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 May 1;200:73-86. doi: 10.1016/j.freeradbiomed.2023.03.002. Epub 2023 Mar 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cigarette Smoking* / adverse effects
  • Cigarette Smoking* / metabolism
  • Epithelial Cells / metabolism
  • Epithelium / metabolism
  • Ferroptosis* / genetics
  • Humans
  • Pulmonary Disease, Chronic Obstructive* / pathology
  • Reactive Oxygen Species / metabolism
  • Sirtuin 3* / genetics
  • Sirtuin 3* / metabolism
  • Tobacco / adverse effects


  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • SIRT3 protein, human
  • Sirtuin 3