Ferroptosis as an Emerging Therapeutic Target in Allergic Diseases

Abstract

Allergic diseases—including allergic asthma, allergic rhinitis, and atopic dermatitis—pose an escalating global health challenge. While traditionally viewed as type 2-driven disorders, many patients remain refractory to current therapies, highlighting the urgent need for novel mechanistic insights and therapeutic approaches. Emerging evidence implicates ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, in allergic pathogenesis. This review synthesizes current knowledge on ferroptosis in allergic diseases, emphasizing its context-dependent roles. In structural cells such as epithelial cells and keratinocytes, ferroptosis compromises barrier integrity, releases damage-associated molecular patterns (DAMPs), and propagates type 2 inflammation. Conversely, in immune cells—including eosinophils, T cells, and group 2 innate lymphoid cells (ILC2s)—dysregulated ferroptosis modulates survival and function, offering both pathogenic and therapeutic implications. Ferroptosis also influences IgE production through B-cell survival and class-switching, and emerging data suggest ferroptotic signals affect mast cell activation and IgE-mediated responses, linking this pathway to humoral allergic inflammation. We further discuss therapeutic strategies that either inhibit ferroptosis to preserve tissue barriers or induce ferroptosis to eliminate pathogenic immune cells. However, the clinical translation of ferroptosis-targeting approaches remains preliminary, with most evidence derived from experimental models, warranting cautious interpretation and rigorous validation. Collectively, ferroptosis represents a mechanistically distinct and promising therapeutic target in allergic diseases, though its clinical utility awaits confirmation. Strategic, context-specific modulation of this pathway holds potential to overcome current therapeutic limitations, particularly for severe, refractory, or non-type 2 endotypes.

Graphical Abstract

Introduction

Allergic diseases, including allergic asthma (AA), atopic dermatitis (AD), allergic rhinitis (AR), and food allergies, represent a global health burden of immense proportion.1,2 Their pathogenesis is traditionally attributed to type 2 immune responses, characterized by the dysregulation of T helper 2 (Th2) cells, elevated immunoglobulin E (IgE) production, and the activity of key effector cells like mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s).3–7 This paradigm has yielded mainstream therapies: corticosteroids, antihistamines, leukotriene antagonists, and cytokine-targeted biologics. However, despite these advances, a substantial subset of patients—particularly those with severe disease—remain symptomatic, experiencing recurrent exacerbations, progressive loss of lung function, and impaired quality of life. For these individuals, even maximal guideline-directed therapy often fails to achieve disease control. Furthermore, non-type 2 endotypes in severe asthma highlight allergic disease heterogeneity, calling for novel pathways beyond canonical type 2 inflammation.8,9 The clinical challenge is compounded by the lack of effective therapies for these non-type 2 phenotypes, leaving a large patient population with few treatment options and an urgent unmet medical need.

Recently, the role of regulated cell death (RCD) in regulating immune responses and tissue homeostasis has attracted substantial attention. Beyond canonical apoptosis, other RCD forms including necroptosis, pyroptosis and ferroptosis are established as active drivers of inflammation and disease progression.10 Importantly, these RCD modalities differ fundamentally in their triggers, molecular executioners, morphological hallmarks, and immunological consequences. Apoptosis, a caspase-dependent process, is characterized by cell shrinkage, membrane blebbing, and formation of apoptotic bodies without content leakage, typically eliciting tolerogenic or non-inflammatory responses.11 In contrast, necroptosis is executed by receptor -interacting protein kinase 3 (RIPK3)-mediated phosphorylation of mixed lineage kinase domain-like protein (MLKL), which disrupts plasma membrane integrity, leading to uncontrolled release of DAMPs and robust pro-inflammatory signaling.12 Pyroptosis, driven by inflammatory caspases (caspase-1/4/5/11) that cleave gasdermin D (GSDMD) to form membrane pores, likewise promotes intense inflammation through secretion of IL-1β and IL-18, and is critically involved in antimicrobial host defense and autoinflammatory conditions.13 In allergic diseases, each of these pathways has been implicated through distinct mechanisms: apoptosis contributes to the clearance of eosinophils and T-cell homeostasis; necroptosis, mediated by receptor-interacting protein kinases and mixed lineage kinase domain-like protein, has been linked to epithelial damage and airway remodeling; and pyroptosis, driven by inflammasome activation and gasdermin-dependent pore formation, amplifies IL-1β/IL-18 release from mast cells and macrophages. However, the relative contribution of these pathways, and their potential crosstalk, remain poorly defined.

