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

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.