Clearance of Senescent Cells by BCL_XL-PROTAC: A Novel Approach to Treat COPD?

Abstract

Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCL_XL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCL_XL, in small airway epithelial cells and fibroblasts from patients with COPD. Treatment of COPD small airway epithelial cells and fibroblasts with BCL_XL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21^CIP1, p16^INK4a and senescence-associated β-galactosidase. The effects of BCL_XL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCL_XL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCL_XL-PROTAC significantly reduced p21^CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment. These findings demonstrate that BCL_XL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.