A FGFR3 decoy receptor attenuates lung fibroblast-to-myofibroblast transition and pulmonary fibrosis - 09/05/26

Fibroblast growth factor (FGF) signaling plays an important role in the pathogenesis of various respiratory diseases, including idiopathic pulmonary fibrosis (IPF). FGF ligands can exert both pro- and anti-fibrotic effects, depending on the responding cell, the expression levels of FGF receptors (FGFR1-4) and the context of other signaling molecules such as Transforming growth factor β (TGF-β). To better understand the functions of specific FGFs in IPF, we evaluated the effect of a modified version of a soluble FGFR3 decoy receptor (designated as “sFGFR3-Fc”), that specifically sequesters pro-fibrotic FGFR3 ligands, FGF1, FGF2 and FGF9 as a potential anti-fibrotic drug.

The effect of several FGFs in the presence or absence of the sFGFR3-Fc was evaluated in vitro on human lung fibroblasts from healthy donors and IPF patients on different readouts: cell proliferation, gel contraction, extracellular matrix (ECM) production and modulation of FGF and TGF-β signaling pathways. The transcriptomic signature of fibroblasts with or without the sFGFR3-Fc was assessed by single-cell RNA-seq. The effect of the sFGFR3-Fc was also evaluated in the bleomycin mouse model, either with a single instillation or with repeated instillations to induce a severe fibrosis. Body weight, Ashcroft score, hydroxyproline, soluble collagen content and lung functions were monitored.

Our results showed that FGF2 stimulated fibroblast proliferation, ECM production and expression of various fibrotic markers. The sFGFR3-Fc was able to reduce these FGF2-mediated responses and also partially attenuate the pro-fibrotic phenotype induced by TGF-β. In the BLM mouse model, lung fibrosis was significantly attenuated by sFGFR3-Fc, as evidenced by a reduced ECM deposition and a restored lung function.

Our data highlight the interplay between the TGF-β and the FGF signaling pathways and demonstrate the potential of targeting pro-fibrotic FGFR3 ligands as therapeutic strategy for IPF.