α, IL-6, IL-1β and iNOS, and intracellular ROS levels. Mechanistic investigations indicated that ZLWH-38 interacted with glycogen synthase kinase-3β (GSK3β) and suppressed downstream NF-κB signaling. In female C57BL/6 mice subjected to LPS-induced lung injury, prophylactic administration of ZLWH-38 markedly attenuated histopathological damage, lowered the lung wet/dry weight ratio, and decreased neutrophil infiltration and cytokine levels in bronchoalveolar lavage fluid and lung tissue. These findings suggest that ZLWH-38 ameliorates ALI by blocking GSK3β and thereby repressing downstream NF-κB signaling to curtail inflammation, offering a novel rationale and mechanistic foundation for ALI therapeutics.