FOXO4 peptide targets myofibroblast ameliorates bleomycin‐induced pulmonary fibrosis in mice through ECM‐receptor interaction pathway

Pulmonary fibrosis (PF) is a progressive interstitial lung disease with limited treatment options. The incidence and prevalence of PF is increasing with age, cell senescence has been proposed as a pathogenic driver, the clearance of senescent cells could improve lung function in PF. FOXO4‐D‐Retro‐Inverso (FOXO4‐DRI), a synthesis peptide, has been reported to selectively kill senescent cells in aged mice. However, it remains unknown if FOXO4‐DRI could clear senescent cells in PF and reverse this disease. In this study, we explored the effect of FOXO4‐DRI on bleomycin (BLM)‐induced PF mouse model. We found that similar as the approved medication Pirfenidone, FOXO4‐DRI decreased senescent cells, downregulated the expression of senescence‐associated secretory phenotype (SASP) and attenuated BLM‐induced morphological changes and collagen deposition. Furthermore, FOXO4‐DRI could increase the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts, and decrease the myofibroblasts in bleomycin (BLM)‐induced PF mouse model. Compared with mouse and human lung fibroblast cell lines, FOXO4‐DRI is inclined to kill TGF‐β‐induced myofibroblast in vitro. The inhibited effect of FOXO4‐DRI on myofibroblast lead to a downregulation of extracellular matrix (ECM) receptor interaction pathway in BLM‐induced PF. Above all, FOXO4‐DRI ameliorates BLM‐induced PF in mouse and may be served as a viable therapeutic option for PF.