Role of Ferroptosis on Lung Epithelial Cells in Disease Progression and Treatment: A Review

Introduction

Ferroptosis is a distinct, iron-dependent form of regulated cell death, first characterized by Dixon et al in 2012 [1]. Unlike apoptosis, necrosis, and autophagy, ferroptosis exhibits a unique morphological and biochemical profile, defined by overwhelming lipid peroxidation, depletion of glutathione, and the accumulation of iron-dependent reactive oxygen species (ROS) [2,3]. Mitochondrial shrinkage, condensed membrane densities, and loss of cristae structure are hallmark ultrastructural changes associated with ferroptosis [3]. Since its discovery, ferroptosis has been increasingly recognized as a key contributor to the pathogenesis of various diseases, particularly through its role in oxidative stress and membrane damage. It has been implicated in the progression of multiple pathological conditions, including tumorigenesis and chemoresistance in various cancers [4], endothelial dysfunction in vascular diseases [5], and immune dysregulation in autoimmune disorders [6]. Lung epithelial cells, made up of bronchial epithelial cells in the airway and alveolar epithelial cells in the distal lung, represent the frontline barrier between the respiratory system and the external environment, performing essential functions in host defense, mucociliary clearance, gas exchange, and immune regulation [7]. These cells are strategically positioned along the tracheobronchial and alveolar regions, where they actively participate in sensing, responding to, and neutralizing airborne pathogens, allergens, and toxic particles. The structural integrity and function of lung epithelial cells are thus indispensable to pulmonary health.

Damage or dysfunction of either bronchial or alveolar epithelial cells has been directly linked to the development and progression of several respiratory disorders. In chronic obstructive pulmonary disease (COPD), epithelial injury results in chronic inflammation, tissue remodeling, and airflow limitation [8]. In asthma, epithelial barrier breakdown facilitates allergen sensitization, airway hyperresponsiveness, and persistent inflammation [9]. In acute lung injury and its severe form, acute respiratory distress syndrome, alveolar epithelial cell death contributes to alveolar-capillary barrier disruption and impaired gas exchange [10]. Moreover, type II alveolar epithelial cells play a central role in pulmonary fibrosis by undergoing injury, apoptosis, and aberrant repair mechanisms that drive fibrotic remodeling [11]. Emerging evidence highlights ferroptosis as a critical mechanism of epithelial cell loss in these lung diseases. Iron overload, glutathione depletion, and oxidative stress – core elements of ferroptosis – have been consistently observed in experimental models and patient tissues of pulmonary disease. For instance, in COPD, cigarette smoke induces oxidative stress and iron accumulation that sensitizes bronchial epithelial cells to ferroptosis [4,8]. Similarly, in asthma, allergens such as house dust mites promote ferroptotic injury through lipid peroxidation pathways and dysregulated antioxidant defenses [9]. In pulmonary fibrosis, ferroptosis of alveolar type II cells has been shown to accelerate epithelial–mesenchymal transition (EMT) and extracellular matrix deposition [11].

Given the complexity and heterogeneity of pulmonary diseases, this review specifically focuses on the role of ferroptosis in bronchial and alveolar epithelial cells across benign (COPD, asthma, infection, fibrosis) and malignant (lung cancer) conditions. In this article, we aimed to review the role of epithelial cell ferroptosis in benign and malignant lung disease, highlighting current mechanistic insights and therapeutic opportunities related to this regulated cell death pathway.

Mechanism of Ferroptosis

IRON METABOLISM AND FERROPTOSIS:

Trivalent iron (Fe3+) must first be reduced to divalent iron (Fe2) in an acidic environment to enable binding to transferrin, the primary iron transport protein [13]. Among several iron uptake pathways, the transferrin–transferrin receptor 1 (TFR1) axis is particularly prominent [14,15]. Studies have shown that TFR1 knockdown mitigates ferroptosis triggered by erastin or cystine deprivation by reducing iron influx into cells [15,16]. As a result, TFR1 has been identified as a marker of ferroptosis sensitivity [17]. Ferritinophagy, a selective autophagic process, releases bioavailable iron from ferritin stores into the labile iron pool, thereby promoting ferroptosis [16,18]. This process is mediated by nuclear receptor coactivator 4 (NCOA4), an autophagic cargo receptor that transports ferritin to the autophagosome for degradation and iron release [19]. Inhibiting NCOA4 reduces lipid peroxidation and intracellular iron accumulation, thereby suppressing ferroptosis [20]. Iron export is mediated by solute carrier family 40 member 1, also known as ferroportin, IREG-1, or MTP-1 – the only known iron exporter in mammals [21]. Deficiency in ferroportin leads to intracellular iron accumulation and induces ferroptosis, underscoring its role in iron homeostasis [22]. Overall, the susceptibility to ferroptosis is governed by the balance of iron uptake, storage, utilization, and efflux.

