Idiopathic Pulmonary Fibrosis (IPF) is a fatal, progressive lung disease characterized by excessive extracellular matrix (ECM) deposition and impaired lung function. Current treatments are limited and not curative. RGTA® compounds, heparan sulfate mimetics like OTR4120, have shown the ability to modulate ECM and support tissue repair, making them strong candidates for IPF therapy.

To evaluate OTR4120?s antifibrotic potential, we used ex vivo human precision-cut lung slices (hPCLS), WI-38 cells, an in vitro model for myofibroblast differentiation, and an in vivo bleomycin-induced lung fibrosis mouse model. Collagen deposition in hPCLS was quantified via second harmonic generation (SHG) microscopy. Transcriptomic changes in WI-38 cells undergoing myofibroblast differentiation and treated with OTR4120 were analyzed via qPCR, bulk RNA-Seq, and pathway analyses.

SHG microscopy revealed a significant reduction in collagen deposition in hPCLS treated with the fibrotic cocktail and OTR4120. In WI-38 cells, OTR4120 treatment downregulated myofibroblast markers in both preventive and therapeutic approaches. Bulk RNA-Seq highlighted significant impacts on fibrosis-related processes, with marked downregulation of TGF-?1 signaling while the Reactome analysis revealed a reduction in immune-related pathways, suggesting other immunomodulatory effects. Co-treatment with the TGF-?1 receptor inhibitor SB431542 further decreased MYF markers, indicating other mechanisms at play. In the in vivo bleomycin-induced lung fibrosis mouse model, OTR4120 promoted fibrosis resolution and restored alveolar architecture.

In conclusion, OTR4120 demonstrates potent antifibrotic effects, positioning it as a promising treatment for fibrosis.