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Background <p>Pulmonary fibrosis (PF) is a progressive interstitial lung disease driven by aberrant extracellular matrix (ECM) remodeling and alveolar destruction. While serotonin (5-HT) promotes fibrogenesis via the 5-HT2B receptor, pharmacological interventions targeting this specific pathway remain scarce.</p> Methods and Results <p>Using a spectrum–effect approach, we screened bioactive phenolic acids from Rosa roxburghii Tratt extracts in a TGF-β1-induced A549 cell model. Evaluating ellagic acid (EA), syringic acid (SA), and gallic acid (GA) both individually and in combination revealed that the EA/GA pairing (EG) yielded the most robust anti-fibrotic activity. Specifically, EG restored E-cadherin expression while suppressing key mesenchymal markers, effectively blunting epithelial–mesenchymal transition (EMT) in vitro. At the signaling level, EG treatment correlated with a downregulation of 5-HT2B-associated pathways, alongside marked reductions in oxidative stress and calcium influx. Our data suggest that EG dampens the Gq–PLCβ–IP3R module, limiting both intracellular calcium mobilization and subsequent NFATc1 activation. Concurrently, we observed a suppression of the CaMKII-dependent NF-κB cascade and its downstream pro-inflammatory targets (TNF-α, IL-6, and COX-2).</p> Conclusions <p>These findings indicate that the EG combination alleviates pro-fibrotic responses in A549 cells by disrupting the 5-HT2B/calcium/inflammation axis. Although in vivo validation is required, this plant-derived combination offers a promising multi-targeted therapeutic strategy against pulmonary fibrosis.</p>

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Ellagic acid and gallic acid combination attenuates pulmonary fibrotic responses in vitro: evidence suggesting involvement of the 5-HT2B/Ca²⁺/inflammatory axis

  • 期刊论文

  • 发表日期：

    2026年8月1日

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  • Chuan Wu,
  • Xiaomeng Wang,
  • Xiangzhi Shen,
  • Dongheng Liu,
  • Shaolin Huang,
  • Wenxi Wang,
  • Lijun Peng,
  • Wenya Yin

摘要

Background

Pulmonary fibrosis (PF) is a progressive interstitial lung disease driven by aberrant extracellular matrix (ECM) remodeling and alveolar destruction. While serotonin (5-HT) promotes fibrogenesis via the 5-HT2B receptor, pharmacological interventions targeting this specific pathway remain scarce.

Methods and Results

Using a spectrum–effect approach, we screened bioactive phenolic acids from Rosa roxburghii Tratt extracts in a TGF-β1-induced A549 cell model. Evaluating ellagic acid (EA), syringic acid (SA), and gallic acid (GA) both individually and in combination revealed that the EA/GA pairing (EG) yielded the most robust anti-fibrotic activity. Specifically, EG restored E-cadherin expression while suppressing key mesenchymal markers, effectively blunting epithelial–mesenchymal transition (EMT) in vitro. At the signaling level, EG treatment correlated with a downregulation of 5-HT2B-associated pathways, alongside marked reductions in oxidative stress and calcium influx. Our data suggest that EG dampens the Gq–PLCβ–IP3R module, limiting both intracellular calcium mobilization and subsequent NFATc1 activation. Concurrently, we observed a suppression of the CaMKII-dependent NF-κB cascade and its downstream pro-inflammatory targets (TNF-α, IL-6, and COX-2).

Conclusions

These findings indicate that the EG combination alleviates pro-fibrotic responses in A549 cells by disrupting the 5-HT2B/calcium/inflammation axis. Although in vivo validation is required, this plant-derived combination offers a promising multi-targeted therapeutic strategy against pulmonary fibrosis.