Ferroptosis is defined as an iron-dependent form of regulated cell death driven by the lethal accumulation of lipid peroxides on cellular membranes, particularly those rich in polyunsaturated fatty acids (PUFAs).14 Its execution is distinct from other RCD morphologically, biochemically, and genetically from apoptosis, necroptosis and pyroptosis.14,15 Among these non-apoptotic pathways, ferroptosis is particularly compelling for allergic diseases for several reasons.16 First, allergic inflammation is inherently associated with oxidative stress, iron dysregulation, and lipid peroxidation—conditions that directly lower the threshold for ferroptotic execution.16,17 Second, unlike necroptosis and pyroptosis, which are primarily driven by receptor-interacting protein kinases or inflammasome-dependent caspases and often lead to massive pro -inflammatory cytokine release, ferroptosis is metabolically coupled to the cellular antioxidant and iron-handling systems that are known to be altered in allergic tissues.16,18 Third, the ferroptotic machinery—particularly the GPX4-glutathione axis and the lipid peroxidation enzymes such as arachidonate 15-lipoxygenase (ALOX15)—has been directly linked to epithelial barrier disruption and type 2 immune amplification, whereas the involvement of necroptosis and pyroptosis in allergic diseases remains less well established and more circumstantial.19–21 Thus, targeting ferroptosis offers a unique opportunity to intervene at the intersection of metabolic vulnerability, oxidative damage, and immune dysregulation, potentially addressing pathogenic mechanisms that are not covered by existing anti-type 2 or anti-inflammatory strategies.

Eosinophils, as key effector cells in allergic inflammation, exhibit a particularly intricate relationship with ferroptosis. While ferroptosis in structural cells such as airway epithelial cells drives barrier disruption and amplifies type 2 inflammation, the induction of ferroptosis in eosinophils presents a paradoxical therapeutic opportunity.22,23 Ferroptosis-inducing agents (FINs), including erastin, RSL3, and artesunate, trigger a non-canonical form of ferroptosis in eosinophils that is iron-dependent and characterized by cytosolic ROS accumulation, yet operates independently of classical lipid peroxidation.22,23 This ferroptosis-like cell death is effectively attenuated by antioxidants such as glutathione and N-acetylcysteine, and importantly, FINs exert synergistic effects with glucocorticoids—enhancing eosinophil clearance and alleviating allergic airway inflammation while potentially allowing reduced steroid doses.22,23 Furthermore, eosinophil-derived mediators such as major basic protein (MBP) can promote ferroptosis in neighboring airway epithelial cells through the mTORC1/PBX1/GABARAPL1 axis, demonstrating that eosinophils are not merely targets of ferroptosis but also active drivers of ferroptotic tissue damage in the allergic microenvironment.24 Thus, the interplay between IgE, eosinophils, and ferroptosis represents a critical mechanistic axis in allergic disease pathogenesis—one that offers both a deeper understanding of disease mechanisms and novel therapeutic opportunities through the strategic modulation of ferroptosis in a cell-type-specific manner.

The core regulatory machinery of ferroptosis revolves around the delicate balance between lipid peroxidation and its suppression. The glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis is the primary defensive system. Depletion of GSH or inhibition of GPX4 is a canonical trigger for ferroptosis.25 Pro-ferroptotically, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) are key to PUFA incorporation.26,27 This peroxidation is catalyzed by reactive oxygen species (ROS) in an iron-dependent manner, primarily via Fenton chemistry. Consequently, cellular iron metabolism, regulated by key proteins including transferrin receptor 1, ferroportin and ferritin, is intrinsically linked to ferroptotic sensitivity.28

The intersection between ferroptosis and inflammatory diseases, including allergic disorders, is becoming increasingly apparent.29 Allergic inflammation triggers oxidative stress, metabolic reprogramming and tissue damage, predisposing cells to ferroptosis. Emerging evidence shows ferroptosis acts not as a bystander but as an active driver of allergic diseases. In asthma, HDM and OVA induce ferroptotic features in airway epithelia: GSH depletion, GPX4 downregulation and lipid peroxide accumulation.30,31 In AD, ferroptosis has been implicated in keratinocyte death, leading to barrier dysfunction, and in the modulation of immune cell activity.32 This mechanistic link opens a promising therapeutic avenue. Targeting ferroptosis entails a dual strategy: protecting vulnerable cells via inhibition or eliminating pathogenic immune cells via induction. Numerous ferroptosis modulators, including inhibitors and iron chelators, are available.33

Given that the current evidence derives predominantly from preclinical models—including cell-based systems and rodent allergen challenge studies—with limited but emerging translational data from human biospecimens and bioinformatic analyses, this review aims to synthesize the rapidly evolving evidence linking ferroptosis to the pathophysiology of major allergic diseases. We will examine the molecular evidence connecting ferroptosis to key allergic manifestations across organ systems. Furthermore, we will critically evaluate the therapeutic potential of ferroptosis modulators, including promising preclinical findings and clinical translation challenges. Bridging fundamental cell biology and clinical allergology, we posit that targeting ferroptosis may offer a novel, mechanistically grounded therapeutic option for allergic diseases, particularly for refractory or non-type-2 variants, though this potential remains to be tested in clinical settings.

