The development of therapeutic strategy against IPF and COPD through TFEB activation

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08213
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: International University of Health and Welfare (2023); Jikei University School of Medicine (2021-2022)
• Principal Investigator: Kuwano Kazuyoshi 国際医療福祉大学, 医学部, 教授 (40205266)
• Co-Investigator(Kenkyū-buntansha): 荒屋 潤 東京慈恵会医科大学, 医学部, 教授 (90468679)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 慢性閉塞性肺疾患 / 特発性肺線維症 / 細胞老化 / オートファジー / TFEB / PPAR

Outline of Final Research Achievements

Inadequate autophagy promotes smoking-induced cellular senescence involved in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) pathogenesis. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome axis. We investigated the therapeutic potential of pemafibrate, a putative TFEB inducer. Pemafibrate enhanced autophagy/mitophagy flux and restored lysosomal acidification observed during cigarette smoke (CS) extract exposure in human bronchial epithelial cells, resulting in reduced cellular senescence. Pemafibrate induced TFEB expression, mitigated alveolar enlargement/airflow obstruction, and increased static lung compliance in a long-term CS-exposed mouse model. It reduced the CS exposure-induced cellular senescence, possibly through mitophagy. In conclusion, pemafibrate is a promising therapeutic agent against COPD and IPF that acts via TFEB-autophagy/mitophagy axis regulation.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

pemafibrateは、COPDモデルマウス、IPFモデルマウスの両方で、病態進展抑制効果を示した。本研究結果からはPPARαmodulatorが高脂血症治療薬としてだけはではなく、COPDやIPFに対する新規の抗細胞老化治療となりうる可能性が示されたと考えている。不可逆的な病態であるIPFやCOPDに対して、抗老化作用を介した、病態を改善させる画期的な治療となる可能性がある。今後は呼吸器疾患治療薬として、吸入療法など局所療法の開発が重要な課題となる。