2. Academic Validation
  3. Cigarette smoke induces the ROS accumulation and iNOS activation through deactivation of Nrf-2/SIRT3 axis to mediate the human bronchial epithelium ferroptosis

Cigarette smoke induces the ROS accumulation and iNOS activation through deactivation of Nrf-2/SIRT3 axis to mediate the human bronchial epithelium ferroptosis

  • Free Radic Biol Med. 2023 Mar 3;S0891-5849(23)00100-4. doi: 10.1016/j.freeradbiomed.2023.03.002.
Yawan Zi 1,  Xiaohui Wang 2,  Yafei Zi 3,  Huilin Yu 2,  Yuan Lan 2,  Yuchen Fan 2,  Cheng Ren 2,  Ke Liao 4,  Hong Chen 5
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Lab of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 3 Chongqing Key Lab of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 4 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: keliaocqmu@sina.com.
  • 5 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: hopehong2003@126.com.
PMID: 36871899 DOI: 10.1016/j.freeradbiomed.2023.03.002
Abstract

Cigarette smoke (CS)-induced oxidative stress drives the pathogenesis of respiratory diseases, in which the activation and accumulation of Reactive Oxygen Species (ROS) play an important role. Ferroptosis, a regulated cell death induced by Fe2+-dependent, lipid peroxidation, and ROS, is closely related to CS-induced airway injury disease, but its mechanism remains unclear. We found that bronchial epithelial Ferroptosis and expression of iNOS in smoking patients were significantly higher than that in non-smokers. The iNOS, induced by CS exposure, was involved in bronchial epithelial cell Ferroptosis, whereas genetic depletion or pharmacologic inactivation of iNOS attenuated the CS-induced Ferroptosis and mitochondrial dysfunction. Our mechanistic studies found that SIRT3 directly bound to and negatively regulated iNOS to mediate Ferroptosis. Moreover, we found that the Nrf-2/SIRT3 signal was deactivated by cigarette smoke extract (CSE)-induced ROS. Collectively, these results linked CS to human bronchial epithelial cell Ferroptosis through ROS deactivation of the Nrf-2/SIRT3 signal to promote iNOS expression. Our study provides new insights into the pathogenesis of CS-induced tracheal injury diseases such as chronic bronchitis, emphysema, and chronic obstructive pulmonary disease.

Keywords

Cigarette smoke; Ferroptosis; Nrf-2/SIRT3; ROS; iNOS.

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