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<p>Acute lung injury (ALI) is a critical condition characterized by uncontrolled inflammation, respiratory insufficiency, and tissue damage, often triggered by pneumonia or sepsis. Aberrant activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and subsequent pyroptosis are key drivers of ALI pathogenesis. Palmatine (PAL), a naturally derived isoquinoline alkaloid with diverse pharmacological effects, was investigated for the therapeutic potential against lipopolysaccharide (LPS)-induced ALI in this study, focusing on NLRP3 inflammasome, pyroptosis, and metabolic regulation. Our findings showed that PAL significantly suppressed NLRP3 inflammasome activation and pyroptosis in LPS/adenosine triphosphate (ATP)-stimulated THP-1 macrophages and inhibited M1 macrophage polarization. In C57BL/6J mice subjected to intratracheal LPS challenge, PAL alleviated lung histopathological injury, decreased tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-18 levels in bronchoalveolar lavage fluid, and reduced lung wet-to-dry ratio and lung tissue myeloperoxidase activity. Transcriptomic analysis revealed that PAL markedly attenuated LPS-induced upregulation of NLRP3 and Gasdermin-D (GSDMD). PAL also downregulated the mRNA expression of <i>Caspase-1</i>,<i> Apoptosis-associated speck-like protein (Asc)</i>,<i> High-mobility group box 1 (Hmgb1)</i>,<i> Il1b</i>, and <i>Il18</i>, as well as the protein levels of cleaved Caspase-1 (p20), GSDMD-N and Caspase-11 in lung tissue. Metabolomic profiling indicated PAL-driven metabolic reprogramming involving the oxidation of branched-chain fatty acids and very long-chain fatty acids. Integrated multi-omics analysis highlighted cytosolic DNA-sensing and NOD-like receptor signaling as key pathways underlying PAL’s effects. Collectively, PAL mitigates ALI by inhibiting NLRP3 inflammasome activation, suppressing pyroptosis, and reprogramming metabolism, supporting its potential as a therapeutic candidate.</p>

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Palmatine Attenuates Lipopolysaccharide-Induced Acute Lung Injury Via Suppression of NLRP3 Inflammasome Activation, Pyroptosis, and Metabolic Remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • Pu Ning,
  • Jing Wu,
  • Qiuyue Long,
  • Yaolin Zheng,
  • Jialing Gan,
  • Xiaoyi Hu,
  • Shixu Song,
  • Xiaomin Li,
  • Mingzheng Jiang,
  • Hongli Ye,
  • Wenyi Yu,
  • Yukun He,
  • Yali Zheng,
  • Zhancheng Gao

摘要

Acute lung injury (ALI) is a critical condition characterized by uncontrolled inflammation, respiratory insufficiency, and tissue damage, often triggered by pneumonia or sepsis. Aberrant activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and subsequent pyroptosis are key drivers of ALI pathogenesis. Palmatine (PAL), a naturally derived isoquinoline alkaloid with diverse pharmacological effects, was investigated for the therapeutic potential against lipopolysaccharide (LPS)-induced ALI in this study, focusing on NLRP3 inflammasome, pyroptosis, and metabolic regulation. Our findings showed that PAL significantly suppressed NLRP3 inflammasome activation and pyroptosis in LPS/adenosine triphosphate (ATP)-stimulated THP-1 macrophages and inhibited M1 macrophage polarization. In C57BL/6J mice subjected to intratracheal LPS challenge, PAL alleviated lung histopathological injury, decreased tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-18 levels in bronchoalveolar lavage fluid, and reduced lung wet-to-dry ratio and lung tissue myeloperoxidase activity. Transcriptomic analysis revealed that PAL markedly attenuated LPS-induced upregulation of NLRP3 and Gasdermin-D (GSDMD). PAL also downregulated the mRNA expression of Caspase-1, Apoptosis-associated speck-like protein (Asc), High-mobility group box 1 (Hmgb1), Il1b, and Il18, as well as the protein levels of cleaved Caspase-1 (p20), GSDMD-N and Caspase-11 in lung tissue. Metabolomic profiling indicated PAL-driven metabolic reprogramming involving the oxidation of branched-chain fatty acids and very long-chain fatty acids. Integrated multi-omics analysis highlighted cytosolic DNA-sensing and NOD-like receptor signaling as key pathways underlying PAL’s effects. Collectively, PAL mitigates ALI by inhibiting NLRP3 inflammasome activation, suppressing pyroptosis, and reprogramming metabolism, supporting its potential as a therapeutic candidate.