Fan Zhang1
E. Guo
Xiansheng Zeng- 1Wuhan University of Science and Technology, School of Medicine, Wuhan, China
- 2Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
In the last decade, ferroptosis has received much attention from the scientific research community. It differs from other modes of cell death at the morphological, biochemical, and genetic levels. Ferroptosis is mainly characterized by non-apoptotic iron-dependent cell death caused by iron-dependent lipid peroxide excess and is accompanied by abnormal iron metabolism and oxidative stress. In recent years, more and more studies have shown that ferroptosis is closely related to the occurrence and development of lung diseases. COPD, asthma, lung injury, lung fibrosis, lung cancer, lung infection and other respiratory diseases have become the third most common chronic diseases worldwide, bringing serious economic and psychological burden to people around the world. However, the exact mechanism by which ferroptosis is involved in the development and progression of lung diseases has not been fully revealed. In this manuscript, we describe the mechanism of ferroptosis, targeting of ferroptosis related signaling pathways and proteins, summarize the relationship between ferroptosis and respiratory diseases, and explore the intervention and targeted therapy of ferroptosis for respiratory diseases.
1 Introduction
In 2003, DOLMA et al. discovered Erastin, an antioxidant that can inhibit glutathione synthesis (1). Subsequently, another compound that activates non-apoptotic cell death, RSL3, was discovered in 2008 by YAGODA et al. and YANG et al (2). In 2012, DIXON et al. officially named iron-dependent nonapoptotic cell death “Ferroptosis” (3). Since then, ferroptosis has been gradually well-known by domestic and foreign scholars, and has aroused widespread concern.
Ferroptosis is a new mode of cell death, which is morphologically, biochemically and genetically different from other forms of cell death (4). Morphologically, ferroptosis is mainly characterized by decreased mitochondrial cristae, changes in the bilateral membrane density of the mitochondrial membrane, and rupture of the outer membrane of the mitochondria, but the morphology and size of the cells remain normal, and chromatin is not condensed (3). Biochemically, ferroptosis continuously consumes intracellular glutathione, resulting in decreased glutathione peroxidase 4 (GPX4) activity, iron-dependent lipid peroxides cannot be reduced and metabolized by GPX4, and Fenton reaction occurs in the form of divalent iron resulting in mitochondrial reactive oxygen species (ROS) accumulation. ROS production leads to DNA damage, metabolic disorders, lipid peroxidation, and further promotes the development of ferroptosis (5–7). Genetically speaking, ferroptosis is a biological process regulated by multiple genes, which roughly includes: iron overload, lipid peroxide accumulation, amino acid metabolism disorders and other changes, and the specific regulatory mechanism needs further study (8).
In addition to attacking the respiratory system of the human body, ferroptosis also causes different degrees of damage to the nervous system, cardiovascular system, digestive system, and urinary system of the human body, seriously threatening human healthy life (9) (Figure 1). With the deepening of studies on the mechanism of ferroptosis, it has been found that ferroptosis plays a role in various biochemical reactions such as cell growth, energy metabolism, and DNA synthesis repair, which are associated with the development of lung diseases (10–12). Increasing studies have shown that ferroptosis plays a role in lung diseases by causing pathological processes such as inflammatory cell infiltration, endothelial cell damage, and disturbed cellular homeostasis (13–15). Eventually, ferroptosis can cause respiratory diseases such as chronic obstructive pulmonary disease (COPD), bronchial asthma, lung injury, pulmonary fibrosis, and lung infection (16).
Figure 1 Ferroptosis is involved in the progression of a variety of organ and system diseases, such as the body’s nervous system, cardiovascular system, digestive system, and urinary system. AIH, autoimmune hepatitis; AMD, age-related macular degeneration; AKI, acute kidney injury; COPD, Chronic obstructive pulmonary disease; CD, Crohn’s disease; FECD, Fuchs’ endothelial corneal dystrophy; I/R injury, ischemia-reperfusion injury; MI, myocardial infarction; NDDs, neurodegenerative diseases; PVL, periventricular leukomalacia; TBI, traumatic brain injury.
In this paper, the mechanism of ferroptosis, the research progress of ferroptosis in a variety of lung diseases, and the related signaling pathways and proteins are targeted to provide new ideas and insights for the prevention and treatment of lung diseases in clinical practice (17).
2 Characteristics and mechanisms of ferroptosis
2.1 Iron overload
Iron is an essential trace element in the body, and iron overload is a key factor in the development of ferroptosis (18). Iron maintains a dynamic balance in uptake, transport, utilization and regulation and is essential to maintain the normal physiological activities of the human body (19). Prostate six-transmembrane epithelial antigen 3 belongs to STEAP family and is an iron reductase that is able to promote the reduction of Fe3+ to Fe2+ during iron metabolism (20). Among them, FPN is the only transporter known to be intracellular iron and is present in all transport cells (21). Heme oxygenase 1 (HO-1) is a major regulator of the antioxidant system, which inhibits lipid peroxidation and protects cells from ferroptosis (22, 23) (Figure 2).
Figure 2 Mechanism of iron overload. Iron maintains a dynamic balance in uptake, transport, utilization and regulation, is absorbed into mucosal epithelial cells in the form of Fe2+, reduces Fe3+ in response to STEAP3, transports it to the cytoplasm through FPN, binds to ferritin and stores in the iron pool of the iron storage system. Finally, divalent metal transporter 1 (DMT1) releases iron ions from endosomes into labile iron pools in the cytoplasm. In response to H2O2, Fe2+ initiates a chain reaction of free radical lipid peroxidation via the Fenton reaction, ultimately leading to ferroptosis. Regulation of iron is systemic regulation of hepcidin produced by hepatic secretion and intracellular regulation of the iron regulatory protein (IRP)/iron response element (IRE) system.
