Niclosamide Ethanolamine Salt Alleviates Idiopathic Pulmonary Fibrosis by Modulating the PI3K-mTORC1 Pathway

Abstract

Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) deposited by myofibroblasts differentiated from pulmonary fibroblasts. More signalling pathways, including the PI3K-Akt-mTOR and autophagy pathways, are involved in IPF pathogenesis. Niclosamide ethanolamine salt (NEN) is a highly effective multitarget small-molecule inhibitor reported in antitumor studies. Here, we reported that in an IPF animal model treated with NEN for 14 days, attractive relief of pulmonary function and hydroxyproline content were observed. To further explore, the therapeutic effect of NEN in IPF and pathological changes in bleomycin-challenged mouse lung sections were assessed. Additionally, the effects of NEN on abnormal proliferation and ECM production in IPF cell models established with TGF-β1-stimulated A549 cells or DHLF-IPF cells were studied. In nonclinical studies, NEN ameliorated lung function and histopathological changes in bleomycin-challenged mice, and the lung hydroxyproline content was significantly diminished with NEN treatment. In vitro, NEN inhibited PI3K-mTORC1 signalling and arrested the cell cycle to prevent uncontrolled fibroblast proliferation. Additionally, NEN inhibited TGF-β1-induced epithelial–mesenchymal transition (EMT) and ECM accumulation via the mTORC1-4EBP1 axis. Furthermore, NEN-activated noncanonical autophagy resensitized fibroblasts to apoptosis. The above findings demonstrated the potential antifibrotic effect of NEN mediated via modulation of the PI3K-mTORC1 and autophagy pathways. These data provide strong evidence for a therapeutic role for NEN in IPF.

2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside ameliorates bleomycin-induced pulmonary fibrosis via regulating pro-fibrotic signaling pathways

“…Besides, THSG administration increased the expression level of LC3B in the lung tissue sections of mice treated with BLM. Recent studies have shown that downregulation of p-mTOR and upregulation of LC3-II protein level, contributing to suppression of collagen deposition and EMT in primary lung fibroblasts and TGF-β1-induced lung epithelial cells, resulting in an alleviation of lung injury and improving lung function in BLM-induced animal models ( Alsayed et al, 2022 ; Pei et al, 2022 ). Accumulating evidence has also shown that the repression of TGF-β1-induced activation of mTOR signaling in lung fibroblasts, which results in the induction of autophagy and the inhibition of myofibroblast activation and ECM production in mice model of BLM-induced pulmonary fibrosis ( Li et al, 2021 ; Lu et al, 2022 ).…”

Disulfiram Exerts anti-pulmonary Fibrosis Effect by Activating PGE2 Synthesis

“…After cultured with TGF-β1 (10 ng/mL) for 24 hours, A549 cells transformed into mesenchymal-like cell [21], then TGF-β1-induced A549 cells and DHLF-IPF cells were treated with different concentration gradient DSF for 24 hours at a density of 8×10 5 /mL. Cell Counting Kit-8 (CCK-8) and propidium iodide/crystal violet (PI/CV) were added to evaluate cell viability and cell death.…”

The magic bullet: Niclosamide

“…Niclosamide was reported to inhibit mTOR signaling in lung cancer, ovarian cancer, cervical cancer, and the diabetic mouse kidney (61)(62)(63)(64)104). Accumulating evidence suggests that niclosamide-mediated mTOR inhibition may be accomplished through at least two distinct mechanisms.…”