Background

Accelerated cellular senescence has been implicated in the pathogenesis of COPD and dysregulation of autophagy-lysosome axis may play a pivotal role in regulating smoking-induced cellular senescence. Transcription factor EB (TFEB) is a master regulator of autophagy-lysosome axis and TFEB malfunction has been demonstrated in COPD lungs. Recent advances suggest that senotherapy targeting cellular senescence is a promising approach for aging-related pathology.

Aims and objectives

To elucidate the senotherapeutic potential of pemafibrate, a putative inducer of TFEB, through activating autophagy-lysosome axis.

Methods

TFEB expression levels in COPD samples were evaluated. The regulatory role of pemafibrate-mediated TFEB expression was examined in cigarette-smoke extract (CSE)-induced autophagy/mitophagy activation, lysosomal dysfunction, and cellular senescence in human bronchial epithelial cells (HBEC) and cigarette-smoke (CS)-exposure mouse models.

Results

TFEB expression levels were reduced in epithelial cells in COPD lungs. Pemafibrate enhanced autophagy/mitophagy flux and restored lysosomal acidification, resulting in reduced cellular senescence during CSE exposure in HBEC. Involvement of pemafibrate-induced TFEB was elucidated by means of TFEB knockdown experiments. Pemafibrate induced TFEB expression and mitigated alveolar enlargement, airflow obstruction, and increased static lung compliance in long term CS exposure mouse model. CS exposure-induced cellular senescence was reduced and the analysis using RNA-seq data from mouse lungs elucidated the involvement of mitophagy.

Conclusions

Pemafibrate may exert senotherapeutic property against COPD pathogenesis via regulating TFEB-mitophagy axis.