Regulation of iron metabolism is divided into systemic regulation by hepcidin, which is produced by hepatic secretion, and intracellular regulation by the iron regulatory protein (IRP)/iron response element (IRE) system (24, 25).In iron overload, the balance of the two major systems regulated by iron in the human body breaks, and excessive divalent iron ions induce ferroptosis by producing hydroxyl radicals through the Fenton reaction.
2.2 Lipid peroxidation
Lipid peroxidation plays a central role in the development of ferroptosis, and lipid peroxidation requires three steps: synthesis of membrane polyunsaturated fatty acids (PUFAs) containing phospholipid substrates, free radical priming, and enzyme induction (26).
2.2.1 Phospholipid substrate synthesis
PUFAs involved in membrane phospholipid synthesis contain multiple carbon-carbon double bonds and more fragile carbon-hydrogen bonds and are therefore more sensitive to oxidation (27). It is esterified by lysophosphatidyltransferase 3 (LPCAT3) and incorporated into membrane phospholipids to form the ferroptosis lipid peroxidation substrate PUFA-PL, which turns on downstream peroxidation (28). Downregulation of LPCAT3 or ACSL4 causes substrate depletion for lipid peroxidation and reduces the risk of ferroptosis (29).
2.2.2 Free radical-mediated lipid oxidation
Peroxidative degradation of PUFA-PL initiated by free radicals can be divided into three stages: initiation, propagation and termination (30). In the initial stage, labile iron, stored intracellularly as ferritin or iron-sulfur clusters, undergoes Fenton reaction and Haber-Weiss re ‐ action with hydrogen peroxide and forms hydroxyl radicals centered on oxygen with peroxyl radicals (31). In the propagation stage, LOOH captures the hydrogen atoms of adjacent lipids through free radicals and undergoes the Fenton-like reaction under the catalysis of ferrous ions, generating alkoxy free radicals (LO ·) and triggering lipid free radical chain reactions to form lipid oxidation cascades, while producing some secondary products such as malondialdehyde (MDA) and 4-hydroxynonaldehyde (4-HNE) (32). Finally, the antioxidant system is abnormal, the peroxide substrate is depleted, the cascade terminates, and causes severe damage to the cell membrane (33).
2.2.3 Enzyme-mediated lipid oxidation
During the enzymatic process, the lipoxygenase (LOXs or ALOXs) family and nadph- cytochrome P450 reductase (POR) are critical to turn on lipid peroxidation during ferroptosis (34). ALOXs/LOXs are iron-containing dioxygenases that catalyze binding of free PUFAs in biofilms, promote PUFA-containing lipid oxidation, and accelerate ferroptosis progression (35).
2.2.4 Deprivation of cysteine and glutathione (GSH)depletion
Cysteine is a sulfur-containing amino acid that can be synthesized endogenously via the transsulfuration pathway or acquired from extracellular cystine by cystine glutamate reverse transporter (System Xc-) (36).
Glutathione is a γ-amide bond- and thiol-containing tripeptide with antioxidant effects and integrated detoxification, and prevents lipid peroxidation in ferroptosis by providing electrons to GPX4 (37). Glutathione is stored in the human body as reduced (GSH) and oxidized (GSSG) forms and plays a key role in the antioxidant system (38). In addition to erastin-induced GSH reduction enervates GPX4 and raise ROS levels (39, 40). In addition, unlike the above system Xc- response, some cytokines can cause glutathione depletion directly by inhibiting GSH ligase, resulting in ferroptosis.
3 Ferroptosis-related signaling molecules and signaling pathways
Ferroptosis is significantly associated with the physiology and pathology of many diseases, and the related signaling pathways and regulators of ferroptosis are important ways to regulate ferroptosis. Therefore, five related pathways of ferroptosis, AMPK signaling, Activating transcription factor 4(ATF4), BECN1 signaling, NOX4 signaling, Yes associated protein/transcription costimulator with PDZ-binding domain (YAP/TAZ), will be discussed below to provide new targets for future disease therapy and new drug research (Figure 3).
Figure 3 Ferroptosis-related signaling molecules and signaling pathways. (A) AMPK promotes complex BECN1-SLC7A11 formation mediated by AMPK, thereby inducing promotion of lipid peroxidation and ferroptosis. (B) ATF4 expression is elevated in cancer and promotes cell survival and tumor growth by inducing genes involved in amino acid metabolism and oxidant defense. (C) NOX4 is the main source of ROS production in cells and is able to inhibit intracellular ROS accumulation and protect against ferroptosis by downregulating NOX4 expression. (D) YAP/TAZ enters the nucleus to promote expression of EMP1, TFRC, and ACSL4, so cells are sensitive to ferroptosis.
3.1 AMPK signaling
It is well-known that the body maintains a dynamic balance of nutrient energy metabolism, and homeostasis will be imbalanced when the body produces stress, and glucose deprivation causes excessive ROS production leading to energy stress, indicating that glucose deprivation induces ferroptosis (41). AMPK, as an important sensor of energy metabolism in the body, opens an energy stress protection program that inhibits cellular ferroptosis by regulating the synthesis of unsaturated fatty acids (42). Overall, AMPK-induced energy stress, a protective mechanism, appears to prevent ischemia-reperfusion injury in body organs (43).
