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Xiebai San mediates the NCOA2-ESR1/2 signaling pathway to intervene in interstitial pneumonia
Yufeng Yao1, Lijun Shao1, Ziqi Li1
1School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China; Engineering & Technology Research Center for Chinese Materia Medica Quality of the Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Background:
Interstitial pneumonia, particularly usual interstitial pneumonia (UIP) and idiopathic pulmonary fibrosis (IPF), is a disease with progressive and fatal disorder, and limited treatment options. Xiebai San (XBS), a classical Chinese herbal formula, has shown clinical promise but its mechanism of action remains unclear.
Purpose:
To clarify the effects and mechanism of XBS on interstitial pneumonia.
Methods:
The in vivo pharmacochemical analysis (UPLC-Q-Exactive-Orbitrap MS/MS), network pharmacology, and GEO database analysis (GSE10667) were applied to predict potential targets of XBS on interstitial pneumonia. BLM-induced mice received XBS (1.4, 2.8, 5.6 g/kg) or dexamethasone (0.5 mg/kg) for 21 days. Lung index, histopathology observation (H&E, Collagen-1 IHC), pulmonary function, and biomarkers of inflammation, oxidative stress and fibrosis were used to evaluated the efficacy of XBS. Reverse-phase protein microarray (RPPM), RT-qPCR, and Western blotting were integrated to clarify its mechanism.
Results:
Thirty-seven components of XBS were identified in vivo, and they were associated with 237 potential targets for interstitial pneumonia. And GEO analysis confirmed the upregulation of key nodes (NCOA2, ESR1, and ESR2) in patients. XBS significantly attenuated BLM-induced lung damage, evidenced by reduced lung index, improved pulmonary function (Penh, EEP, PIF, PEF), decreased inflammatory infiltrates, collagen deposition, and alveolar destruction. XBS suppressed proinflammatory cytokines (TNF-α, IL-1β), oxidative stress (MDA, MPO), restored antioxidants (GSH, SOD), and inhibited fibrotic factors (TGF-β1, α-SMA, Collagen-1/3). Mechanistically, XBS downregulated the mRNA and protein expression of NCOA2 and ESR1/2, subsequently inhibiting glycolytic metabolic reprogramming (G6PC, PFKFB3, HIF-1α) and the TGF-β1/ERK1/2-Smad7 pro-fibrotic signaling pathway.
Conclusion:
XBS alleviates BLM-induced interstitial pneumonia via NCOA2-ESR1/2-driven glycolytic metabolic reprogramming and TGF-β1/ERK1/2-Smad7 fibrotic signaling, offering a mechanistic rationale for interstitial pneumonia.
Insights
Xiebai San (XBS) effectively treats interstitial pneumonia by modulating key molecular pathways. This study elucidates XBS's mechanism, targeting NCOA2-ESR1/2, glycolytic reprogramming, and fibrotic signaling in lung injury.
Area of Science:
- Pharmacology
- Traditional Chinese Medicine
- Pulmonary Medicine
Background:
- Interstitial pneumonia, including idiopathic pulmonary fibrosis (IPF), is a progressive and fatal lung disease with limited therapeutic options.
- Xiebai San (XBS), a traditional Chinese herbal formula, shows clinical potential for treating interstitial pneumonia, but its underlying mechanisms are not well understood.
Purpose of the Study:
- To investigate the therapeutic effects of XBS on interstitial pneumonia.
- To elucidate the molecular mechanisms by which XBS exerts its effects in interstitial pneumonia.
Main Methods:
- In vivo pharmacochemical analysis, network pharmacology, and GEO database analysis were used to identify potential targets of XBS.
- Bleomycin (BLM)-induced mouse model of interstitial pneumonia was established to evaluate XBS efficacy.
- Histopathology, pulmonary function tests, and molecular assays (RPPM, RT-qPCR, Western blotting) were employed to assess treatment effects and mechanisms.
Main Results:
- XBS treatment significantly reduced lung damage, inflammation, oxidative stress, and fibrosis in BLM-induced mice.
- XBS modulated key molecular targets including NCOA2, ESR1, and ESR2, subsequently inhibiting glycolytic metabolic reprogramming and the TGF-β1/ERK1/2-Smad7 signaling pathway.
- Thirty-seven components of XBS were identified in vivo, associated with 237 potential targets for interstitial pneumonia.
Conclusions:
- XBS demonstrates significant therapeutic effects against BLM-induced interstitial pneumonia.
- The mechanism involves the downregulation of NCOA2-ESR1/2, inhibition of glycolytic metabolic reprogramming, and suppression of the TGF-β1/ERK1/2-Smad7 fibrotic signaling pathway.
- XBS offers a promising therapeutic strategy for interstitial pneumonia with a clarified mechanistic basis.
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