A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis

Pulmonary fibrosis(PF)is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium.Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8(DHNNPQIR-NH_(2))could be modified to improve stability and antifibrotic activity,and the unnatural hydrophobic amino acids a-(4-pentenyl)-Ala and D-Ala were considered in this study.DR3penA(DHa-(4-pentenyl)-ANPQIR-NH_(2))was verified to have a longer half-life in serum and to significantly inhibit oxidative damage,epithelial-mesenchymal transition(EMT)and fibrogenesis in vitro and in vivo.Moreover,DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration.A mechanistic study revealed that DR3penA increased the expression of aquaporin 5(AQP5)by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase(MAPK)pathway,indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5.Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8.Thus,our findings suggest that DR3penA,as a novel and low-toxic peptide,has the potential to be a leading compound for PF therapy,which provides a foundation for the development of peptide drugs for fibrosis-related diseases.