Arylsulfatase K attenuates airway epithelial cell senescence in COPD by regulating parkin-mediated mitophagy

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by irreversible airflow limitation, primarily due to cigarette smoke (CS) exposure. Emerging research underscores the pivotal role of cellular senescence in the pathogenesis of COPD. The arylsulfatase family, known for its involvement in various age-related diseases, has yet to be investigated in the context of COPD. This study investigated the role of the arylsulfatase family, particularly ARSK, in COPD pathogenesis. Bioinformatics analysis and clinical validation revealed significantly reduced ARSK expression in COPD patients' lungs, especially in airway epithelium. ARSK overexpression alleviated CS-induced epithelial cellular senescence and improved mitophagy and mitochondrial function, while ARSK knockdown had an opposite effect. In vivo , Arsk-AAV administration relieved lung senescence and impaired lung function upon CS exposure, whereas airway-specific Arsk knockout aggravated these effects. Mechanistically, ARSK interacted with Parkin (PRKN) to regulate the phosphorylation of PRKN at serine 65 and subsequent mitophagy, thus attenuating cellular senescence. Additionally, the androgen receptor (AR) was identified as a transcription factor binding to the ARSK promoter, modulating its expression. These findings highlight the protective role of ARSK against epithelial cellular senescence, offering a potential therapeutic target for COPD. Cigarette smoke impairs the expression of AR in airway epithelial cells, thereby diminshing the transcription and expression of ARSK. This reduction disrupts the interaction between ARSK and PRKN, facilitating the phosphorylation of PRKN at serine 65 and its subsequent translocation to mitochondria. This cascade of events triggers excessive mitophagy, leading to mitochondrial dysfunction and subsequent cellular senescence, which drives the progression of COPD.