REV-ERB α/β disruption drives Environmental Tobacco Smoke-induced senescence through a cGAS-STING signaling promoting lung

Spatial transcriptomic analysis of smoker lungs demonstrates parallel alterations marked by increased expression of senescence-associated genes (CDKN1A, SERPINE1), activation of DNA damage and innate immune sensors (TREX1, TMEM173), and repression of core clock genes (ARNTL, PER2, NR1D1), particularly within AT2 cells and fibroblasts. Pharmacological clearance of senescent cells using the BCL-2 inhibitor ABT-263 effectively reverses these molecular and cellular phenotypes.

Together, these findings reveal early epithelial remodeling and fibrotic priming during environmental smoke exposure and establish a mechanistic link between senescence, circadian disruption, and innate immune activation through the cGAS-STING pathway. The SCPS axis, therefore, represents an early molecular checkpoint of fibrotic susceptibility and a potential therapeutic target in environmentally driven lung injury.</p>