3.2 ATF4 signaling
ATF4, a basic leucine zipper protein, is an important factor involved in the regulation of mitochondrial stress, pathological stress, apoptosis, inflammation, related pathways, and proteins (44). Under stress conditions, the expression of ATF4 is up-regulated by phosphorylating and activating eukaryotic translation initiation factor 2a (elF2a), and ATF4 regulates gene expression after entering the nucleus, which has an effect on the development, growth, metabolic function, and oxidative response of the body. ATF4-C/EBP homologous protein (CHOP) is an important pathway to regulate pathological phenomena such as ER stress, ROS production, lipid peroxidation, and iron metabolism, and inhibition of this pathway prevents the progression of ferroptosis-related diseases such as acute lung injury (45).
3.3 NOX4 signaling
NOX4 is the main source of ROS production in cells, and it produces large amounts of superoxide through electron reduction reactions of NADPH. Among the NOX isoforms of the human gene, NOX4-mediated oxidative stress specifically impacts cell development and atrophy and is involved in the development of lung disease (46). By downregulating NOX4 expression, it was able to inhibit intracellular ROS accumulation, infiltration of inflammatory cells, as well as mitochondrial dysfunction, further indicating that Nox4 is involved in apoptosis through oxidative stress pathways (47). Therefore, knockdown of NOX4 factor or drug intervention may inhibit ferroptosis in cells.
3.4 YAP/TAZ signaling
The YAP/TAZ, as a pair of recently elucidated transcriptional regulators, is involved in the regulatory mechanism of Hippo signaling pathway and also plays an important role in cell differentiation, tissue homeostasis, organ development, and cancer development in the body (48). The expression of YAP/TAZ has been demonstrated in a variety of tumors and is significantly associated with anti-tumor therapy, clinical prognosis (49).
4 Ferroptosis defense pathways
Among the protective mechanisms against peroxidative damage, GSH/GPX4 axis is considered to be a major factor in the progression against ferroptosis, while non-GPX4-dependent antioxidant pathways also play an important role in the regulation of ferroptosis (Figure 4).
Figure 4 Defense Pathways of Ferroptosis. GPX4 specifically catalyzes the loss of oxidative activity of lipid peroxides in a glutathione (GSH)-dependent manner and is thought to be a major factor in the progression against ferroptosis. FSP1 does not rely on glutathione to convert ubiquinone to reduced ubiquinone on cell membranes and can inhibit peroxidation and protect against ferroptosis. DHODH traps free radicals to inhibit lipid peroxidation in mitochondria by regulating dihydroubiquinone production in the inner mitochondrial membrane. The GCH1/BH4 pathway acts as an endogenous antioxidant pathway, and GCH1 mainly protects cells from ferroptosis through the antioxidant effect of BH4. NRF2 protects body cells from ferroptosis by up-regulating multiple signals through antioxidant effects. FSP1, ferroptosis suppressor protein 1; GPX4, glutathione peroxidase 4.
4.1 GSH/GPX4 axis
GSH, as the main free radical scavenger in cells, maintains biosynthesis from three amino acids, Cys), glycine, and glutamate, and resists ferroptosis progression and lipid peroxidation (50). Glutathione peroxidase 4 (GPX4) is an antioxidant enzyme containing selenocysteine (Ser) that uses GSH as a substrate to catalyze the reduction of PLOOH to non-toxic PLs-alcohol (PL-OH) and prevent the occurrence of ferroptosis using its unique catalytic ability (51, 52). The System Xc- is the core precursor of GSH synthesis and an important cofactor for GPX4 to scavenge membrane lipid peroxides and reduce oxidative stress, which plays a key role in inducing the development of ferroptosis (53).
4.2 NAD(P)H/FSP1-CoQ axis
Ferroptosis suppressor protein 1 (FSP1), formerly known as AIFM2, is a flavoprotein that was identified to be closely associated with ferroptosis and independent of the GPX4-GSH pathway (54). FSP1 is modified by N-terminal myristoylation and targets a variety of cell membrane structures including cytoplasmic membranes, Golgi apparatus, and perinuclear structures, and mutating the myristoyl modification site of FSP1 loses its FSP1-mediated anti- ferroptosis function (55). As NAD(P) H-dependent ubiquinone (CoQ) oxidoreductase, FSP1 inhibits the occurrence of lipid peroxidation by reducing the incomplete oxidation product of CoQ/ubiquinone to ubiquinol (CoQH2), while indirectly promoting α-tocopherol regeneration (vitamin E, a natural fat-soluble antioxidant) and jointly resisting ferroptosis.
4.3 GCH1/BH4/DHFR axis
Guanosine triphosphate cyclohydrolase 1 (GCH1) exerts its powerful anti-gpx4 inhibitory effect on ferroptosis by activating tetrahydrobiopterin (BH4) and dihydrobiopterin (BH2) (56). GCH1 selectively prevented the consumption of phospholipids containing two polyunsaturated fatty acid acyl tails, and increased BH4/BH2 to inhibit lipid peroxidation and iron ion denaturation (57). Another mechanism by which BH4 inhibits ferroptosis reduces CoQ to CoQH2 to enhance resistance to ferroptosis. Supplementation of BH2 in vitro promotes regeneration and protects cells from ferroptosis through the turnover of BH4 (58). In addition, higher levels of GCH1 were also detected in a large number of lung cancer tissue samples.
4.4 Mitochondria DHODH
DHODH, located on the inner mitochondrial membrane, is able to catalyze pyrimidine nucleotide synthesis, and its loss of activity leads to the accumulation of lipid peroxides in mitochondria and triggers the development of ferroptosis in GPX4-low expressing cells (59). DHODH inhibits lipid peroxidation by converting mitochondrial CoQ to CoQH2, unlike FSP1 localized outside the membrane, ectopic expression of FSP1 does not protect cells from ferroptosis (60). The application of the DHODH inhibitor brequinar inhibited the growth of tumor cells with low GPX4 expression in vitro, and the combined treatment of brequinar and the SLC7A11 inhibitor sulfasalazine abolished the growth of tumor cells with high GPX4 expression (61).