Ferroptosis

Ferroptosis, a non-apoptotic form of regulated cell death driven by iron-dependent lipid peroxidation (LPO), was discovered and named in 2012.14,34,35 As a non-apoptotic cell death modality, it is defined by three cardinal features: iron-catalyzed LPO, glutathione (GSH) depletion, and impaired cystine import.14,36 The initial discovery that certain small-molecule anti-cancer agents, notably erastin, trigger ferroptosis prompted the development of specific inhibitors such as ferrostatin-1 and liproxstatin-1.14 These pharmacological tools enabled the unambiguous identification of key molecular regulators, including glutathione peroxidase 4 (GPX4) and the system x_c⁻ cystine/glutamate antiporter, thereby defining core ferroptotic pathways.37–39 The initiation of ferroptosis requires the synergistic action of three essential components: the synthesis of oxidated lipids, reactive oxygen species (ROS), and the activity LPOs.40–43 Through Fenton reactions, iron catalyzes the production of reactive oxygen species (ROS).44,45 And the enzymatic propagation of lipid peroxidation by lipoxygenases culminates in the accumulation of deadly LPOs that execute ferroptotic cell death43,46 (Figure 1). The imbalance between the pro ferroptosis (oxidation) system and the anti ferroptosis (antioxidant) system can lead to the accumulation of lethal lipid peroxides (known as lipid hydroperoxides), which can accumulate on the cell membrane, disrupt membrane integrity, and cause fatal cell lysis.47–50

Figure 1.

The ferroptosis signaling cascade.

Metabolic Prerequisites for Ferroptosis

Iron-mediated Fenton reaction, synthesis and peroxidation of phospholipids containing polyunsaturated fatty acids (PUFA-PLs), and mitochondrial metabolism are the main prerequisites for iron death.41,45,49,51 Specifically, the accumulation of redox active iron drives the generation of lipid free radicals, while the esterification mediated by ACSL4-LPCAT3 and the incorporation of polyunsaturated fatty acids into membrane phospholipids provide oxidizable substrates for the propagation of lipid peroxidation.27,41,52–54 Meanwhile, mitochondria produce ROS through the tricarboxylic acid cycle and electron transfer chain, and provides coenzyme Q10 to fuel the FSP1 defense system against ferroptosis, thus playing a dual role.47,51,55 These interrelated prerequisites converge on a set of core defense pathways - most notably the GPX4-GSH, FSP1-CoQ10, and DHODH systems which collectively control the cell threshold for lethal lipid peroxidation and ferroptosis.39,55,56

Iron-Dependent Phospholipid Peroxidation

Ferroptosis is executed by phospholipid peroxidation, which critically depends on polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), redox-active iron, and ROS.37,53,56,57 The accumulation of peroxidised PUFA-PLs constitutes the central lethal event driving ferroptosis. Lipid peroxidation proceeds via both enzymatic and non-enzymatic pathways and follows the classical chain reaction of initiation, propagation, and termination.53,57,58 Initiation involves iron-catalysed Fenton chemistry generating hydroxyl radicals that abstract hydrogen from PUFA bis-allylic carbons, or direct enzymatic radical production.46,58 Propagation amplifies lipid peroxyl radicals, which attack neighbouring PUFA chains. Termination occurs through radical coupling or quenching by radical-trapping antioxidants. The availability of oxidation-prone PUFA-PLs is governed by ACSL4 and LPCAT3, which sequentially activate and esterify PUFAs into membrane phospholipids.27,53,58,59 Multiple enzymatic systems generate the oxidants that fuel this process: lipoxygenases, particularly 12/15-LOX (ALOX15), directly oxygenate PUFA-PLs.46,60 POR and CYB5R1 utilise NADPH to produce H₂O₂ for iron-dependent initiation at the endoplasmic reticulum.61 NOX enzymes contribute superoxide at the plasma membrane.62 Mitochondria additionally generate substantial ROS via the tricarboxylic acid cycle and electron transport chain, thereby promoting lipid peroxidatio.63 Ultimately, the iron–lipid interplay yields PUFA-PL hydroperoxides (PUFA-PL-OOH) whose decomposition generates reactive aldehydes such as 4-HNE and MDA that propagate membrane damage and execute ferroptosis.64,65

