Inhibiting Neuropilin-1 as a novel therapeutic approach to mitigate pulmonary fibrosis: Highlighting the potential anti-fibrotic effects of ATWLPPR peptide

Latent transforming growth factor 1 (TGF-β1) is present in substantial quantities in healthy tissues. The regulation of TGF-β1 under fibrotic conditions predominantly relies on mechanisms that activate latent TGF-β1 to its active/mature form rather than its secretion and synthesis. Consequently, one strategy for mitigating pulmonary fibrosis involves targeting activation of the master cytokine TGF-β1 from its latent form. Recent evidence suggests Neuropilin-1 (NRP-1) is an activator of TGF-β1 with significant biological functions, including acting as a co-receptor for TGF-β1 and facilitating divergent Smad signaling in favor of fibrogenesis. In the present study, we conducted an initial preclinical investigation to validate NRP-1 as a potential target in fibrosis, utilizing a specific NRP-1 inhibitor, ATWLPPR (A7R). A7R is a heptapeptide that specifically binds to NRP-1 to inhibit its activity. This study was performed using a 21-day model of bleomycin-induced pulmonary fibrosis in Swiss Albino mice. Our results demonstrated that the inhibition of NRP-1 by A7R exhibited promising anti-fibrotic activity. We found that A7R downregulated the expression of epithelial-mesenchymal transition proteins. A7R demonstrated significant potential to attenuate the expression of TGF-β1 and its downstream Smad signaling through substantial inhibition of NRP-1. Additionally, we observed a reduction in collagen deposition after A7R treatment. Notably, the anti-fibrotic effect of A7R was comparable to that of pirfenidone. In conclusion, our study demonstrated that the NRP-1 specific inhibitor A7R, exhibits considerable potential to attenuate pulmonary fibrosis, although further comprehensive investigations are required.