LSC - 2025 - Exploring the antifibrotic potential of the heparan sulfate mimetic OTR4120

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 <italic>ex vivo</italic> human precision-cut lung slices (hPCLS), WI-38 cells, an <italic>in vitro</italic> model for myofibroblast differentiation, and an <italic>in vivo</italic> 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-β1 signaling while the Reactome analysis revealed a reduction in immune-related pathways, suggesting other immunomodulatory effects. Co-treatment with the TGF-β1 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.