Senotherapeutic role of pemafibrate through autophagy/mitophagy regulation in chronic obstructive pulmonary disease
Year: 2026
Type: preprint
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 FEV 1.0 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.
Source: medRxiv
Authors: Sachi Matsubayashi-Hosokawa, Saburo Ito, Yusuke Hosaka, Masahiro Yoshida, Tsukasa Kadota, Mitsuo Hashimoto, Satoki Hatano, Tomoya Maruyama, Shota Fujimoto, Saiko Nishioka, Shun Inukai, Yu Fujita, Shunsuke Minagawa, Hiromichi Hara, Takeo Nakada, Katsutoshi Nakayama, Takashi Ohtsuka, Kazuyoshi Kuwano, Jun Araya
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funder: Kowa Company
OpenAlex ID: W7206175014