Iron in Ferroptosis

Iron-dependent lipid peroxidation occurs through two interrelated mechanisms: the non-enzymatic Fenton reaction and the activation of iron-containing enzymes, ultimately leading to ferroptosis.60,66 In the pathway driven by the Fenton reaction, ferrous ions (Fe²⁺) reduce hydrogen peroxide to generate hydroxyl radicals (HO•), which initiate lipid peroxidation by abstracting diene-allyl hydrogen from the polyunsaturated fatty acyl chains of membrane phospholipids.67–69 The resulting carbon-centered lipid radicals rapidly trap molecular oxygen, producing lipid peroxyl radicals that subsequently form phospholipid hydroperoxides (PUFA-PL-OOH).70,71 These hydroperoxides are inherently unstable in the presence of labile iron, undergoing reductive cleavage to regenerate alkoxyl radicals that attack neighboring acyl chains, thereby propagating the peroxidative cascade across the lipid bilayer.43,72 This self-amplifying chain reaction underscores why the cellular labile iron pool acts as a rheostat for ferroptotic sensitivity: processes that expand this pool - such as transferrin receptor-mediated iron uptake, inactivation of the iron exporter ferroportin, or NCOA4-dependent autophagic degradation of ferritin - lower the threshold for ferroptosis execution.73–75

Beyond its direct participation in the Fenton reaction, the intracellular labile iron pool also fuels ferroptosis by serving as an obligate cofactor for a subset of dioxygenases that catalyze the enzymatic oxygenation of membrane phospholipids.76 In this pathway, the acyl-CoA synthetase ACSL4 first ligates free polyunsaturated fatty acids with coenzyme A to generate PUFA-CoA thioesters.27,76 These activated intermediates are then re-esterified into phospholipids by LPCAT3, thereby enriching cellular membranes with peroxidation-competent substrates.59,76 Iron-dependent enzymes - most notably arachidonate lipoxygenases (ALOXs) and cytochrome P450 oxidoreductase (POR) - subsequently catalyze the stereospecific insertion of molecular oxygen into the esterified PUFA chains, producing phospholipid hydroperoxides in a regulated, spatially restricted manner.77–79 The enzymatic and Fenton-driven pathways converge on a common pool of phospholipid hydroperoxides. Within this pool, labile iron sustains repeated redox cycling of the hydroperoxides, thereby propagating lipid radical chain reactions and amplifying peroxidative damage. When the accumulated lipid peroxide burden exceeds the reducing capacity of the GPX4-GSH and FSP1-CoQ10 defense systems, irreversible membrane disruption occurs and ferroptotic cell death is executed. Iron thus contributes to ferroptosis at two distinct yet interconnected levels: first, by triggering lipid peroxidation through Fenton chemistry, and second, by accelerating the process as an essential cofactor for peroxidases, which establishes cellular iron metabolism as a principal determinant of ferroptotic sensitivity.55,60,61,72,80

Anti-Ferroptotic Defense Network

Ferroptosis represents an iron-dependent, oxidative cell death program executed by uncontrolled phospholipid peroxidation. To counter this lethal process, cells have evolved a multilayered, functionally redundant inhibitory network. These systems are not merely scavengers but are organized into distinct modules—enzymatic cascades, metabolite-dependent radical quenching pathways, and membrane remodeling processes—each intersecting with lipid, iron, and redox metabolism.55,56,81 Their collective goal is to intercept both initiating radical species and propagating lipid hydroperoxides before irreversible membrane collapse occurs. A defining characteristic of this defense network is its spatial organization: some arms operate in the cytosol, while others are confined to specific organelles, ensuring compartment-specific protection.55,56,82,83 The existence of GPX4-dependent and GPX4-independent surveillance mechanisms further illustrates the biological necessity of safeguarding cellular membranes against oxidative injury. This integrated network dynamically adjusts ferroptotic thresholds in response to metabolic demands, differentiation states, and extracellular cues, underscoring the principle that multiple fail-safe layers are essential for maintaining membrane integrity in an iron- and oxygen-rich environment.84,85

The GPX4–GSH Antioxidant Axis

The principal enzymatic barrier against phospholipid autoxidation is provided by the selenoprotein GPX4.86 GPX4 catalyzes the two-electron reduction of phospholipid hydroperoxides to their corresponding alcohols, using reduced GSH as an electron donor, effectively breaking the lipid radical chain at the propagation step. The catalytic cycle depends on a continuous supply of GSH, which requires cystine import via the system Xc⁻ antiporter, composed of SLC7A11 and SLC3A2.39,42,86,87 Distinct cytosolic and mitochondrial GPX4 isoforms ensure spatially confined peroxide detoxification.88 The cytosolic isoform predominantly protects extramitochondrial membranes, while the mitochondrial isoform safeguards respiratory chain components.56,89 Notably, GPX4 synthesis requires selenium in the form of selenocysteine, an unusual amino acid decoded from a UGA codon by dedicated insertion machinery, linking dietary trace element availability to ferroptosis resistance.90,91 GPX4 thus constitutes the primary, high-capacity enzymatic reductase that directly detoxifies phospholipid hydroperoxides, positioning the GSH–GPX4 axis as the frontline defense against ferroptotic membrane damage.

