rhCC16 Suppresses Cellular Senescence and Ameliorates COPD-Like Symptoms by Activating the AMPK/Sirt1-PGC-1-α-TFAM Pathway to Promote Mitochondrial Function.

Chronic obstructive pulmonary disease (COPD) is a widespread lung disease marked by alveolar wall damage, leading to inflammation and fibrosis. Key risk factors include age, smoking, sex, and education, with smoking being the most crucial. These factors are globally consistent and linked with aging. Club cell secretory protein 16 (CC16), primarily secreted by non-ciliated bronchial epithelial cells, is crucial for pulmonary health, offering anti-inflammatory and antioxidant benefits. CC16 levels are notably reduced in COPD, suggesting its enhancement as a potential treatment. In this study, cellular senescence of BEAS-2B cells was stimulated using cigarette smoke extract (CSE) and the function of recombinant human CC16 protein (rhCC16) in cellular senescence was assessed by detecting the levels of β-galactosidase, p16, p21, ROS and the underlined mechanism was revealed by measuring mitochondrial biogenesis and metabolism. Additionally, COPD mice were prepared, and rhCC16's role on the cellular senescence of lung tissues was examined. Our findings showed that rhCC16 ameliorated cellular senescence in BEAS-2B cells and lung tissues of COPD mice accompanied by lower levels of β-galactosidase, p16, p21 and ROS. Mechanically, rhCC16 mitigated senescence via triggering PGC-1α expression through the AMPK/SIRT1 pathway and fostering mitochondrial biogenesis and metabolism to reduce the levels of ROS. Furthermore, the results also indicated that rhCC16 exerted its effect via both integrin α4β1 and clathrin-mediated endocytosis. Collectively, rhCC16 suppresses cellular senescence and ameliorates COPD-like symptoms by activating the AMPK/Sirt1-PGC-1-α-TFAM pathway to foster mitochondrial function.