Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan-Dec:17:17534666231208628.
doi: 10.1177/17534666231208628.

Ferroptosis triggers airway inflammation in asthma

Minming Li  1   2 , Min Li  1 , Yunjiao Hou  1 , Huilin He  1 , Ruonan Jiang  1   2 , Chu Wang  1 , Shibo Sun  3
Affiliations
Review

Ferroptosis triggers airway inflammation in asthma

Minming Li et al. Ther Adv Respir Dis. 2023 Jan-Dec.

Abstract

Ferroptosis is a regulatory cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress. Many signaling pathways such as iron metabolism, lipid metabolism, and amino acid metabolism precisely regulate the process of ferroptosis. Ferroptosis is involved in a variety of lung diseases, such as acute lung injury, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Increasing studies suggest that ferroptosis is involved in the development of asthma. Ferroptosis plays an important role in asthma. Iron metabolism disorders, lipid peroxidation, amino acid metabolism disorders lead to the occurrence of ferroptosis in airway epithelial cells, and then aggravate clinical symptoms in asthmatic patients. Moreover, several regulators of ferroptosis are involved in the pathogenesis of asthma, such as Nrf2, heme oxygenase-1, mevalonate pathway, and ferroptosis inhibitor protein 1. Importantly, ferroptosis inhibitors improve asthma. Thus, the pathogenesis of ferroptosis and its contribution to the pathogenesis of asthma help us better understand the occurrence and development of asthma, and provide new directions in asthma treatment. This article aimed to review the role and mechanism of ferroptosis in asthma, describing the relationship between ferroptosis and asthma based on signaling pathways and related regulatory factors. At the same time, we summarized current observations of ferroptosis in eosinophils, airway epithelial cells, and airway smooth muscle cells in asthmatic patients.

Keywords: Nrf2; airway epithelial cells; asthma; ferroptosis; lipid peroxidation.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
A flow-through of iron metabolism in a healthy versus inflamed/asthmatic cell. Fe3+ is reduced to Fe2+ under the action of ferric reductase. Fe2+ is stored in the ferritin. NCOA4 is a unique transport receptor for ferritinophagy, which delivers ferritin to lysosomes for degradation to release free iron. Iron metabolism in airway epithelial cells and ASMs, iron catalyzes the formation of highly destructive hydroxyl radicals and ROS through Fenton reaction. Iron metabolism in eosinophils, T2 cytokines lead to the accumulation of high numbers of eosinophils in the airway wall. Over-production of ROS resulting from infiltrating eosinophils lead to development of oxidative stress in asthma. Fe3+, ferric ion; ferric reductase, prostate six transmembrane protein 3; NCOA4, nuclear receptor co-activator 4; ROS, reactive oxygen species.
Figure 2.
Figure 2.
The reactive pathways between lipid peroxides, PUFAs, and PE degradation. PE needs the action of ACSL4 and LPCAT3, combining with AA and AdA to form the oxidation site PE-AA/AdA. Subsequently, PE-AA/AdA is easily oxidized by ALOX15 to form PE-AA/AdA-OOH with cytotoxicity, thus promoting ferroptosis. 15LO1 binds to PEBP1 to oxygenate PE on the membrane, thereby damages the membrane and drives ferroptosis. PUFAs have a high affinity with hydroxyl radicals and the hydrogen atoms between its double bonds are easily oxidized by radicals to generate lipid peroxides. 15LOX1, 15 lipoxygenase-1; 15LOX2, 15 lipoxygenase-2; AA, acyl-arachidacyl-adrenoyl groups; ACSL4, acyl-CoA synthetase long-chain family member 4; AdA, adrenoyl; ALOX15, arachidonate 15-lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; PE, phosphatidylethanolamines; PEBPE, PE-binding protein-1; ROS, reactive oxygen species.
Figure 3.
Figure 3.
Amino acid metabolism for the synthesis of GSH in healthy and inflamed/asthmatic cells. Cysteine can be further converted to reduced GSH by ATP-dependent cytoplasmic enzymes glutamate-cysteine ligase and glutathione synthase. With the help of GPX4, GSH reduces H2O2 to H2O, scavenge free radicals, and maintain the equilibrium state of intracellular free radical content. Moreover, as a cofactor of GPX4, GSH participates in the reducing of lipid peroxides LOOH and converts the LOOH into L-OH to prevents ferroptosis. GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione oxidized; NADPH, nicotinamide adenine dinucleotide phosphate; SLC3A2, solute carrier family 3 member 2; SLC7A11, 7 member 11 of the solute carrier family; L-OH, lipid alcohols; LOOH, lipid hydroperoxides; Nrf2, nuclear factor erythroid 2-related factor 2.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Yoshida M, Minagawa S, Araya J, et al.. Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nat Commun 2019; 10: 3145. - PMC - PubMed
    1. Tang D, Kang R, Berghe TV, et al.. The molecular machinery of regulated cell death. Cell Res 2019; 29: 347–364. - PMC - PubMed
    1. Castillo Ferrer C, Berthenet K, Ichim G. Apoptosis-Fueling the oncogenic fire. FEBS J 2021; 288: 4445–4463. - PMC - PubMed
    1. Xu X, Lai Y, Hua ZC. Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep 2019; 39: BSR20180992. - PMC - PubMed
    1. Klionsky DJ, Petroni G, Amaravadi RK, et al.. Autophagy in major human diseases. EMBO J 2021; 40: e108863. - PMC - PubMed
-