The FSP1–CoQH₂ Membrane Defense System

Parallel to GPX4, ferroptosis suppressor protein 1 (FSP1) provides an orthogonal defense mechanism that functions independently of the glutathione system.85,92,93 N-terminal myristoylation irreversibly anchors FSP1 to the inner leaflet of the plasma membrane, where it acts as an NAD(P)H-dependent oxidoreductase that reduces coenzyme Q₁₀ (CoQ) to ubiquinol (CoQH₂).55 Ubiquinol donates a hydrogen atom to phospholipid peroxyl radicals, terminating chain reactions directly within the lipid bilayer.93 Beyond radical quenching, FSP1 has been implicated in coordinating the ESCRT-III membrane repair machinery to sites of peroxidative damage, enabling physical restoration of membrane domains.48,94 The therapeutic relevance of this pathway is underscored by the development of specific FSP1 inhibitors, such as iFSP1, which sensitize cancer cells to ferroptosis-inducing agents.95 By operating independently of glutathione and anchoring directly to the plasma membrane, FSP1 provides a spatially confined backup system that sustains ferroptosis resistance when the GPX4–GSH pathway is compromised or overwhelmed.

The GCH1–BH4 Dual-Function Defense Module

A distinct GPX4-independent protective route is orchestrated by GTP cyclohydrolase 1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis.81 BH4 acts as a potent radical-trapping antioxidant, competing with phospholipids for peroxyl radicals and thereby diverting oxidative damage away from membrane lipids.96 Simultaneously, GCH1 activation induces lipid remodeling that preferentially enriches monounsaturated fatty acyl chains in cellular membranes while depleting polyunsaturated species, reducing the density of peroxidation-accessible bis-allylic carbons.81,96 The coordinated action of direct radical quenching and substrate limitation positions the GCH1–BH4 pathway as a versatile, tunable defense layer capable of adapting to varying oxidative challenges.81,96,97 Thus, the GCH1–BH4 module thus exemplifies a dual-function defense strategy: it couples direct radical scavenging with substrate-level lipid remodeling, offering a tunable layer of protection that complements the more specialized GPX4- and FSP1-dependent systems.

The DHODH–CoQH₂ Mitochondrial Defense Pathway

Within the mitochondrial inner membrane, dihydroorotate dehydrogenase (DHODH) provides organelle-autonomous ferroptosis protection.56 DHODH, an essential enzyme in de novo pyrimidine biosynthesis, couples the oxidation of dihydroorotate to orotate with the reduction of ubiquinone to ubiquinol, creating a local reservoir of radical-trapping antioxidant within the mitochondrial compartment.56,98 The functional significance of this pathway becomes evident when cytosolic anti-ferroptotic systems are compromised: in cells with low GPX4 expression, DHODH activity is critical for preventing mitochondrial lipid peroxidation and ferroptosis execution.56,99 This organelle-level compensation illustrates a broader design principle wherein intermediary metabolism is directly coupled to cellular defense, transforming a biosynthetic enzyme into a guardian of mitochondrial integrity.56,100 DHODH therefore represents an organelle-autonomous defense mechanism that couples pyrimidine biosynthesis to ubiquinol production, safeguarding the mitochondrial inner membrane against lipid peroxidation independently of the cytosolic anti-ferroptotic machinery.

MBOAT1/2-Mediated Membrane Lipid Remodeling

An additional layer of ferroptosis protection resides in the enzymatic restructuring of the cellular phospholipid pool by the acyltransferases MBOAT1 and MBOAT2. These membrane-bound enzymes catalyze the transfer of monounsaturated fatty acyl chains into lysophosphatidylethanolamine, displacing oxidation-prone polyunsaturated species and thereby reducing the density of bis-allylic carbon atoms in cellular membranes.101 MBOAT1 and MBOAT2 exhibit tissue-specific expression governed by sex hormone receptors. MBOAT1 is activated by the estrogen receptor, while MBOAT2 is controlled by the androgen receptor which introduces a sex-dependent rheostat for ferroptosis susceptibility.101,102 Importantly, this lipid remodeling pathway operates independently of GPX4 and FSP1, providing a backup defense mechanism when canonical antioxidant systems are overwhelmed. MBOAT1 and MBOAT2 thus execute a pre-emptive defense strategy: by reducing the abundance of oxidizable phospholipid substrates at the membrane level, they diminish ferroptosis susceptibility before lipid peroxidation can be initiated, independently of the canonical GPX4 and FSP1 systems.