4.5 Keap1-Nrf2-ARE axis
Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor involved in cellular oxidative responses that advance iron storage, curb iron uptake, limits ROS production, and ultimately regulates ferroptosis in the activated state (62, 63). In addition to its role in iron metabolism, NRF2 regulates basal and inducible glutathione synthesis expression of SLC7A11 and γ-glutamylcysteine synthetase (γ-GCS) to protect against ferroptosis. Additionally, NRF2 accelerates the progression of ferroptosis by increasing Fe2+ from the labile iron pool by regulating heme oxygenase 1 (HO-1) (64, 65).
5 Small-molecule modulators of ferroptosis
5.1 Small molecule inducers of ferroptosis
RSL3 and erastin are small molecule compounds that induce ferroptosis in tumor cells with mutations in the oncogene RAS (66, 67). RSL3 acts by inhibiting the enzymatic activity of GPX4 and irreversibly inactivates GPX4, in which Altretamine and Withaferin A as anti-tumor drugs can directly inhibit GPX4-mediated ferroptosis in tumor cells and provide new strategies for anti-tumor therapy (68, 69).
5.2 Small molecule inhibitors of ferroptosis
Inhibitors of ferroptosis act by inhibiting lipid peroxidation and iron accumulation. Fer-1 and Lip-1 act as aromatic amine antioxidants and are able to prevent lipid ROS accumulation and inhibit ferroptosis (70). By downregulating 5-lipoxygenase (5-LOX), zileuton and N-acetylcysteine protect cells from lipid peroxidation caused by reactive oxygen species generation (71, 72). ACSL4 esterifies free fatty acids and is a key enzyme in regulating lipid composition. Rosiglitazone, pioglitazone, and troglitazone specifically inhibited ACSL4 activity to prevent ferroptosis and cellular lipid oxidation (73). In addition, another sign of ferroptosis is iron overload, and the iron chelators desferrioxamine (DFP) have the effect of inhibiting ferroptosis.
5.3 Regulation of ferroptosis by natural compounds
Recently, an increasing number of natural products have been isolated from natural resources as reagents for drug development for the treatment and prevention of diseases (74). These natural compounds are able to maintain effects such as iron homeostasis in the body, which are associated with inhibition of ferroptosis. Recently, it has been shown that artemisinin and its derivatives (artesunate, dihydroartemisinin) can not only treat malaria, but also induce iron apoptosis in cancer cells through a series of reactions (75, 76). Baicalein, discovered in a natural product library screen, is a natural ferroptosis inhibitor that inhibits ferroptosis by inhibiting erastin induction and 12/15-LOX activity.
6 Ferroptosis in pulmonary disease
Ferroptosis, as a mode of cell death, plays an important role in COPD, asthma, lung injury, lung cancer, pulmonary fibrosis and lung infection. Therefore, it seems important to investigate the relationship between lung disease and ferroptosis to provide new ideas for clinical treatment (Figure 5).
Figure 5 Ferroptosis in pulmonary disease. Ferroptosis plays an important role in the pathogenesis of lung diseases such as COPD, asthma, lung injury, lung cancer, pulmonary fibrosis, and lung infection. ACMs, airway smooth muscle cells; ECM, extracellular matrix; IL-1, interleukin-1; MDA, Malondialdehyde; T cells, T lymphocyte; TNF, tumor necrosis factor.
6.1 COPD
COPD is an incompletely reversible systemic disease with airflow limitation. The pathological changes are mainly airway remodeling and/or abnormal alveolar wall elasticity. Pulmonary function test is the main objective index, which is manifested as decreased forced expiratory volume in 1 s (FEV1) (77, 78). COPD occurs mainly due to hand environment and genetic influences, and continuous exposure to cigarette smoke is one of the important environmental factors leading to COPD and the most common (79).Tobacco smoke induces inflammatory factor infiltration through ER stress, causing hypoxia in small airways and alveoli, accelerating the progression of COPD and inducing ferroptosis in lung epithelial cells (80). As macrophages accumulate causing accumulation of the inflammatory factor LTB4, ACSL4 expression is upregulated, thereby inducing ferroptosis in lung epithelial cells (81). In addition, the stimulation of herb smoke caused the accumulation of unstable iron and the enhancement of lipid peroxidation, again indicating that ferroptosis is closely related to COPD (82). The above mechanisms were mainly triggered by NCOA4-mediated iron autophagy and were not significantly associated with the GPX4 defense pathway (83). NCOA4 plays an important role in the pathogenesis of emphysema in COPD by polarizing M2 macrophages and inducing the secretion of inflammatory cells in bronchial epithelial cells (84).
The mechanism of iron responsive element binding protein 2 (IREB2) susceptibility to COPD is different from that of smoking. Overexpression of IREB2 indirectly leads to a significant decrease in lung compliance and total lung capacity, while it can cause inflammatory infiltration to increase IL-6 expression, induce hepcidin to regulate iron homeostasis, and induce FEV1 decline in COPD mice (85, 86). In parallel, elevated levels of IREB2 lead to accumulation of labile iron pools (LIPs) and lipid peroxidation, triggering iron overload in lung epithelial cells. Ferroptosis of airway epithelial cells and alveolar epithelial cells induces airway remodeling and emphysema, respectively, thereby causing COPD (87). Appropriate iron supplementation delays the onset and progression of COPD.
