Novel therapeutic strategy: Nrf2 activation in targeting senescence-related changes in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, largely driven by the accumulation of senescent bronchial epithelial cells, which contribute to inflammation and tissue remodeling. This study investigates the therapeutic potential of nuclear factor erythroid 2-related factor 2 (Nrf2) activation in targeting senescence-related changes to alleviate COPD progression. METHODS: Single-cell transcriptome analysis, in vitro COPD cell models, and a COPD mouse model were utilized to examine the effects of Nrf2 activation. Specifically, the study focused on the impact of Nrf2 on senescent ciliated epithelial cells and the associated secretory phenotype. Respiratory function tests and lung pathology assessments were conducted to evaluate the intervention's efficacy in the mouse model. RESULTS: The study identified a significant presence of senescent ciliated epithelial cells in COPD patients, contributing to disease progression. Nrf2 activation in vitro reduced senescence markers, enhanced cell proliferation, and decreased inflammatory cytokines. In vivo, Nrf2 activation significantly improved lung function and reduced pathological damage in the COPD mouse model. CONCLUSIONS: The findings underscore the potential of Nrf2 activation as a therapeutic strategy to mitigate COPD progression by modulating the senescence-associated secretory phenotype (SASP). This study suggests that Nrf2 activators could offer a promising approach to improving clinical outcomes for COPD patients.