7-Dehydrocholesterol as a Metabolic Ferroptosis Barrier

The most recently identified ferroptosis defense system involves the cholesterol biosynthetic intermediate 7-dehydrocholesterol (7-DHC), generated by lathosterol oxidase (SC5D).103 7-DHC contains a conjugated 5,7-diene moiety that makes it highly susceptible to oxidation, enabling it to act as a sacrificial radical trap at the plasma membrane, mitochondria, and endoplasmic reticulum.104 This peroxidation-shielding mechanism redirects oxidative damage away from phospholipids, protecting multiple organellar compartments from lipid peroxide propagation. Genetic or pharmacological blockade of SC5D leads to 7-DHC depletion and sensitizes cells to ferroptosis, while supplementation with exogenous 7-DHC rescues viability.103,104 This discovery illustrates how intermediates of central carbon metabolism can be co-opted as non-enzymatic ferroptosis barriers, and suggests that perturbations in cholesterol metabolism may have unintended consequences on ferroptosis susceptibility. 7-DHC thus functions as a non-enzymatic, metabolite-level radical sink distributed across multiple organellar membranes, adding a final, evolutionarily conserved layer to the ferroptosis defense repertoire that operates through direct radical trapping rather than enzymatic catalysis.

Collectively, these defense modules form a robust, hierarchically organized network. The GPX4–GSH pathway provides the primary enzymatic capacity for peroxide reduction, while the FSP1–ubiquinol and GCH1–BH4 systems serve as independent backups at the plasma membrane, each relying on distinct cofactors and metabolic inputs. Organelle-autonomous protection is conferred by DHODH within mitochondria and by 7-DHC across multiple subcellular sites, whereas MBOAT1/2-mediated phospholipid remodeling pre-emptively lowers the oxidizable substrate load. The relative contribution of each pathway varies considerably with cell lineage, metabolic context, and the nature of the ferroptotic stimulus. Understanding how these surveillance systems are transcriptionally coordinated, post-translationally tuned, and metabolically integrated will be essential for illuminating ferroptosis in disease pathogenesis and developing rational strategies to modulate ferroptotic thresholds for therapeutic benefit.

Role of Ferroptosis in the Pathogenesis of Allergic Diseases

Emerging evidence highlights ferroptosis as a critical pathogenic mechanism across various allergic disorders. In conditions such as allergic rhinitis, asthma, and atopic dermatitis, dysregulated ferroptosis disrupts epithelial barrier integrity, amplifies oxidative stress and inflammation, and modulates immune cell survival and function. This section systematically examines how ferroptosis contributes to the initiation and progression of allergic diseases through distinct yet interconnected pathways, offering insights into its role as both a driver of tissue damage and a potential therapeutic target.

Role of Ferroptosis in the Pathogenesis of Allergic Rhinitis

Emerging research solidifies ferroptosis as a driver in the pathogenesis of allergic rhinitis (AR), primarily by compromising nasal epithelial barrier integrity and amplifying local inflammatory responses (Figure 2). The implicated mechanisms converge on iron dysregulation, lipid peroxidation (LPO), and oxidative stress, though they are initiated by diverse upstream signals. A foundational study demonstrated that environmental exposure to PM2.5 induces acute nasal epithelial injury via an AMPK-mediated autophagic pathway that subsequently triggers ferroptosis.105 This process is characterized by oxidative stress, labile iron accumulation, LPO, and downregulation of key anti-ferroptotic proteins (xCT, GPX4, FTH1, FTL). The causal role of ferroptosis was confirmed by the protective effects of inhibitors Fer-1 and DFO, both in vitro and in vivo, where they mitigated epithelial inflammation, mucus hypersecretion, and pro-inflammatory cytokine release (IL-1β, IL-6, TNF-α).105 This establishes a direct link between a common environmental pollutant and ferroptosis-dependent epithelial damage, which likely facilitates allergen sensitization and penetration.

Figure 2.

Proposed molecular mechanisms of type 2 inflammation and epithelial barrier dysfunction. PM2.5 and allergens promote Th2 cell activation and the release of IL-4, IL-5, and IL-13. IL-13 upregulates FABP4, which in turn enhances the expression of ACSL4 and TFR1, thereby promoting polyunsaturated fatty acid (PUFA) metabolism and iron uptake, ultimately leading to lipid peroxidation and ferroptosis. Simultaneously, PM2.5 increases ROS levels and the AMP/ATP ratio, inhibits mTORC1, and activates AMPK/ULK1-mediated excessive autophagy. Autophagy-dependent degradation of FTH1 and FTL elevates the labile Fe²⁺ pool, further promoting ferroptosis. METTL3-mediated m⁶A modification stabilizes PTBP1, which downregulates TXNIP and reduces antioxidant defenses (including SOD2, Prx, and GPX4), thereby exacerbating oxidative stress. Ferroptosis and ROS release damage-associated molecular patterns (DAMPs), which activate the NLRP3 inflammasome and trigger the secretion of IL-18, IL-6, and TNF-α. Epithelial barrier integrity is compromised through downregulation of ZO-1, occludin, and claudin-1. IL-13 also induces overproduction of the mucin MUC5AC in goblet cells, resulting in mucus hypersecretion. Collectively, these processes sustain a type 2 inflammatory cycle involving eosinophils, B cells, IgE, mast cells, and Th2 cytokines, thereby driving airway hyperresponsiveness and remodeling.