DNA dioxygenase 10-11 translocation 2 (TET2) is an important demethylase that regulates cigarette induced lipid peroxidation by demethylating GPX4, thereby reducing ferroptosis in COPD airway epithelial cells (80). The combination of the methylation inhibitor 5 ′ -aza-2 ′ -deoxycytidine (5-aza) and the antioxidant n -acetylcysteine (NAC) was strongly resistant to the production of inflammatory mediators induced by cigarettes in COPD (23).
In conclusion, the role of pulmonary iron regulation as well as iron metabolism in COPD remains to be investigated.Targeted iron therapy and lipid-specific anti-oxidation may be a strategy for the treatment of COPD and needs to be more reliably validated.
6.2 Asthma
Asthma is a chronic inflammatory respiratory disease characterized by airway altitude sickness and reversible airflow limitation (88). The main clinical symptoms are recurrent cough, sputum, wheezing, etc., which seriously threaten human health and occur frequently in children and the elderly. Airway inflammation and airway altitude sickness (AHR) are the core link in the pathological changes and recurrent attacks of asthma (89). Asthma is a chronic airway inflammatory disease that is closely associated with inflammatory cell infiltration (lymphocytes, mast cells, eosinophils, neutrophils), type II cytokine secretion (IL-4, IL-13, IL-5), and airway epithelial cell damage (90, 91).Oxidative stress response is closely associated with inflammation and AHR (92). Multiple markers of lipid peroxidation have been identified in patients with asthma, further suggesting that the pathophysiology of asthma is associated with ferroptosis (93). Correlative studies have shown that alveolar epithelial cell iron content is positively correlated with the progression of asthma. Substantial iron deposition is found in acellular cells of asthmatic patients causing airway inflammation and oxidative stress, thereby inducing ferroptosis (94). Among them, allergen exposure increases ROS production, breaks oxidative balance, accelerates oxidative stress progression, and is also responsible for aggravating asthma symptoms (95).
The ferroptosis defense pathway associated with asthma is mainly the Nrf2 pathway, which plays a role in resisting the progression of asthma course through anti-inflammatory mechanisms (96). Combined with ARE, Nrf2 inhibits the expression of type II cytokines in airway epithelial cells, inhibits oxidative stress, and slows the symptoms and signs of asthma (97). Nrf2-Keap1 signaling not only resists oxidative effects in asthma, but also promotes the expression of systemic Xc- and GPX4 factors, regulates SLC7A11 activity, reduces ROS production, and ultimately inhibits ferroptosis (98). Recent studies have found that licorice can activate the activity of Nrf2 and play a protective role in airway altitude sickness, providing new ideas for the clinical treatment of asthma (99).
15LO1, an abundant lipid peroxidase in airway epithelial cells (HAECs) of asthmatic patients, promotes the development of asthma, and its expression level is positively correlated with the severity of asthma (100). Type II cytokines interact with 15LO1 to promote inflammatory cell infiltration to induce inflammatory responses (101). 15LO1 binds to phosphatidylethanolamine-binding protein 1 (PEBPl) under cytokine stimulation, activates lipid peroxidation, and promotes ferroptosis in airway epithelial cells of asthmatic patients (102). It can be seen that specific inhibitors of 15LO1 are expected to provide new strategies for the treatment of steroid-resistant asthma.
6.3 Lung injury
6.3.1 Acute lung injury
ALI is mainly characterized by alveolar epithelial cell damage, pulmonary interstitial edema, and neutrophil infiltration (103). Clinically, the main symptoms are decreased lung compliance and bilateral pulmonary inflammatory infiltrates in hypoxemia (104). Ferroptosis is the main driver of ischemia-reperfusion injury (I/R) and is closely related to the pathogenesis of lipopolysaccharide (LPS) -induced septic ALI, and can aggravate further tissue and organ damage (73, 105). Activation of NRF2 enhances resistance to lipid peroxidation induced lung injury by ferroptosis factors (GPX4, SlC7A11) in murine models of ALI, thereby protecting alveolar epithelial cells from ferroptosis (106, 107). In addition, the metabolites obacunone and itaconate significantly reduced lung injury by inducing activation of the NRF2 pathway (108, 109). By observing the ALI model, we could find that MDA expression increased, GSH and GPX4 expression decreased, and mitochondrial morphology changed in order to assess the degree of lung damage caused by ferroptosis at different I/R durations (110, 111).
In addition, the cells involved in ALI pathology and inflammatory response were mainly mast cells (MCs) and polymorphonuclear neutrophils (PMN) (112). MC is involved in the progression of ALI after autologous liver transplantation by regulating PMN apoptosis (113). At the same time, Nrf2 factor plays a protective role against sepsis-induced lung injury by activating antioxidant enzyme responses (108). However, the clinical treatment of ALI is still an exploratory stage at home and abroad. Currently, an increasing number of studies have shown that lipid peroxidation, which is a key cause of ferroptosis, plays an important role in ALI severity (114). Therefore, ferroptosis is closely related to ALI and may become an important therapeutic target for ALI (115).
6.3.2 Radiation-induced lung injury
Radiotherapy is one of the important methods to treat lung tumors, and RILI (radiation pneumonitis and radiation pulmonary fibrosis) caused by radiotherapy is a common complication (116).
