Shegan Mahuang Decoction ameliorates pulmonary fibrosis progression by inhibiting CCL3-mediated NETosis

  • Phytomedicine. 2026 Aug:158:158386. doi: 10.1016/j.phymed.2026.158386.
Wencheng Zhou  1 ,  Zhisen Wang  2 ,  Haojie Du  3 ,  Wanjun Zhao  4 ,  Tao Zhang  4 ,  Zhengcheng Liu  5 ,  Jiao Qu  6 ,  Yang Sun  7
Affiliations
  • 1. Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China; Clinical Pharmacy Teaching and Research Office, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311402, China.
  • 2. Department of Pharmacy, Zhejiang Hospital, Hangzhou 310013, China.
  • 3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China; State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital School of Life Sciences Chemistry and Biomedicine Innovation Center Nanjing University, Nanjing 210023, China.
  • 4. State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital School of Life Sciences Chemistry and Biomedicine Innovation Center Nanjing University, Nanjing 210023, China.
  • 5. Department of Thoracic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital School of Life Sciences Chemistry and Biomedicine Innovation Center Nanjing University, Nanjing 210023, China. Electronic address: [email protected].
  • 7. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China; State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital School of Life Sciences Chemistry and Biomedicine Innovation Center Nanjing University, Nanjing 210023, China. Electronic address: [email protected].
PMID: 42275874 DOI: 10.1016/j.phymed.2026.158386
Abstract

Background: Pulmonary fibrosis (PF) represents a spectrum of chronic lung disorders for which effective therapeutic options remain limited. Shegan Mahuang Decoction (SGMH) is a traditional Chinese medicine with potential therapeutic effects for respiratory system diseases. The precise mechanism of SGMH in treating PF has not yet been elucidated.

Purpose: This study aims to investigate the effectiveness and mechanism of SGMH in the treatment of PF.

Methods: To investigate the effect of SGMH on PF, we established a mouse model and assessed inflammatory and neutrophil extracellular traps (NETs)-related markers. The target gene of SGMH was screened through integrated multi-omics analysis. The mechanisms of SGMH were explored through a series of experiments, encompassing NETs depletion with DNase I, the Pad4-/- mouse model, and pharmacological modulation via intraperitoneal administration of recombinant CCL3 (rCCL3) or a CCL3 neutralizing antibody (anti-CCL3).

Results: SGMH ameliorated Bleomycin-induced lung tissue damage. It also inhibited pulmonary inflammation and NETs formation. Both DNase I-mediated NETs clearance and the Pad4-/- mice model showed that SGMH could not further ameliorate PF, indicating that SGMH blocks the PF development by inhibiting NETs formation. Multi-omics analysis and experimental validation found that SGMH inhibits NETs formation by targeting CCL3. Administration of rCCL3 restored NETs formation and attenuated the anti-fibrotic effect of SGMH. Moreover, treatment with anti-CCL3 alone inhibited PF, whereas its combination with SGMH did not further enhance the therapeutic effect.

Conclusion: This study demonstrated that SGMH ameliorates PF progression by inhibiting CCL3-mediated NETosis, suggesting its potential clinical application for PF treatment.

Keywords
CCL3; Neutrophil extracellular traps; Pulmonary fibrosis; Shegan Mahuang Decoction.
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