Building on this finding that cytokines are central to AR pathology, another investigation delineated a specific mechanism by which the key type 2 cytokine IL-13 promotes ferroptosis. It was shown that IL-13 stimulation upregulates fatty acid-binding protein 4 (FABP4) in human nasal epithelial cells, which in turn drives a ferroptotic cascade evidenced by increased lipid ROS, iron levels, ACSL4 and TFR1 upregulation, and suppression of xCT, GPX4, and FTH1.19 Crucially, FABP4 knockdown reversed these ferroptotic markers and concurrently alleviated IL-13-induced inflammatory mediator release, mucin MUC5AC overproduction, and tight junction disruption. The reversal of FABP4’s protective effects by the ferroptosis inducer erastin confirmed ferroptosis as the essential mechanistic link through which FABP4 regulates allergic pathology.19

Extending beyond protein-level regulation, a third line of research revealed an epigenetic layer controlling ferroptosis in AR. This study identified that the methyltransferase METTL3 exacerbates AR by catalyzing m6A modification on PTBP1 mRNA, enhancing its stability.106 Elevated PTBP1 upregulates TXNIP, a regulator of oxidative stress, culminating in ferroptotic cell death within the nasal mucosa. This axis correlated with reduced GPX4 and MnSOD, increased ACSL4, MDA, and ROS in AR models.106 Silencing METTL3 or pharmacologically inhibiting ferroptosis with ferrostatin-1 alleviated these changes and AR symptoms, demonstrating that METTL3-mediated m⁶A modification is a key upstream regulator of ferroptosis in this context.106

In summary, ferroptosis contributes to AR pathogenesis through interconnected pathways initiated by environmental triggers (PM2.5 via AMPK-autophagy),105 dysregulated cytokine signaling (IL-13 via FABP4),19 and epigenetic modifications (METTL3-m6A-PTBP1-TXNIP).106 The common terminal pathway involves iron overload, glutathione depletion, GPX4 downregulation, and lethal LPO, leading to nasal epithelial cell death, barrier dysfunction, and the amplification of a type 2 inflammatory microenvironment. These collective findings position the ferroptosis pathway and its regulators as promising diagnostic and therapeutic targets for allergic rhinitis.

Role of Ferroptosis in the Pathogenesis of Allergic Asthma

The pathogenesis of allergic asthma, a complex chronic inflammatory airway disease, has traditionally centred on dysregulated type 2 immunity. However, emerging evidence positions ferroptosis as a pathogenic driver through multiple converging molecular and cellular mechanisms. At the core, ferroptosis in asthma is precipitated by a three-layered disruption: (i) depletion of the glutathione-GPX4 antioxidant axis, (ii) iron overload and dysregulated ferritinophagy, and (iii) enzymatic lipid peroxidation, notably via the 15-LOX1/ALOX15 pathway. These interrelated processes are amplified by cytokines (IL-6, IL-13, IL-17A), environmental pollutants (PM2.5, dibutyl phthalate), and epigenetic modifiers (METTL3, ALKBH5), all of which converge on epithelial barrier injury and the release of DAMPs that propagate type 2 inflammation. Initial transcriptomic analyses in airway smooth muscle cells had already identified dysregulation of iron-metabolism genes (eg, SLC39A14), glutathione synthesis genes (GCLC, GCLM), and the cystine/glutamate antiporter subunit SLC7A11 as ferroptosis-prone signatures.107 Subsequent studies have since dissected the upstream signals and downstream effectors, which are organised below by their primary site of action—epithelial, immune, or environmental—to avoid repetition and to highlight the integrated nature of the ferroptosis network in asthma107 (Figure 3). This disruption of the antioxidant axis is further compounded by the differential expression of ferroptosis-associated lncRNAs such as GABPB1-AS1, linking transcriptional regulation to iron-mediated cell death.107

Figure 3.

Molecular pathways linking allergen/pollutant exposure to type 2 inflammation and asthma. Key mediators include cytokines (eg, IL-6, IL-13, IL-33), lipid peroxidation regulators (15LO1, GPX4, ACSL4), epigenetic modifiers (METTL3, ALKBH5), and signaling nodes (STING, Nrf2, UBE2N/TAX1BP1/TRIM11). Their interplay drives airway hyperresponsiveness, mucus hypersecretion, and remodeling, underpinning asthma pathogenesis.