LIPID PEROXIDATION IN FERROPTOSIS:

Polyunsaturated fatty acids (PUFAs), enriched in cellular membranes, are highly susceptible to peroxidation, due to their unstable double bonds, resulting in irreversible damage to cellular structures and function [23]. PUFA-containing phospholipids, especially phosphatidylethanolamines, are major substrates for lipid peroxidation and pivotal executors of ferroptosis [24,25]. Enzymes, such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3, are responsible for activating PUFAs and incorporating them into membrane phospholipids [26]. These enzymes are regarded as key positive regulators of ferroptosis [27,28]. Ferroptosis involves enzymatic and non-enzymatic lipid peroxidation mechanisms [29]. Iron-dependent lipoxygenases enzymatically catalyze PUFA peroxidation, producing phospholipid hydroperoxides [30,31]. However, the role of lipoxygenases enzymes is still debated, as their inhibition shows inconsistent effects on erastin- and RAS-selective lethal–induced ferroptosis [32,33]. Non-enzymatic peroxidation involves the Fenton reaction, in which Fe2+ reacts with hydrogen peroxide to form hydroxyl radicals, potent inducers of lipid peroxidation and ferroptosis [23].

The Defense Systems Against Ferroptosis

CYST(E)INE/GLUTATHIONE/GLUTATHIONE PEROXIDASE 4 SYSTEM:

This is the classical and most extensively studied defense pathway against ferroptosis [34]. The system Xc− antiporter, composed of the catalytic subunit SLC7A11 and the regulatory subunit SLC3A2, imports extracellular cystine in exchange for glutamate [35,36]. Once inside, cystine is reduced to cysteine, a precursor for glutathione synthesis [37,38]. Glutathione peroxidase 4 (GPX4) is a selenium-dependent enzyme that reduces phospholipid hydroperoxides to lipid alcohols, using glutathione as an electron donor [30,39]. This step is essential for preventing lipid ROS accumulation and maintaining membrane integrity [40].

NAD(P)H/FERROPTOSIS SUPPRESSOR PROTEIN 1/UBIQUINONE SYSTEM:

In GPX4-deficient settings, ferroptosis can still be suppressed via ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-dependent oxidoreductase [41]. FSP1 reduces ubiquinone (CoQ10) to ubiquinol, which traps lipid peroxyl radicals and halts lipid peroxidation. FSP1 also synergizes with α-tocopherol (vitamin E), enhancing antioxidant defense [42,43].

GTP CYCLOHYDROLASE 1/TETRAHYDROBIOPTERIN/DIHYDROFOLATE REDUCTASE SYSTEM:

A genome-wide CRISPR/dCas9 overexpression screen identified GTP cyclohydrolase 1 (GCH1) as a novel ferroptosis resistance gene [44]. GCH1 synthesizes tetrahydrobiopterin (BH4), a potent radical-trapping antioxidant, that inhibits lipid peroxidation. Although initially linked to CoQ10 regulation, BH4 also acts synergistically with α-tocopherol [44,46]. Dihydrofolate reductase (DFH2) regenerates BH4; inhibition of DFH2 (eg, with methotrexate) enhances ferroptosis, confirming its regulatory role [47].

DIHYDROOROTATE DEHYDROGENASE/COQ10 SYSTEM:

Dihydroorotate dehydrogenase (DHODH), located in the inner mitochondrial membrane, provides mitochondria-specific defense against ferroptosis [48]. In GPX4-deficient cancer cells, DHODH reduces CoQ10 to ubiquinol within mitochondria, independent of FSP1 [49]. This mechanism emphasizes the compartmentalized redox control in ferroptosis regulation. Figure 1 illustrates these 4 major ferroptosis defense mechanisms, each playing critical roles in modulating oxidative damage and preserving epithelial integrity under stress.

Ferroptosis of Lung Epithelial Cells in Pulmonary Diseases

PHYSIOLOGICAL STRUCTURE AND FUNCTIONS:

The lung epithelial cells cover the airways continuously and present diverse morphologies and functions at different anatomical sites [50]. The epithelial cells in the upper respiratory tract are pseudostratified columnar epithelial cells. They consist of various cells, including basal cells, ciliated cells, mucus-producing goblet cells, club cells, and neuroendocrine cells [51]. As the airway narrows, the epithelial structure transitions into columnar and eventually simple squamous forms, representing the monolayer of alveolar epithelial cells. Type I and type II alveolar epithelial cells are the 2 categories. Type I cells line most of the alveolar surface area and form a thin vapor-liquid barrier with endothelial cells, facilitating the exchange of oxygen and carbon dioxide. Type II cells synthesize and secrete pulmonary surfactant to prevent alveolar collapse, and they possess progenitor properties, enabling them to differentiate and restore the alveolar epithelium following injury [52,53]. All types of lung epithelial cells play essential roles in the development and progression of various lung diseases.

FERROPTOSIS OF LUNG EPITHELIAL CELLS IN DIFFERENT LUNG DISEASES:

Lung epithelial cells play a pivotal role in the defense against pulmonary diseases, through multiple coordinated mechanisms. They not only serve as a physical barrier against inhaled pathogens and particulates but also actively participate in host defense by producing antimicrobial peptides and chemotactic factors that recruit inflammatory cells. Additionally, they modulate adaptive immunity by secreting innate immune mediators, including cytokines and repellent factors, thereby orchestrating immune responses within the pulmonary microenvironment [51,54]. Beyond their immunological functions, lung epithelial cells contribute to the pathogenesis of various respiratory disorders via different mechanisms, such as oxidative stress [55], cellular senescence [56], EMT [57], and mitochondrial dysfunction [58]. Programmed cell death in lung epithelial cells – particularly apoptosis [59], pyroptosis [60], and ferroptosis [61] – has emerged as a critical determinant of disease progression in a wide range of pulmonary pathologies. Among these, ferroptosis, an iron-dependent form of regulated necrosis driven by lipid peroxidation, has garnered attention as a central mechanism in lung disease pathogenesis. In COPD, cigarette smoke induces ferroptotic death of bronchial epithelial cells, leading to structural airway damage. In asthma, exposure to interleukin-13 (IL-13) and house dust mite allergens promotes epithelial ferroptosis, amplifying airway inflammation. In infectious diseases, such as those caused by SARS-CoV-2 and Pseudomonas aeruginosa, ferroptosis of lung epithelial cells contributes to severe pulmonary injury. Moreover, in pulmonary fibrosis, agents such as transforming growth factor-beta (TGF-β) and silica trigger ferroptosis in alveolar epithelial cells, accelerating fibrotic remodeling. In lung cancer, ferroptosis plays a dual role, influencing tumor cell survival, therapy resistance, and responsiveness to radiotherapy (Figure 2).

