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연세대학교 의과대학

Eur. Resp. J., Feb 15 2024, 2300580 | https://doi.org/10.1183/13993003.00580-2023 Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis

Chanho Lee^1,2,7, Se Hyun Hyun^3,7, Jisu Han^1,4, Ju Hye Shin², Byunghun Yoo^1,2, Yu Seol Lee^1,4, Jeong Su Park¹, Beom Jin Lim⁵, Jin Gu Lee⁶, Young Sam Kim², Song Yee Kim^2,7 and Soo Han Bae^1,4,7⇑

¹Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea

²Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

³Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea

⁴Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea

⁵Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea

⁶Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

⁷These authors contributed equally to this work

^⇑Corresponding author: Soo Han Bae

Abstract

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. 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 retrospectively reviewed, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. 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. In conclusion, our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-19)
연구진국내 연구진
분야 생명과학 > 분자생물학

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