Radiation promotes the development of RILI, mainly promotes the infiltration of inflammatory cells to secrete various chemokines. ROS produced by radiation may be the original trigger for inducing ferroptosis in RILI, and the Keap1-NRF2 pathway has a protective effect against radiation-induced ferroptosis in alveolar epithelial cells (117). In a mouse model of RILI, inhibition of expression of the key factor GPX4 induced ROS accumulation leading to lipid peroxidation, further suggesting that ferroptosis RILI plays an important role. In addition, it has been found that the cascade of multiple cytokines is also involved in the process of ferroptosis in radiation-induced ALI. Transcription growth factor β1 (TGF-β1) and ROS synergize to promote ferroptosis in radiation-induced ALI and jointly aggravate lung injury, while Nrf2 slows radiation-induced ALI and the development of ferroptosis by reducing the expression of TGF-β1 and inhibiting iron ion absorption (118). ferroptosis has now been identified as playing an important role in radiation-induced ALI. Ferroptosis inhibitors may be an effective treatment for radiation-induced ALI, providing new insights into reducing ROS damage, preventing and treating radiation-induced lung injury. Ferroptosis inducers synergized with radiotherapy by enhancing cytoplasmic lipid peroxidation without increasing DNA damage or caspase activation, whereas ferroptosis inhibitors inhibited radiation-induced RILI and ferroptosis by inhibiting lipid peroxidation and enhancing GPX4 expression (119, 120).
6.4 Lung cancer
Lung cancer is one of the most common malignant tumors worldwide, with a very high morbidity and mortality (121), and its pathological types mainly include non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) (122, 123). NSCLC is the most common type of lung cancer and is divided into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large cell carcinoma. In recent years, the incidence of LUAD has increased.
Cysteine desulfurase (NFS1) acts on lung tissue in a hyperoxic environment and there are amplified regions of the LUAD genome that are highly expressed. Simple inhibition of NFS1 activity does not slow LUAD growth and requires co-activation of the iron starvation response in cooperation with inhibition of glutathione organisms to trigger ferroptosis in vitro. Iron metabolism imbalance is closely related to the occurrence and development of lung cancer. USP35 combined with transportin (FPN) synergistically stabilized serum ferritin levels and inhibited ferroptosis to delay lung cancer cell growth (124).
SLC7A11 is centrally expressed in LUSC and is involved in body regulation (125). SLC7A11 expression increased in response to stimulation with the transcription factor SOX2, rendering lung cancer cells more resistant to upper iron (126). The expression of SLC7A11 and SOX2 was positively correlated in LSCC, and SOX2 plays an important role in the squamous cell fate of cells of different origins. In addition, RBMS1 acts as an RNA-binding protein and promotes ferroptosis by binding to the 3 ′ UTR region of SLC7A11 thereby promoting its translation and inhibiting SLC7A11-mediated cystine uptake (127).
SCLC is characterized by poor malignancy and prognosis and early metastasis (128). SCLC accounts for 15% of lung cancers and is associated with smoking, including neuroendocrine (NE) and non-neurosecretory (Non-NE) types (129). NE-SCLC are more susceptible to ferroptosis through isoform-specific lipidome remodeling, breaking oxidative balance (125). Chemotherapy resistance in Non-NE types is well-known because of peroxidation of specific membrane lipids of ACSL4 and LPCAT3, which induce ferroptosis. Combined treatment with ferroptosis mechanisms improves survival in lung cancer patients by inhibiting single-pathway targeting observed isoform plasticity.
6.5 Fibrotic lung diseases
Pulmonary fibrosis is a lung disease in which fibroblasts proliferate, a large amount of extracellular matrix accumulates leading to scarring, accompanied by inflammatory cell infiltration and destruction of alveolar wall structure (130, 131). At present, the pathogenesis and mechanism of pulmonary fibrosis are not clear, and there is a lack of effective treatment, and the prognosis of this patient is often poor. While the finding of ferroptosis is closely related to pulmonary fibrosis, it plays a key role in the pathogenesis of pulmonary fibrosis with iron overload, ROS accumulation, lipid peroxidation, and inhibition of GPX4 activity. When the level of iron in the body increases, it promotes the transformation of fibroblasts into myofibroblasts and accelerates the development of pulmonary fibrosis (132).
Ferroptosis is involved in the pathogenesis of pulmonary fibrosis, and the main triggers are ROS accumulation and glutathione depletion. The imbalance of antioxidant system is the key factor causing ROS accumulation and the occurrence and development of early pulmonary fibrosis. Nrf2-ARE, as an important pathway of ferroptosis, reduces the expression of free iron and smooth muscle actin by up-regulating the expression of HO-1, reduces collagen fiber synthesis, and finally inhibits ferroptosis-related pulmonary fibrosis (133). Type II alveolar epithelial cells (ATll) are critical cells for maintaining alveolar structure and function. The cell membrane contains a large number of polyunsaturated fatty acids and abundant mitochondrial content, and has a high susceptibility to ferroptosis (134). In bleomycin(BLM)-induced pulmonary fibrosis mouse specimens, ATII was found to contain a large number of iron ions, accompanied by pathological changes of fibrosis such as collagen deposition (135–137). Also, Fcn B secreted by exosomes from blm-induced alveolar macrophages promotes lung injury and fibrosis via ferroptosis in a blm-induced mouse model (137).
Liproxstatin-1, an ferroptosis inhibitor, delayed fibroblast differentiation into myofibroblasts and reduced pulmonary fibrosis by limiting collagen deposition and decreasing GPX4 expression (138, 139). Paraquat (PQ) is a highly toxic pesticide that causes diffuse fibrosis of the lungs.The toxic mechanism of PQ is mainly ROS imbalance leading to lipid peroxidation, mitochondrial damage, resulting in cellular ferroptosis (140). Recent studies have found that fine particulate matter (PM2.5) degrades heme-containing proteins through HO-1 and releases iron in fibrotic cells, resulting in mitochondrial ROS production, induced ferroptosis and aggravated pulmonary fibrosis (141). However, ferroptosis inhibitors such as desferrioxamine and Er-1 can play a key role in the treatment of pulmonary fibrosis induced by PQ and PM2.5.