FERROPTOSIS AND PULMONARY INFECTIONS:

Pulmonary infections caused by bacteria and viruses can induce severe injury to lung epithelial cells, with ferroptosis emerging as a pivotal mechanism in this process [62]. P. aeruginosa has been found to secrete a rare bacterial enzyme, arachidonate 15-lipoxygenase, which distinguishes it from most other pathogens [62]. Subsequent studies revealed that this enzyme oxidizes host arachidonoyl-phosphatidylethanolamine via the expression of lipoxygenase, thereby inducing ferroptosis in human bronchial epithelial cells [63]. Beyond this mechanism, P. aeruginosa was observed to induce ferroptosis through the chaperone-mediated autophagy lysosomal degradation pathway, suggesting multiple layers of pathogenic manipulation. In response, lung epithelial cells upregulate inducible nitric oxide synthase (iNOS) and produce nitric oxide (NO), which together confer resistance to ferroptosis, a defense mechanism that functions independently of GPX4. Interestingly, co-culture experiments demonstrated that when the GPX4/glutathione pathway is impaired, macrophages can protect epithelial cells from P. aeruginosa-induced ferroptosis, with iNOS/NO possibly acting as a parallel or distant signaling mechanism [64]. These findings underscore the importance of modulating epithelial anti-ferroptosis responses and enhancing immune–epithelial interactions as potential therapeutic avenues in targeting ferroptosis in lung infections.

COVID-19 disease, caused by SARS-CoV-2, emerged in late 2019 and rapidly spread across the globe [65], prompting the World Health Organization to declare it a pandemic on March 11, 2020 [66]. Its pathogenesis involves a complex interplay of immune dysregulation, including cytokine storms [67], coagulation disorders [68], iron metabolism abnormalities [69], and oxidative stress [70]. Recent research has shown that SARS-CoV-2 downregulates GPX4, a crucial ferroptosis inhibitor, thereby establishing a mechanistic link between ferroptosis and COVID-19 [71]. The virus enters host cells through its spike protein binding to the ACE2 receptor, which is abundantly expressed in lung epithelial cells, allowing high levels of viral replication [72,73]. Infected 16 human bronchial epithelial (16HBE) cells exhibit significantly increased ROS levels [74]. Hormonal studies have demonstrated that estrogen and growth hormone mitigate oxidative stress and slow the decline in malondialdehyde levels in BEAS-2B epithelial cells, whereas testosterone appears to exacerbate oxidative damage [75]. Furthermore, treatment with dimethyl fumarate, a known nuclear factor erythroid 2–related factor 2 (NRF2) activator, has been shown to alleviate alveolar epithelial cell injury in patients with COVID-19 [76]. Overall, while substantial evidence links ferroptosis with COVID-19 pathogenesis, the precise molecular pathways by which SARS-CoV-2 induces ferroptosis in lung epithelial cells remain incompletely understood, warranting further investigation.

FERROPTOSIS IN CHRONIC INFLAMMATORY LUNG DISEASES:

Chronic inflammatory lung diseases, such as COPD and bronchial asthma, are characterized by persistent or episodic airway inflammation, in which ferroptosis has emerged as a key contributor to epithelial damage and disease progression. In COPD, one of the leading causes of chronic respiratory morbidity and mortality worldwide, irreversible airflow limitation develops as a result of chronic exposure to harmful particles, most notably cigarette smoke, which disrupts epithelial integrity and alveolar structure [77,78]. Cigarette smoke-derived particulate matter impairs iron homeostasis, leading to excessive iron accumulation and oxidative stress in bronchial epithelial cells [79]. This cellular stress, in turn, promotes ferroptosis, particularly through NCOA4-mediated ferritinophagy that increases intracellular iron availability. The process is further modulated by GPX4, whose downregulation sensitizes cells to lipid peroxidation and ferroptotic death [80]. Ferroptosis in COPD is also influenced by the inflammatory milieu, in which macrophages play a central role. Increased expression of protein arginine methyltransferase 7 in macrophages leads to enhanced histone methylation and promotes the synthesis of leukotriene B4, a potent lipid mediator of inflammation. Leukotriene B4 then stimulates the expression of ACSL4 – a critical marker and effector of ferroptosis – in adjacent epithelial cells, rendering them more susceptible to ferroptotic injury [81]. Collectively, these findings suggest that ferroptosis acts as both an effector and amplifier of chronic epithelial injury in COPD, and that therapeutic interventions targeting ferroptosis-related pathways could potentially interrupt the cycle of inflammation and tissue degradation.

