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

Ferroptosis is a newly discovered type of iron-dependent programmed cell death, which is different from apoptosis, necrosis, or autophagy [1,2]. Lipid peroxidation and oxidative stress play a major role in ferroptosis [[3], [4], [5], [6]]. When iron overload occurs in cells, the production of iron-related reactive oxygen species (ROS) increases through the Fenton reaction, and a large amount of ROS interacts with polyunsaturated fatty acids (PUFAs) on the cell membrane to induce lipid peroxidation, resulting in the accumulation of lipid peroxides [4,6]. The core molecular mechanism of ferroptosis involves regulating the balance between oxidative damage and antioxidant defense [6]. Ferroptosis can therefore cause bronchial degeneration and damage, but the mechanism is still unclear.

Smoking induces oxidative stress and the release of inflammatory factors by promoting the production of ROS [7]. The inducible nitric oxide synthase (iNOS) expression can be induced by stimulation of inflammatory mediators, oxidative stress, and other factors [8]. Continued activation of iNOS produces large amounts of nitric oxide (NO), and the reaction of excess NO with superoxide (O2•−) to produce peroxynitrite (ONOO−) [9]. It has been reported that NO contributes to the ferroptosis of malignant mesothelioma (MM) cells via lysosomal localization with the formation of ONOO− [10]. These results therefore suggest that iNOS may be involved in cigarette smoke (CS)-induced ferroptosis.

Sirtuin3 (SIRT3) protein, a member of the Sirtuin protein family, is a class III deacetylase that depends on nicotinamide adenine dinucleotide [11]. SIRT3 maintains mitochondrial homeostasis, which confers SIRT3 with the function of mitochondrial ROS scavenging and antioxidant defense [12,13]. Studies have shown that SIRT3 plays a role in resisting ferroptosis [14]. Because CS exposure promotes expression of iNOS [15,16], and down-regulates the activity and expression of SIRT3 in bronchial epithelial cells [17], we hypothesized that iNOS and SIRT3 played a regulatory role in CS-induced ferroptosis in a dependent or independent manner.

Nuclear factor erythroid 2-related factor 2 (Nrf-2) is a major regulator of oxidative stress signaling. Nrf-2 inhibits ferroptosis and oxidative damage by transactivating many cytoprotective genes involved in iron metabolism, glutathione (GSH) metabolism, and ROS scavenging [18]. Iron metabolism-related protein such as transferrin (TF), transferrin receptor 1 (TFRC1), divalent metal transporter 1 (DMT1), ferritin heavy chain 1 (FTH1), and ferritin light chain (FTL) are all key components in ferroptosis [19]. It is worth noting that many are cascade proteins related to redox reactions and iron accumulation, namely ferritin light chain and heavy chain (FTL/FTH1), glutamate cysteine ligase (GCLC/GCLM), and even glutathione peroxidase 4 (GPX4) itself, are target genes of Nrf-2, especially during oxidative stress [[20], [21], [22]]. Therefore, Nrf-2 is essential for ferroptosis. A previous study showed that Nrf-2 directly bound to the SIRT3 promoter and inhibited oxidative stress [23]. Together, these studies showed that Nrf-2/SIRT3 may be involved in the processes of occurrence and development of ferroptosis. However, whether there is a relationship between iNOS and Nrf-2/SIRT3 during ferroptosis remains unknown.

The present study therefore aimed to show that ferroptosis is important in CS-induced bronchial epithelial cell death. Furthermore, we identified the mechanism of CS-induced ferroptosis of bronchial epithelial cells, involving up-regulation of iNOS and accumulation of ROS by inhibiting the Nrf-2/SIRT3 pathway. Overall, this study provides novel mechanistic insights into chronic bronchial damage caused by cigarette smoke.

留言 (0)

沒有登入
gif