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 ).

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.

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).

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).

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).

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.

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).

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).

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.

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.

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).

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).

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).

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.

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.

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.

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.

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.

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.