Similarly, in bronchial asthma, which is characterized by reversible airway obstruction and hyperresponsiveness, epithelial cell injury plays a central role in disease onset and exacerbation [82–84]. Damaged epithelial cells release a cascade of inflammatory mediators, including cytokines and chemokines, which initiate and sustain the recruitment of immune cells into the airway [85,86]. Recent studies have shown that ferroptosis contributes to epithelial dysfunction in asthma, particularly in models involving exposure to the house dust mite, a common environmental trigger. House dust mite–induced ferroptosis is mediated through NCOA4-driven iron autophagy and modulated by the ferritin heavy chain (FTH) [87,88]. Pro-inflammatory cytokines, such as IL-6, exacerbate this response by activating ferroptotic signaling cascades within the airway epithelium [89]. A key molecular driver in this context is the oxidation of polyunsaturated phosphatidylethanolamine by 15-lipoxygenase (15-LO), which is facilitated by its interaction with phosphatidylethanolamine-binding protein 1 (PEBP1). The formation of the PEBP1-15-LO complex enhances substrate specificity and leads to the accumulation of lipid peroxides, central to ferroptosis induction [90]. Additionally, PEBP1 has been shown to modulate the interplay between autophagy and ferroptosis in IL-13-stimulated hyperinflammatory asthma models using airway epithelial cells, highlighting its role as a regulatory node [91]. Disruption of the 15-LO-PEBP1-GPX4 axis exacerbates redox imbalance and intensifies type 2 inflammation, thereby embedding ferroptosis within the core pathophysiology of asthma [92]. These insights reveal that ferroptosis not only contributes to epithelial injury but also actively shapes the inflammatory landscape in chronic lung diseases, offering novel targets for therapeutic modulation.

FERROPTOSIS IN LUNG CANCER:

Lung cancer continues to be a major global health burden, being one of the most frequently diagnosed malignancies and a leading cause of cancer-related mortality. It is broadly classified into small cell lung cancer and non-small cell lung cancer (NSCLC) [93,94]. Most forms of lung cancer arise from epithelial origins, particularly from the bronchial and alveolar lining, and are closely associated with chronic oxidative stress, which induces DNA damage and drives malignant transformation [95]. Among the key pathological features of lung cancer is the EMT, a process that imparts enhanced motility, invasiveness, and therapeutic resistance to tumor cells [96]. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical regulator in cancer biology, exhibiting paradoxical roles. On one hand, ferroptosis limits tumor progression by inducing death in malignant cells; on the other hand, it can promote immune evasion and cancer cell survival under certain microenvironmental contexts [97–99]. In epithelial-derived cancers such as lung cancer, ferroptosis exerts notable anti-tumor effects by modulating EMT, drug resistance, and response to radiation therapy [100].

In lung adenocarcinoma and squamous cell carcinoma, studies have shown that the E3 ubiquitin ligase MIB1 is frequently upregulated, promoting EMT and simultaneously enhancing sensitivity to ferroptosis by targeting the NRF2 pathway for proteasomal degradation. This dual function suggests that tumors with elevated MIB1 expression may be more amenable to ferroptosis-based interventions [101]. Similarly, circSCN8A has been reported to act as a sponge for miR-1920, leading to upregulation of ACSL4, a key ferroptosis mediator. This cascade suppresses EMT and exerts potent anticancer activity in NSCLC models [102]. Furthermore, combinatorial treatment using falnidamol and cisplatin has demonstrated synergistic effects by promoting ferroptosis, inhibiting EMT, and reducing cellular proliferation in NSCLC, largely through downregulation of DUSP26 expression [103].

Ferroptosis also plays a pivotal role in overcoming therapeutic resistance, which is a persistent challenge in lung cancer management. For instance, the combination of betulin and gefitinib has been shown to reverse resistance in EGFR wild-type/KRAS-mutant NSCLC by inducing ferroptosis and suppressing EMT in A549 cells [104]. In another strategy to counter cisplatin resistance, the antitumor agent APR246 downregulates the NRF2/SLC7A11/glutathione pathway through post-ubiquitination degradation of NRF2, leading to ferroptotic cell death in otherwise resistant lung cancer populations [105].

Radioresistance is another major obstacle in the treatment of lung cancer, particularly for tumors that do not respond adequately to conventional radiotherapy. Induction of ferroptosis has shown promise in enhancing radiation-induced cytotoxicity in tumor cells [106,107]. In particular, lung cancer subtypes with Keap1 deficiency demonstrate increased resistance to radiation via upregulation of the ferroptosis inhibitor SLC7A11 [108]. Moreover, the activation of the GSTP1-Keap1-NRF2 feedback loop during radiotherapy further enhances SLC7A11 expression, limiting ferroptosis and perpetuating radioresistance [107]. In KEAP1-mutant lung cancer cells, FSP1 has been identified as a modulator of NRF2 transcription and plays a cooperative role in conferring resistance to ferroptosis and radiotherapy [109,110]. Collectively, these insights highlight the multifaceted roles of ferroptosis in lung cancer, not only in driving or suppressing EMT and overcoming drug resistance, but also in sensitizing tumors to radiation. Modulating ferroptotic pathways may thus offer a compelling strategy for improving the efficacy of current lung cancer therapies.

