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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Zang-Si-Wei and its core constituent ellagic acid alleviate LPS-induced acute lung injury by modulating PI3K/AKT signaling and NLRP3-associated pyroptosis

  • Doudou Tang1,2,3,4,5,6
  • Boyang Song2,3,4,5,6
  • Huihui Wang7
  • Yewei Wang7
  • Mingjie Chen8
  • Shangjie Wu2,3,4,5,6
8 affiliations
  1. 1Department of Internal Medicine, Hunan Institute for Tuberculosis Control (Hunan Chest Hospital)
  2. 2Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University
  3. 3Hunan Centre for Evidence-based Medicine, Central South University
  4. 4Research Unit of Respiratory Disease, Central South University
  5. 5Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province
  6. 6Diagnosis and Treatment Center of Respiratory Disease in Hunan Province
  7. 7Department of Hematology, The Second Xiangya Hospital, Central South University
  8. 8Shanghai NewCore Biotechnology Co., Ltd.
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Abstract

Background: Acute lung injury (ALI) is a life-threatening respiratory condition characterized by uncontrolled pulmonary inflammation and epithelial barrier dysfunction. Zang-Si-Wei Qingfei Mixture (ZSW) is a promising Tibetan herbal formula used clinically to alleviate pulmonary symptoms, yet its pharmacological targets and therapeutic pathways in ALI have not been fully explored. This study aims to identify the bioactive constituents of ZSW and elucidate their protective and therapeutic mechanisms in ALI.

Methods: ZSW’s components were identified via liquid chromatography-tandem mass spectrometry (LC-MS/MS) previously and network pharmacology. Target affinity was evaluated using molecular docking and molecular dynamics simulations. In vivo , C57BL/6J mice with lipopolysaccharide (LPS)-induced ALI were used to evaluate the pretreatment and post-treatment effects of ZSW and its core component, Ellagic Acid (EA). In vitro , MLE-12 cells and the PI3K/mTOR dual inhibitor BEZ235 were utilized to investigate the role of PI3K/AKT signaling and NLRP3 inflammasome activation and pyroptosis.

Results: EA was identified as ZSW’s core bioactive constituent, demonstrating high binding stability with AKT1, PIK3CA, and PIK3R1. In vivo , ZSW and EA significantly attenuated lung histological damage, edema, and alveolar-capillary hyperpermeability. Both markedly reduced pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in bronchoalveolar lavage fluid. Mechanistically, ZSW and EA inhibited PI3K and AKT phosphorylation and were accompanied by decreased NLRP3 inflammasome-associated proteins (decreased NLRP3, ASC, and cleaved Caspase-1) and GSDMD-mediated pyroptosis (decreased GSDMD-N and lactate dehydrogenase release). Notably, the 6-h post-LPS therapeutic model showed that both treatments effectively reversed established lung injury.

Conclusion: ZSW and EA exert anti-inflammatory and lung-protective effects, accompanied by modulation of PI3K/AKT signaling and suppression of NLRP3 inflammasome-associated pyroptosis. This provides robust scientific evidence for ZSW’s clinical application and highlights EA as a promising therapeutic candidate for acute inflammatory lung diseases.

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Cite

BibTeXRIS
BibTeX
@article{tang2026zangsiwei,
  title = {{Zang-Si-Wei and its core constituent ellagic acid alleviate LPS-induced acute lung injury by modulating PI3K/AKT signaling and NLRP3-associated pyroptosis}},
  author = {Doudou Tang and Boyang Song and Huihui Wang and Yewei Wang and Mingjie Chen and Shangjie Wu},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1966973},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1966973/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Zang-Si-Wei and its core constituent ellagic acid alleviate LPS-induced acute lung injury by modulating PI3K/AKT signaling and NLRP3-associated pyroptosis
AU  - Doudou Tang
AU  - Boyang Song
AU  - Huihui Wang
AU  - Yewei Wang
AU  - Mingjie Chen
AU  - Shangjie Wu
PY  - 2026
DA  - 2026/10/27
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1966973
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1966973/full
AB  - Background: Acute lung injury (ALI) is a life-threatening respiratory condition characterized by uncontrolled pulmonary inflammation and epithelial barrier dysfunction. Zang-Si-Wei Qingfei Mixture (ZSW) is a promising Tibetan herbal formula used clinically to alleviate pulmonary symptoms, yet its pharmacological targets and therapeutic pathways in ALI have not been fully explored. This study aims to identify the bioactive constituents of ZSW and elucidate their protective and therapeutic mechanisms in ALI.  Methods: ZSW’s components were identified via liquid chromatography-tandem mass spectrometry (LC-MS/MS) previously and network pharmacology. Target affinity was evaluated using molecular docking and molecular dynamics simulations. In vivo , C57BL/6J mice with lipopolysaccharide (LPS)-induced ALI were used to evaluate the pretreatment and post-treatment effects of ZSW and its core component, Ellagic Acid (EA). In vitro , MLE-12 cells and the PI3K/mTOR dual inhibitor BEZ235 were utilized to investigate the role of PI3K/AKT signaling and NLRP3 inflammasome activation and pyroptosis.  Results: EA was identified as ZSW’s core bioactive constituent, demonstrating high binding stability with AKT1, PIK3CA, and PIK3R1. In vivo , ZSW and EA significantly attenuated lung histological damage, edema, and alveolar-capillary hyperpermeability. Both markedly reduced pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in bronchoalveolar lavage fluid. Mechanistically, ZSW and EA inhibited PI3K and AKT phosphorylation and were accompanied by decreased NLRP3 inflammasome-associated proteins (decreased NLRP3, ASC, and cleaved Caspase-1) and GSDMD-mediated pyroptosis (decreased GSDMD-N and lactate dehydrogenase release). Notably, the 6-h post-LPS therapeutic model showed that both treatments effectively reversed established lung injury.  Conclusion: ZSW and EA exert anti-inflammatory and lung-protective effects, accompanied by modulation of PI3K/AKT signaling and suppression of NLRP3 inflammasome-associated pyroptosis. This provides robust scientific evidence for ZSW’s clinical application and highlights EA as a promising therapeutic candidate for acute inflammatory lung diseases.
SN  - 1663-9812
ER  -