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

  • Inflammation. 2025 Dec 20;49(1):11. doi: 10.1007/s10753-025-02358-6.
Pu Ning  1 ,  Jing Wu  2  3 ,  Qiuyue Long  2  3 ,  Yaolin Zheng  2  3 ,  Jialing Gan  2  3 ,  Xiaoyi Hu  2  3 ,  Shixu Song  2  3 ,  Xiaomin Li  2  3 ,  Mingzheng Jiang  2  3 ,  Hongli Ye  2  3 ,  Wenyi Yu  4 ,  Yukun He  4 ,  Yali Zheng  5  6 ,  Zhancheng Gao  7  8  9 ,  Orcid  1
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
  • 2. Department of Respiratory, Critical Care and Sleep Medicine, School of Medicine, Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361101, China.
  • 3. Institute of Chest and Lung Diseases, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361101, China.
  • 4. Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, 100044, China.
  • 5. Department of Respiratory, Critical Care and Sleep Medicine, School of Medicine, Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361101, China. [email protected].
  • 6. Institute of Chest and Lung Diseases, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361101, China. [email protected].
  • 7. Department of Respiratory, Critical Care and Sleep Medicine, School of Medicine, Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361101, China. [email protected].
  • 8. Institute of Chest and Lung Diseases, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361101, China. [email protected].
  • 9. Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, 100044, China. [email protected].
PMID: 41420798 DOI: 10.1007/s10753-025-02358-6
Abstract

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.

Keywords
Acute lung injury; Macrophages; Metabolomics; NLRP3 inflammasome; Palmatine; Pyroptosis.
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