Senotherapeutic role of pemafibrate through autophagy/mitophagy regulation in chronic obstructive pulmonary disease
- 1Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Abstract
Inadequate autophagy promotes smoking-induced cellular senescence involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome axis. For the first time, we investigated the therapeutic potential of pemafibrate, a putative TFEB inducer. COPD lung epithelial cells showed reduced TFEB expression. 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. TFEB knockdown demonstrated involvement of pemafibrate-induced TFEB in these effects. Pemafibrate induced TFEB expression, mitigated alveolar enlargement and airflow obstruction, and attenuated the CS-induced increase in static lung compliance in a long-term CS-exposed mouse model. It reduced the CS exposure-induced cellular senescence, possibly through autophagy/mitophagy, as suggested by bulk RNA sequencing of mouse lungs. A retrospective cohort study showed that patients given pemafibrate displayed attenuated FEV1.0 decline compared with those given bezafibrate or fenofibrate. In conclusion, pemafibrate is a promising therapeutic agent for COPD, potentially exerting its effects through the regulation of the TFEB-autophagy/mitophagy-lysosome axis.
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BibTeX
@misc{matsubayashi2026senotherapeutic,
title = {{Senotherapeutic role of pemafibrate through autophagy/mitophagy regulation in chronic obstructive pulmonary disease}},
author = {S. Matsubayashi and S. Ito and Y. Hosaka and M. Yoshida and T. Kadota and M. Hashimoto and S. Hatano and T. Maruyama and S. Fujimoto and S. Nishioka and S. Inukai and Y. Fujita and S. Minagawa and H. Hara and T. Nakada and K. Nakayama and T. Ohtuska and K. Kuwano and J. Araya},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.26361865},
url = {https://www.medrxiv.org/content/10.64898/2026.08.31.26361865v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Senotherapeutic role of pemafibrate through autophagy/mitophagy regulation in chronic obstructive pulmonary disease
AU - S. Matsubayashi
AU - S. Ito
AU - Y. Hosaka
AU - M. Yoshida
AU - T. Kadota
AU - M. Hashimoto
AU - S. Hatano
AU - T. Maruyama
AU - S. Fujimoto
AU - S. Nishioka
AU - S. Inukai
AU - Y. Fujita
AU - S. Minagawa
AU - H. Hara
AU - T. Nakada
AU - K. Nakayama
AU - T. Ohtuska
AU - K. Kuwano
AU - J. Araya
PY - 2026
DA - 2026/08/31
PB - medRxiv
DO - 10.64898/2026.08.31.26361865
UR - https://www.medrxiv.org/content/10.64898/2026.08.31.26361865v1
AB - Inadequate autophagy promotes smoking-induced cellular senescence involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome axis. For the first time, we investigated the therapeutic potential of pemafibrate, a putative TFEB inducer. COPD lung epithelial cells showed reduced TFEB expression. 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. TFEB knockdown demonstrated involvement of pemafibrate-induced TFEB in these effects. Pemafibrate induced TFEB expression, mitigated alveolar enlargement and airflow obstruction, and attenuated the CS-induced increase in static lung compliance in a long-term CS-exposed mouse model. It reduced the CS exposure-induced cellular senescence, possibly through autophagy/mitophagy, as suggested by bulk RNA sequencing of mouse lungs. A retrospective cohort study showed that patients given pemafibrate displayed attenuated FEV1.0 decline compared with those given bezafibrate or fenofibrate. In conclusion, pemafibrate is a promising therapeutic agent for COPD, potentially exerting its effects through the regulation of the TFEB-autophagy/mitophagy-lysosome axis.
ER -