FERROPTOSIS IN LUNG INJURY:

Ferroptosis has emerged as a pivotal contributor to the pathogenesis of acute lung injury, an inflammatory condition characterized by disruption of both the pulmonary endothelial and epithelial barriers [111]. The alveolar-capillary interface is made up of the microvascular endothelium and the alveolar epithelium, both of which are vulnerable to oxidative and mechanical insults. The persistence of pulmonary edema, impaired epithelial regeneration, and subsequent progression to fibrosis are closely associated with epithelial injury, compromised barrier integrity, and inadequate repair mechanisms [112,113]. Moreover, dysregulated iron metabolism and excessive generation of ROS play integral roles in mediating oxidative damage during acute lung injury [114,115].

In studies involving intestinal ischemia/reperfusion–induced lung injury, ferroptosis has been mechanistically linked to pulmonary epithelial damage. The inhibitory role of iASPP in hypoxia/reoxygenation-induced ferroptosis in mouse lung epithelial (MLE)-2 cells was shown to operate through activation of the NRF2/HIF-1α/TF signaling pathway [116]. Targeting ferroptotic signaling in lung epithelial cells is therefore considered a viable therapeutic strategy in acute lung injury. Notably, iquiritin apioside was found to mitigate lung epithelial ferroptosis by modulating HIF-1α activity, thereby alleviating lung injury [117]. Furthermore, NRF2 activation has been demonstrated to suppress ferroptosis by modulating the STAT3/SLC7A11 axis under hypoxia/glucose deprivation-reoxygenation conditions in MLE-12 cells [118], and through upregulation of TERT and SLC7A11 expression [119].

Lipopolysaccharide-induced sepsis is another prominent model of acute lung injury in which ferroptosis plays a pathogenic role. Ferroptosis inhibition in this context has shown promising therapeutic effects [120]. Specifically, JMJD3 has been reported to protect against lipopolysaccharide-induced epithelial ferroptosis, and its targeted knockout in alveolar epithelial cells significantly attenuated acute lung injury by enhancing NRF2 expression [121]. Additionally, MLK3 expression is elevated in lipopolysaccharide-treated MLE-12 epithelial cells; its knockdown reduces epithelial damage by inhibiting p53-mediated ferroptotic signaling [122]. The volatile anesthetic sevoflurane, already known for its lung-protective properties, has been shown to exert anti-ferroptotic effects in BEAS-2B epithelial cells via upregulation of HO-1 [123]. Radiation-induced lung injury also involves ferroptotic processes. Inhibition of ferroptosis has been shown to attenuate radiation-induced lung injury, as demonstrated in A549 lung epithelial cells, in which the p62-KEAP1-NRF2 pathway conferred protection against lipid peroxidation and ferroptotic cell death [124,125]. Moreover, treatment with the HSP90 inhibitor NVP-AUY922 ameliorated ferroptosis in radiation-exposed BEAS-2B cells by suppressing autophagic degradation of the HSP90/CAM complex, further underscoring the interplay between stress-response pathways and ferroptosis regulation in lung injury [126].

FERROPTOSIS AND PULMONARY FIBROSIS:

Pulmonary fibrosis represents a progressive and often irreversible condition characterized by recurrent alveolar epithelial injury, proliferation of fibroblasts, and extensive extracellular matrix deposition. These pathological changes are triggered by a wide range of etiologies, including infections, mechanical injury, pharmaceuticals, autoimmune responses, and environmental exposures, ultimately resulting in aberrant lung remodeling and a gradual loss of pulmonary function [127]. Among the various pathological mechanisms, dysfunction and apoptosis of type II alveolar epithelial cells have been identified as critical initiators in the fibrotic cascade [128,129]. Elevated serum lipid peroxide concentrations have been observed in patients with idiopathic pulmonary fibrosis, correlating positively with iron–deferramine chelate complex levels, thus implicating iron-driven oxidative stress in disease pathogenesis [130].

Experimental models further substantiate this relationship. Bleomycin-induced lung fibrosis and genetically or chemically induced murine models of iron overload exhibit hallmark features of fibrotic inflammation, including heightened ROS production, epithelial cell loss, and deteriorated pulmonary mechanics. Notably, iron accumulation has been significantly elevated in idiopathic pulmonary fibrosis lung samples, compared with in non-fibrotic controls, with an inverse relationship to pulmonary function indices [131]. These findings highlight the mechanistic involvement of ferroptosis in pulmonary fibrosis.

Of particular interest is the role of EMT, a process by which epithelial cells acquire mesenchymal characteristics, facilitating fibrogenesis. The potent fibrogenic cytokine TGF-β induces EMT and myofibroblast differentiation in alveolar epithelial cells during fibrotic remodeling [133]. In murine models, alveolar epithelial ferroptosis is detected early in the course of bleomycin-induced fibrosis, suggesting its role in initiating and sustaining tissue injury [134]. In MLE-12 cells, treatment with erastin, a classical ferroptosis inducer, triggers intracellular iron accumulation, autophagic marker upregulation, and ROS generation, collectively driving EMT via autophagy-dependent ferroptotic mechanisms [130]. Epigenetic regulation also contributes to this interplay. The histone methyltransferase SETDB1 has been reported to inhibit ferroptosis in TGF-β-treated A549 epithelial cells by repressing Snail, a key transcription factor involved in EMT [135]. In contrast, the DNA methylation reader ubiquitin-like, containing PHD and RING finger domains, 1 (UHRF1) has been shown to promote ferroptosis in type II alveolar epithelial cells by downregulating key antioxidant proteins GPX4 and FSP1, thereby exacerbating epithelial vulnerability during fibrotic progression [136]. Additionally, exposure to silica has been found to induce ferroptosis-like features in HBE cells, indicating that environmental factors can also contribute to ferroptotic mechanisms in pulmonary fibrosis [137].