6.6 Pulmonary infection
6.6.1 Tuberculosis
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection causing chronic infectious diseases that affect human life and health. TB is the main cause of death caused by a single source of infection (142). With the incidence of multi-drug resistant tuberculosis increasing year by year, the prevention and treatment situation is very severe, and anti-tuberculosis treatment is of great significance in clinical practice. Mtb is highly contagious, and when inhaled into the body, it activates macrophages in the alveoli to produce an adaptive immune response, thereby eliminating Mycobacterium tuberculosis. At the same time, Mtb can also evade macrophage killing by inducing macrophage necrosis through negative regulation. In recent years, increasing evidence suggests that ferroptosis is significantly associated with pathogenicity and dissemination of Mtb. In mice acutely infected with Mtb, alveolar macrophage necrosis was significantly associated with a phenotype of ferroptosis, mainly characterized by decreased Gpx4 expression, increased lipid peroxidation, and mitochondrial hyperoxidation (143). Protein tyrosine phosphatase A (PtpA) secreted by Mtb interacts with host RanGDP to enter the nucleus and promotes arginine methyltransferase 6 (PRMT6) -mediated methylation of H3R2me2a on the GPX4 promoter, resulting in decreased GPX4 expression and ferroptosis induction in host cells and promoting Mtb pathogenicityand dissemination (144). These results suggest that gpx4-dependent iron cell apoptosis may be targeted by blocking the Mtb ptpa- host PRMT6 interface, providing a new therapeutic strategy for the treatment of tuberculosis (145).
Subsequently, GPX4 knockout mice were found to aggravate TB infection, while overexpression of GPX4 significantly reduced bacterial load and risk of infection. Meanwhile, Fer-1 could reduce lipid peroxidation and inhibit cellular ferroptosis in Mtb-infected macrophages (146). In summary, ferroptosis is closely related to the occurrence and development of Mtb infection, and inhibition of ferroptosis can inhibit Mtb infection and pulmonary inflammatory response.
6.6.2 Coronavirus disease 2019
It is a pulmonary infectious disease caused by SARS-CoV-2 virus infection causing severe acute respiratory distress (147). SARS-CoV-2 targets various systemic functions of the body, with the lungs and throat of the respiratory system as the main targets (148). Abnormal lipid expression in pneumocytes was found to result in increased pneumocyte apoptosis and ferroptosis in mice infected with SARS-CoV-2 virus (149). Reactive breakdown products of lipid peroxides were observed in a case of severe COVID-19 infection with myocarditis (150). In addition, SARS-CoV-2 inhibited GPX4 mRNA expression to induce apoptosis by attacking lung macrophages and monocytes (151). Related studies showed that expression levels of major signaling factors for ferroptosis, including GPX4 and SLC7A11, were significantly upregulated in sera from patients with novel coronavirus infection (152, 153).
Recent studies have found that SARS-CoV-2 ORF3a can increase the sensitivity of cells to iron ions through the Keap1-NRF2 axis on the one hand, accelerate the degradation of NRF2 by Keap1 on the other hand, weaken the resistance of cells to oxidative stress, and induce ferroptosis in cells on the other hand (154). In addition, vitamin K reduces the level of reactive oxygen species by regulating the expression of antioxidant enzymes and can also prevent ferroptosis by reducing the inflammatory response (155).
In summary, ferroptosis plays a diversified role in COVID-19, and understanding the signaling mechanism of ferroptosis during SARS-CoV-2 virus infection will help to advance the clinical treatment and drug research and development of the disease, and targeting iron-tropic organics seems to be a potential novel therapeutic strategy for COVID-19.
6.6.3 Pseudomonas aeruginosa
Respiratory diseases are inextricably linked to respiratory microbiota infections, and Pseudomonas aeruginosa (PA) is one of the most common pathogenic groups (156). PA is the main species of nosocomial infection, which can be found in most patients with long-term mechanical ventilation in intensive care units and is also an important opportunistic pathogen causing acute lung injury and acute respiratory distress syndrome (157). PA contains secretory vesicles that catalyze the host PUFA reaction by 15LOX, thereby making virulence factors to induce ferroptosis (158). Although PA uses LOX to participate in the ferroptosis process, 15LOX has a significant lack of lipid substrates (159). Also, it has been shown that PA decreases the effects of host GPx4 to induce lipid peroxidation by activating lysosomal chaperone-mediated autophagy (160). Using a macrophage infection model, P. aeruginosa RNase E variants cause host infection damage by increasing host cell siderophore production and iron cell apoptosis (161). In summary, PA is closely related to ferroptosis, while 15LOX-induced ferroptosis progression serves as a therapeutic target, providing new therapeutic ideas for non-antibiotic treatment of PA-induced airway infections.
7 Targeting ferroptosis in lung disease
COPD is associated with iron imbalance, and treatment to correct disorders of body iron metabolism may be helpful in the treatment of the disease. In a mouse model exposed to cigarettes, regarding the progression of resistance to COPD, with the exception of GPx4 knockdown, desferrioxamine and ferristatin-1 are a possible target for the treatment of ferroptosis-induced COPD (82). At the same time, chelators, iron supplementation, or low-iron diets are current methods to correct iron levels and avoid COPD damage to the body.
Asthma is characterized by recurrent and difficult to cure as the main clinical features. Relevant clinical and serial experiments have shown that acupuncture has a regulatory effect on mucosal and cellular immunity in patients with allergic asthma and may be an adjuvant method for the treatment of asthma (162, 163). In the mouse asthma model treated with acupuncture, the expression of ferroptosis regulator MDA was down-regulated and GSH was up-regulated, further elaborating that the effect of acupuncture on asthma is associated with the regulation of ferroptosis.However, the regulatory mechanisms involved need to be investigated.
