The novel peptide DR4penA attenuates the bleomycin‐ and paraquat‐induced pulmonary fibrosis by suppressing the TGF ‐ β /Smad signaling pathway

Abstract Pulmonary fibrosis (PF), which is caused by continuous alveolar epithelial cell injury and abnormal repair, is referred to as a difficult disease of the lung system by the World Health Organization due to its rapid progression, poor prognosis, and high mortality rate. However, there is still a lack of ideal therapeutic strategies. The peptide DR8 (DHNNPQIR‐NH 2 ), which is derived from rapeseed, exerted antifibrotic activity in the lung, liver, and kidney in our previous studies. By studying the structure–activity relationship and rational design, we introduced an unnatural hydrophobic amino acid ( α ‐(4‐pentenyl)‐Ala) into DR8 and screened the novel peptide DR4penA (DHN α ‐(4‐pentenyl)‐APQIR‐NH 2 ), which had higher anti‐PF activity, higher antioxidant activity and a longer half‐life than DR8. Notably, DR4penA attenuated bleomycin‐ and paraquat‐induced PF, and the anti‐PF activity of DR4penA was equivalent to that of pirfenidone. Additionally, DR4penA suppressed the TGF‐ β /Smad pathway in TGF‐ β 1‐induced A549 cells and paraquat‐induced rats. This study demonstrates that the novel peptide DR4penA is a potential candidate compound for PF therapy, and its antifibrotic activity in different preclinical models of PF provides a theoretical basis for further study.