Treatment Approaches Targeting Ferroptosis in Lung Epithelial Cells

FERROPTOSIS INHIBITORS AND INDUCERS:

Ferrostatin-1 is a lipid peroxidation inhibitor that blocks erastin-induced ferroptosis [138]. Ferrostatin-1 reverses ferroptosis in BEAS-2B bronchial epithelial cells subjected to chronic intermittent hypoxia, thereby alleviating chronic intermittent hypoxia–induced lung injury [61]. In an IL-13-induced bronchial asthma model, ferrostatin-1 also ameliorated ferroptosis in BEAS-2B cells, suggesting a novel therapeutic approach for asthma. However, the specific molecular targets and detailed mechanisms of action in bronchial epithelial cells require further exploration [139]. Patients with cystic fibrosis are particularly vulnerable to P. aeruginosa infection, which triggers ferroptosis in human bronchial epithelium. In this context, ferrostatin-1 has shown potential to counteract ferroptosis and serve as a therapeutic option [140]. Liproxstatin-1 is another ferroptosis inhibitor. It reverses lipopolysaccharide- and IL-13-induced ferroptosis and inflammatory responses in the bronchial epithelial cells 16HBE and BEAS-2B [141]. Deferoxamine, an iron-chelating agent, has demonstrated efficacy in attenuating ferroptosis and mitochondrial dysfunction in bleomycin-exposed MLE-12 cells, suggesting its therapeutic potential in ferroptosis-related epithelial injury [129]. Other antioxidants, such as N-acetyl-L-cysteine, a ROS scavenger, also counteract ferroptosis in bronchial epithelial cells [89]. N-acetyl-L-cysteine has been shown to downregulate PM2.5-induced ferroptosis in primary mouse lung epithelial cells via the TGF-β signaling pathway [142]. On the contrary, erastin, a ferroptosis inducer, can be combined with gemcitabine to enhance its anti-lung cancer effect [143]. Sulfasalazine, another inducer, triggers ferroptosis by inhibiting the Xc− system, thereby impeding the proliferation of lung cancer cells [144].

NATURAL PRODUCTS:

Natural products are extensively used in the treatment of various diseases [145,146], and their regulatory role in ferroptosis has become a subject of increasing interest. With the integration of computational modeling and bioinformatic databases, the molecular mechanisms of these compounds are being progressively elucidated [147]. Recent evidence indicates that many naturally derived agents modulate ferroptosis, thus offering promising therapeutic potential in the context of lung diseases [148,149].

Realgar, a traditional mineral-based antioxidant, demonstrates anti-cancer activity in KRAS-mutated lung cancer through Raf pathway regulation and induction of ferroptosis [150]. Curcumin, a polyphenol from Curcuma longa, has shown broad anticancer effects [151]. When combined with autophagy inhibitors, such as chloroquine or siBeclin1, it promotes ferroptosis-induced autophagy, enhancing therapeutic efficacy in NSCLC models [152]. Additionally, curcumin mitigates cigarette smoke–induced lung epithelial damage by exerting anti-ferroptotic effects [153].

Ferulic acid, a plant-derived antioxidant, acts via the NRF2/HO-1 signaling axis to protect alveolar epithelial cells from ferroptosis in acute lung injury [154]. Resveratrol, abundantly found in fruits and vegetables [155], inhibits erastin-induced ferroptosis in BEAS-2B cells through modulation of the NRF2/Keap1 pathway [156], supporting its role in ameliorating various pulmonary conditions. Proanthocyanidins, flavonoids obtained from safflower [157], exhibit a wide range of biological activities, including antioxidant, anti-inflammatory, and antiviral effects [158]. They safeguard alveolar epithelial cells under inflammatory conditions [159] and have been shown to suppress ferroptosis in interferon-γ-induced acute lung injury models [160]. Dihydroquercetin, another potent flavonoid, reverses cigarette smoke–induced ferroptosis in HBE cells via NRF2 activation. Notably, this protective effect is nullified upon NRF2 inhibition with ML385 [161]. Furthermore, in silica-induced pulmonary fibrosis, dihydroquercetin alleviates ferroptosis in bronchial epithelial cells by downregulating the LC3/FTH1/NCOA4-mediated iron autophagy pathway, thereby exerting a protective anti-fibrotic effect [137]. Altogether, natural compounds exhibiting potent antioxidant and regulatory effects on ferroptosis represent attractive candidates for therapeutic development [162]. Nevertheless, the clinical translation of these agents necessitates standardized protocols for their extraction and characterization. Further research is also essential to unravel the precise molecular pathways through which these natural products modulate ferroptotic signaling in lung epithelial cells.

