Abstract

Background Cigarette smoke (CS)-induced epithelial ferroptosis is a pivotal driver of airway inflammation and remodeling in chronic obstructive pulmonary disease (COPD). Although Rab26 is known to protect against inflammatory injury, the precise molecular mechanism linking Rab26 to mitochondrial integrity and ferroptotic cell death remains largely unexplored. This study aims to elucidate a novel regulatory axis involving Rab26, mitochondrial voltage-dependent anion channel 1 (VDAC1), and the cGAS-STING pathway in the pathogenesis of COPD. Methods A COPD mouse model was established using Rab26-deficient (Rab26 −/− ) mice exposed to cigarette smoke, alongside wild-type mice treated with a pharmacological STING inhibitor to validate pathway involvement. Ferroptosis and inflammation were assessed in vitro and in vivo . Crucially, we employed co-immunoprecipitation (Co-IP), chemical cross-linking, and transmission electron microscopy (TEM) to investigate the molecular interaction between Rab26 and VDAC1, and to monitor VDAC1 oligomerization and mitochondrial DNA (mtDNA) release. Results We observed significantly downregulated Rab26 expression in lung tissues from COPD patients and CS-exposed mice. In vivo , Rab26 deficiency markedly exacerbated airway inflammation, emphysema, and epithelial ferroptosis. Mechanistically, we identified a novel interaction wherein Rab26 physically binds to VDAC1. Under CS exposure, loss of Rab26 promotes VDAC1 oligomerization, leading to mitochondrial membrane permeabilization and the leakage of mtDNA into the cytosol. This cytosolic mtDNA subsequently triggers the aberrant hyperactivation of the cGAS-STING pathway, which represses the antioxidant SLC7A11/GPX4 axis and drives lethal ferroptosis. Conversely, restoring Rab26 or blocking STING signaling effectively inhibited VDAC1-mediated mtDNA release and alleviated ferroptotic injury. Conclusions This study provides that Rab26 acts as a guardian of mitochondrial integrity by preventing