Rab26 mitigates ferroptosis in airway epithelium induced by cigarette smoke through suppression of VDAC1 oligomerization-mediated cGAS-STING activation

  • Free Radic Biol Med. 2026 Sep:253:177-194. doi: 10.1016/j.freeradbiomed.2026.05.315.
Xin Tian  1 ,  Wen Zhang  2 ,  Zaichun You  1 ,  Yang Mao  3 ,  Qiuhong Huang  1 ,  Li Zeng  1 ,  Weiping Hu  4 ,  Dongqin Wei  1 ,  Hang Qian  5 ,  Mingzhou Zhang  5 ,  Li Luo  5 ,  Jing Zhang  6 ,  Guansong Wang  7 ,  Binfeng He  8
Affiliations
  • 1. Department of General Practice, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
  • 2. Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
  • 3. Clinical Medical Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
  • 4. Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 5. Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China; Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, 400037, China.
  • 6. Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 7. Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China; Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, 400037, China. Electronic address: [email protected].
  • 8. Department of General Practice, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China; Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, 400037, China. Electronic address: [email protected].
PMID: 42176907 DOI: 10.1016/j.freeradbiomed.2026.05.315
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 VDAC1 oligomerization. We define a previously unrecognized Rab26-VDAC1-cGAS-STING signaling axis that regulates airway epithelial Ferroptosis. Targeting this axis offers a compelling therapeutic strategy to arrest inflammation and disease progression in COPD.

Keywords
COPD; Ferroptosis; Rab26; STING; VDAC1 oligomerization; cGAS.
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