NANOMATERIALS:

Janus nanoparticles have emerged as advanced drug delivery tools, with significant interest in cancer therapy applications [163]. To overcome drug resistance in tumors, researchers have incorporated Fe3O4 into nanoparticles, producing FTG/L&SMD, which enhances iron deposition and induces ferroptosis via the Fenton reaction, thereby inhibiting tumor growth [164]. Smart nanoclusters demonstrate improved permeability and enhanced radiosensitization against lung cancer. Upon X-ray exposure, they trigger Fenton-driven hydroxyl radical production, thereby inducing ferroptosis and exerting anti-tumor effects [165]. To explore in vivo ferroptosis in type II alveolar epithelial cells during radiation-induced lung injury, researchers labeled the surfactant-associated protein C. Treatment with a bioengineered nanoreactor (SOD@ARA290-HBc) protected these alveolar epithelial type II cells from ferroptosis. This formulation reduced pulmonary fibrosis in mice after radiotherapy. Additionally, SOD@ARA290-HBc–pretreated A549 cells showed enhanced resistance to ferroptosis, indicating its therapeutic value for post-radiation pulmonary fibrosis [166].

Comparative Insights Across Lung Diseases

Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in the pathogenesis of a wide spectrum of lung diseases. Although the downstream outcomes of ferroptosis, namely lipid peroxidation, oxidative stress, and epithelial injury, are commonly observed across diseases, the upstream triggers, modulators, and associated cellular events vary depending on the pathological context [23,55]. By comparing the mechanisms of ferroptosis across conditions, such as COPD, asthma, pulmonary infections, acute lung injury, lung fibrosis, and lung cancer, it is possible to identify overlapping molecular pathways, diverging etiological factors, and converging therapeutic targets.

In COPD, ferroptosis is prominently induced by cigarette smoke, which causes iron accumulation and ROS generation in bronchial epithelial cells [77,78]. Key mediators include NCOA4-mediated ferritinophagy, leading to increased labile iron pools, and GPX4 downregulation, resulting in impaired antioxidant defense [20,21,137]. The chronic inflammatory environment, marked by macrophage infiltration and histone methylation-mediated upregulation of leukotriene B4, further amplifies epithelial sensitivity to ferroptosis through upregulation of ACSL4, a pro-ferroptotic enzyme [81]. These findings suggest that ferroptosis in COPD is driven by persistent exogenous insult (smoke exposure) and immune dysregulation.

In contrast, asthma involves a distinct immunological landscape in which ferroptosis is initiated by allergen exposure, particularly house dust mite allergens. Here, IL-13 plays a central role in initiating ferroptosis through oxidative stress and PEBP1-15-LO-mediated lipid peroxidation. This differs from COPD, in which iron handling is the major trigger [62,90]. Asthma also involves a unique interaction between ferroptosis and autophagy, modulated by PEBP1 [90,91]. The involvement of IL-6 and type 2 inflammatory cytokines further distinguishes the ferroptosis profile of asthma, emphasizing cytokine-mediated oxidative stress rather than particulate exposure or infection.

In pulmonary infections, bacterial and viral pathogens exploit ferroptosis to enhance epithelial damage and immune evasion. For example, P. aeruginosa secretes lipoxygenase that oxidizes host phosphatidylethanolamine lipids, directly inducing ferroptosis in bronchial epithelial cells. Simultaneously, the host attempts to counteract this via iNOS/NO-mediated resistance pathways [62–64], independent of GPX4, illustrating a host–pathogen arms race centered on ferroptosis regulation. Similarly, in SARS-CoV-2 infection, ferroptosis is triggered via spike protein–ACE2 interactions, subsequent ROS production, and GPX4 downregulation [64]. Hormonal regulation and NRF2 signaling have been implicated in ferroptosis modulation during COVID-19 [161], further distinguishing viral infection-induced ferroptosis from bacterial mechanisms.

In acute lung injury and acute respiratory distress syndrome, ferroptosis is often a result of systemic or local inflammation, sepsis, or ischemia/reperfusion injury. Unlike chronic diseases, acute lung injury is characterized by acute epithelial barrier disruption, and ferroptosis contributes to the propagation of alveolar damage and delayed resolution. Studies show that ferroptosis here is regulated by the NRF2/STAT3 and TERT/SLC7A11 pathways, and inhibition of ferroptosis via compounds such as ferrostatin-1 or HIF-1α stabilizers provides protection, emphasizing its role in acute oxidative and hypoxic injury. Compared with COPD and asthma, in which ferroptosis is chronic and progressive, acute lung injury features rapid onset and resolution with timely intervention [10,111].

In lung fibrosis, ferroptosis is intricately linked with EMT and autophagy [11]. Damage to type II alveolar epithelial cells, iron overload, and lipid peroxidation initiate EMT, resulting in fibroblast proliferation and extracellular matrix deposition. While similar markers, such as GPX4 and NCOA4, are involved in COPD, fibrosis additionally involves epigenetic regulators, such as SETDB1 and UHRF1, which modulate ferroptosis via transcriptional control of Snail and DNA methylation, respectively [130,135]. These findings underscore a more complex regulatory landscape in fibrosis that connects ferroptosis with tissue remodeling and repair failure.

