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Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis.
- Source :
-
The European respiratory journal [Eur Respir J] 2024 May 16; Vol. 63 (5). Date of Electronic Publication: 2024 May 16 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Background: We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis.<br />Methods: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe.<br />Results: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline.<br />Conclusion: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.<br />Competing Interests: Conflict of interest: The authors have applied for a patent entitled “Pharmaceutical composition for preventing, improving, alleviating or treating pulmonary fibrosis containing ezetimibe as an active ingredient”. The authors have nothing else to disclose.<br /> (Copyright ©The authors 2024.)
- Subjects :
- Animals
Humans
Mice
Male
Female
Mice, Transgenic
Bleomycin
Lung pathology
Lung drug effects
Fibroblasts metabolism
Fibroblasts drug effects
Retrospective Studies
Aged
Middle Aged
Mice, Inbred C57BL
Myofibroblasts drug effects
Myofibroblasts metabolism
Cholesterol metabolism
Ezetimibe therapeutic use
Ezetimibe pharmacology
Idiopathic Pulmonary Fibrosis drug therapy
Autophagy drug effects
Drug Repositioning
Disease Models, Animal
Anticholesteremic Agents therapeutic use
Anticholesteremic Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1399-3003
- Volume :
- 63
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The European respiratory journal
- Publication Type :
- Academic Journal
- Accession number :
- 38359963
- Full Text :
- https://doi.org/10.1183/13993003.00580-2023