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

Abstract

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.

Platycodin D ameliorates ammonia‐induced pulmonary fibrosis by repressing TGF‐β1‐mediated extracellular matrix remodeling

“…Abnormal activation of the ECM‐receptor interaction pathway possesses a critical role in disease pathogenesis (Li, Feng, et al., 2022; Nersisyan et al., 2021; Zhang et al., 2022). The ECM‐receptor pathway has also been implicated in the onset and progression of pulmonary fibrosis (Fan et al., 2022; Han et al., 2022). The TGF‐β1 pathway is a crucial driver of ECM formation and accumulation, thus actively contributing to the fibrosis process (Lodyga & Hinz, 2020).…”

Kidney fibrosis: from mechanisms to therapeutic medicines

“…Recently, several creative studies validated the efficacy and safety of senescent cell clearances, applying transgenic mice with selectively sensitive pharmacological agents, 92,93 or the mice access to antiapoptotic drugs. 92,94,95 Moreover, various strategies are being tested to prevent the formation of senescent cells (e.g., exercise, weight loss), [96][97][98] trigger the apoptosis of senescent cell (e.g., ABT-263, FOXO4-DRI), 92,99 reduce the secretion of SASP (e.g., metformin, sirolimus), 100,101 and take advantage of senescent cell metabolic activity to activate compounds (e.g., galactooligosaccharide conjugated drugs). 102 In addition, the treatment of CDK4/6 inhibitor PD-0332991, could result in a transient cell cycle arrest after injury, suppressed DNA damage, tubular epithelial cell apoptosis, interstitial inflammatory response, and restored kidney function.…”

Longevity-Promoting Pathways and Transcription Factors Respond to and Control Extracellular Matrix Dynamics During Aging and Disease

“…Another promising approach is by a peptide (FOXO4-D-Retro-Inverso (DRI)) that blocks the interaction of FOXO4 with p53, which drives senescent cells into apoptosis ( Baar et al, 2017 ). Treating bleomycin-induced pulmonary fibrosis mice with FOXO4-DRI reduced the number of senescent cells and myofibroblasts, attenuated collagen deposition, and downregulated ECM receptors ( Han et al, 2022 ), suggesting a FOXO4-dependent reprogramming to ameliorate pulmonary fibrosis.…”