Lung cancer presents a duality in ferroptosis, where it can suppress or promote tumor progression. Ferroptosis inhibits tumor proliferation by inducing oxidative death, but can also mediate immune evasion or resistance to therapy through upregulation of anti-ferroptotic mechanisms, such as SLC7A11 or FSP1 [41,43,108]. Moreover, EMT-associated changes in lung epithelial cells contribute to increased invasiveness and ferroptosis susceptibility [134]. This dual nature is unique among lung diseases and highlights the need for context-specific modulation of ferroptosis in cancer. Taken together, these comparative insights emphasize that although ferroptosis is a unifying mechanism of epithelial cell injury across lung diseases, its regulation is highly context-specific. Shared features, such as lipid peroxidation and GPX4 suppression, coexist with disease-specific triggers, such as allergens, infections, cigarette smoke, or radiation. Targeting ferroptosis in a disease-specific manner, either through inhibition or induction, can therefore yield novel therapeutic approaches tailored to the molecular pathology of each condition.

Future Perspectives

Despite substantial advances in our understanding of ferroptosis in lung epithelial cells, many gaps remain in translating this knowledge into clinical practice. Future research directions should prioritize the mechanistic elucidation of ferroptosis signaling across different lung pathologies, explore its interactions with other cell death pathways, and develop targeted interventions with therapeutic potential.

One critical area for future exploration is the temporal and spatial regulation of ferroptosis within the lung microenvironment. While many studies have identified ferroptosis markers at static time points, little is known about the dynamic changes in ferroptosis susceptibility during disease initiation, progression, and resolution. Longitudinal studies using animal models and patient-derived tissues could elucidate the stages at which ferroptosis is most detrimental – or beneficial – across diseases like acute lung injury, pulmonary fibrosis, and lung cancer. Moreover, spatial mapping of ferroptosis-related proteins and lipid peroxidation products across different epithelial compartments may help localize zones of epithelial vulnerability.

Another promising avenue is the interplay between ferroptosis and immune responses. The lung epithelium is closely involved in immunoregulation, and ferroptotic cell death can release damage-associated molecular patterns that modulate both the innate and adaptive immune responses. In infectious and inflammatory conditions, such as COVID-19, asthma, or sepsis-induced acute lung injury, understanding how ferroptosis influences cytokine production, immune cell recruitment, and resolution of inflammation will be pivotal. This could reveal therapeutic windows in which ferroptosis inhibition not only protects epithelial cells but also restores immune homeostasis.

Crosstalk between ferroptosis and other cell death modalities, including apoptosis, necroptosis, and pyroptosis, remains an underexplored but crucial aspect. Emerging evidence suggests that these pathways are not mutually exclusive and may operate in tandem or sequentially. Dissecting how ferroptosis integrates with these parallel mechanisms will help define the dominant death pathways in various pathological contexts and can guide combination therapies that target multiple routes of cell death.

On the translational front, drug development and repurposing efforts must be intensified. While inhibitors, such as ferrostatin-1 and liproxstatin-1, and inducers, such as erastin and sulfasalazine, have shown promise in vitro and in preclinical models, their pharmacokinetics, delivery efficiency, and toxicity profiles in humans remain largely unknown. This necessitates more robust pharmacological profiling, particularly in lung-targeted delivery systems. Nanotechnology, for example, offers an attractive platform to improve bioavailability and specificity of ferroptosis modulators. Engineered nanoparticles can deliver antioxidants or iron chelators directly to inflamed or tumor-affected lung tissues, as demonstrated in early animal studies. However, further clinical validation and regulatory assessment are required before these strategies can be implemented.

Another forward-looking strategy involves the use of biomarkers to monitor ferroptosis activity in patients. Biomarkers such as ACSL4, lipid peroxidation byproducts (eg, malondialdehyde, 4-HNE), and iron metabolism-related proteins (eg, TFR1, ferritin) could be integrated into diagnostic panels to stratify patients based on ferroptosis risk or to monitor treatment efficacy. Integration of multi-omics platforms, including transcriptomics, metabolomics, and lipidomics, could provide deeper insight into ferroptosis-associated molecular signatures, guiding diagnosis and personalized therapy. Finally, clinical trials targeting ferroptosis in lung diseases are urgently needed. While extensive evidence supports the relevance of ferroptosis in disease mechanisms, there is a lack of human trials evaluating ferroptosis-based therapies. Early-phase studies investigating the use of ferroptosis inhibitors in acute respiratory distress syndrome, or ferroptosis inducers in lung cancer, would be instrumental in translating benchside findings to bedside interventions. Moreover, patient stratification based on ferroptosis-related gene expression or oxidative stress profiles can optimize trial outcomes and therapeutic success. Collectively, ferroptosis stands at the intersection of oxidative biology, cell death, and pulmonary pathology. Continued multidisciplinary efforts integrating molecular biology, immunology, pharmacology, and clinical sciences will be key to unlocking the therapeutic potential of targeting ferroptosis in lung epithelial cells.

Conclusions

Ferroptosis has emerged as a central mechanism contributing to lung epithelial cell dysfunction across a broad spectrum of pulmonary diseases, including COPD, asthma, pulmonary infections, fibrosis, acute lung injury, and lung cancer. Its involvement in promoting oxidative stress, lipid peroxidation, and inflammatory responses underpins its pathological relevance, while its selective induction in malignancies offers a unique therapeutic opportunity. Targeting ferroptosis through small-molecule inhibitors, bioactive natural compounds, and nanotechnology-based delivery systems holds promise for disease-specific intervention. However, successful clinical translation demands a precise understanding of the context-dependent roles of ferroptosis and rigorous validation in disease models. Continued exploration of ferroptotic pathways in distinct lung epithelial cell types will not only enhance our comprehension of disease mechanisms but will also facilitate the development of novel, targeted treatment strategies.