Studies have shown that iron sag is an effective mechanism to induce ALI, and inhibition of iron sag provides a more reliable means to prevent and treat ALI induced by i/R or lps. Liprostatin-1 and Ferrostatin-1 were able to ameliorate lung histopathological damage, pulmonary edema alterations, and lipid peroxidation progression in I/R mice (107, 110).
Ferroptosis has become an effective therapeutic target for lung cancer, especially for lung cancer types with drug resistance (164, 165). Platinum inhibits iron cell apoptosis by high depletion of GSH through activation of the Wnt/NR2F2/GPX4 pathway.GPX4 inhibitors have been found to enhance the anticancer effects of Platinum providing new therapeutic ideas for lung cancer patients (166). In addition, nanotechnology of tumor in situ iron mineralization provides a new scheme for the early diagnosis of lung cancer, using Prussian blue/calcium peroxide nanocomposite technology to induce iron mineralization in lung cancer cells, while causing oxidative stress to induce apoptosis and ferroptosis, and inhibiting the malignant growth of tumor cells (167). Recent studies have found that self-assembled ph sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) technology kills lung tumor cells by participating in the Fenton response and inducing ferroptosis in an acidic environment through radiation therapy and iron ion release (168). Immunotherapy is currently one of the effective methods for anti-lung cancer tumor therapy, in which immune checkpoint inhibitors (ICIs) mainly exert anti-tumor effects by activating T cells, and currently approved ICIs have drugs targeting CTLA4, PD-1 and PD-L1 (169). Activated CD8+ T cells release interferon-gamma, down-regulate the expression of SLC7A11 and SLC3A2, and inhibit the uptake of cystine by lung cancer cells to achieve anti-tumor effects (170). In addition, some nanoparticles induce ferroptosis to achieve inhibition of lung cancer tumors, of which SRFFe IITA (SFT) and zero-valent iron nanoparticles (ZVI-NP) are effectively combined with ferroptosis by photodynamic therapy and immunostimulation to treat lung tumors (171, 172).
In the physiological and pathological changes of pulmonary fibrosis, liproxstatin-1 can activate the Nrf2 pathway to downregulate transforming growth factor β1 (TGF-β1) and delay the progression of pulmonary fibrosis (118). Substantial iron deposition was found in alveolar epithelial cells of lung fibrosis samples, whereas deferoxamine (DFO) prevented lung fibrosis progression and ferroptosis by stabilizing iron metabolism in the lung (136). In addition, SODARA290-HBc, a newly constructed bioengineering nanoreactor, protects alveolar epithelial cells from radiation and iron poisoning by inhibiting oxidative stress, inflammation, and regulating the phenotype of infiltrating macrophages in the RILI mouse model (173).
Iron metabolism disorders are inextricably linked to the development of pulmonary tuberculosis, and biomarker levels of iron ions provide new ideas for the diagnosis of pulmonary tuberculosis (174). Isoniazid (INH), as an anti-tuberculosis drug, damages the liver and induces lipid peroxidation leading to apoptosis of liver cells through glutathione depletion (175). Thus, anti-ferroptosis appears to be an effective target for treating TB or delaying TB progression.
SARS-CoV-2 virus is a pathogenic agent of novel coronavirus infection and is closely associated with the development of ferroptosis. Studies have shown that iron-sulfur cofactor is a cofactor of SARS-CoV-2 virus and a therapeutic target of COVID-19 (176). Two candidates, DFO and imatinib, were identified to be effective in blocking SARS-CoV-2 infection and infection-related ferroptosis in a mouse model of sinoatrial node-like pacemaker cell dysfunction infected with novel coronavirus (177).
8 Conclusion
For ferroptosis, as research progresses, the documented related signaling pathways between induction and inhibition mechanisms, as well as the regulatory pathways of ferroptosis, are explored. This paper also reviews the relationship between ferroptosis and respiratory diseases. However, despite increasing evidence from animal experimentation demonstrating the effectiveness of targeted ferroptosis therapy in lung disease, questions remain regarding its clinical role.
SLC7A11 and GPX4 are important regulators of ferroptosis, and multiple ferroptosis inducers exert anti-ferroptosis effects in alveolar cells through them. Specifically, high expression of SLC7A11 and GPX4 is a potential target for the treatment of lung diseases. However, expression levels of SLC7A11 and GPX4 differ in a variety of respiratory diseases. Therefore, it becomes particularly important to screen key genes that provide relevant evidence for targeted therapy for clinical ferroptosis. In addition, an increasing number of studies have shown that ferroptosis, as an adjuvant clinical treatment option, will become a new target for the treatment of various lung diseases that are currently incurable.
Author contributions
FZ: Writing – original draft. YX: Writing – original draft. QM: Writing – original draft. EG: Writing – review & editing. XZ: Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: ferroptosis, lung diseases, iron metabolism, respiratory disorders, therapy
Citation: Zhang F, Xiang Y, Ma Q, Guo E and Zeng X (2024) A deep insight into ferroptosis in lung disease: facts and perspectives. Front. Oncol. 14:1354859. doi: 10.3389/fonc.2024.1354859
Received: 19 December 2023; Accepted: 28 February 2024;
Published: 18 March 2024.
Edited by:
Qingfei Zheng, The Ohio State University, United StatesReviewed by:
Zhi-Bin Wang, Central South University, ChinaRong Cai, Shanghai Jiao Tong University, China
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*Correspondence: E. Guo, Z3VveWl5aV9sb3ZlQDEyNi5jb20=; Xiansheng Zeng, emVuZ3hpYW5zaGVuZzIwNkAxNjMuY29t