Ferroptosis as a Driver of Airway Epithelial Injury and Barrier Dysfunction

The airway epithelium is the first line of defense against allergens and pollutants, and its integrity is crucial for maintaining immune homeostasis. Numerous studies demonstrate that exposure to common asthma triggers induces ferroptosis in these cells, leading to a cascade of inflammatory events. In both cellular and murine models, ferroptosis is characterized by iron overload, lipid peroxidation, mitochondrial dysfunction, and depletion of key antioxidants such as GPX4 and glutathione.108 This process disrupts epithelial barrier integrity and promotes the release of pro-inflammatory cytokines, thereby exacerbating airway hyperresponsiveness and remodeling.108 Allergens such as house dust mite (HDM) trigger hallmark ferroptotic features—GSH depletion, mitochondrial dysmorphology, and increased ROS—through downregulation of SLC7A11 and GPX4 and upregulation of ACSL4.109 Similarly, the birch pollen allergen Bet v 1 induces ferroptosis in alveolar epithelial type II cells via ACSL4 upregulation and GPX4/xCT downregulation.18 Environmental pollutants, including dibutyl phthalate and PM2.5, aggravate asthma by promoting iron accumulation, GSH depletion, and lipid peroxidation markers (MDA, 4-HNE), with GPX4 downregulation as a common endpoint.110,111 The critical consequence of epithelial ferroptosis is the release of DAMPs and alarmins; HDM-induced ferroptosis, mediated through NCOA4-dependent ferritinophagy, leads to HMGB1, IL-33, and TNF-α release, driving eosinophilic type 2 inflammation^31^. In mixed granulocytic asthma, epithelial ferroptosis disrupts E-cadherin, impairing barrier integrity.112 Several regulatory pathways modulate ferroptosis in asthma: downregulation of mitochondrial FUNDC1 disrupts the FBXL2/AR/GPX4 axis,30 loss of TRIM11 destabilizes UBE2N/TAX1BP1 signaling,113 whereas club cell protein CC16 exerts protection by activating NRF2 to upregulate GPX4 and SLC7A11.114

Cytokine-Mediated and Epigenetic Regulation of Epithelial Ferroptosis

Key cytokines elevated in the asthmatic milieu actively promote ferroptosis. IL-6 induces ferroptosis in bronchial epithelial cells by elevating intracellular Fe²⁺ and downregulating SLC7A11, GPX4, and FTH1 while upregulating NOX1.115 IL-17A, associated with neutrophilic asthma, induces Fe²⁺ overload, depletes the xCT-GSH-GPX4 axis, and activates TNF-α signaling.116 IL-13, a central type 2 effector, drives ferroptosis via STAT6-mediated upregulation of SOCS1, which ubiquitinates and degrades SLC7A11, crippling cystine import and GSH synthesis.117 IL-13 also upregulates 15-LOX1, driving compartmentalized mitochondrial ferroptosis that, together with mitophagy, disrupts epithelial differentiation.118 IL-33 suppresses GPX4, leading to lipid ROS accumulation and epithelial cell death.119 Epigenetic regulation adds another layer: METTL3 downregulation reduces m6A modification on GPX4 mRNA, decreasing its stability and promoting ferroptosis,120 whereas ALKBH5 removes m6A marks from GPX4 mRNA, similarly reducing GPX4 expression.121 Conversely, histone acetyltransferase KAT2A enhances SLC7A11 transcription via H3K79 succinylation, inhibiting ferroptosis,122 while SMAD4 promotes ferroptosis through IL-17A signaling.123

The Central Role of the 15-LOX1/ALOX15 Pathway and Immune Cell Dynamics

The 15-lipoxygenase 1 (15-LOX1)/ALOX15 pathway serves as a critical nexus bridging lipid metabolism, ferroptosis, and asthma. In allergic asthma, airway epithelial cells upregulate 15-LOX1, which forms a complex with PEBP1 to generate the ferroptotic phospholipid signal 15-HpETE-PE.124 PEBP1 also binds LC3 to activate pro-survival autophagy, creating a balance between death and survival. Under IL-13 stimulation, the 15-LOX1-PEBP1 complex generates hydroperoxy -phospholipids that deplete GSH, creating a pro-ferroptotic redox environment.21 Multi-tissue bioinformatics confirms ALOX15 as a central regulator, and its inhibition by chicoric acid prevents ferroptosis and alleviates asthma.125,126

The role of ferroptosis in immune cells is dichotomous. Pathogenic ILC2s and Th2 cells enhance cystine uptake and upregulate GPX4 and TXNRD1 to resist ferroptosis, enabling their expansion.127 Conversely, ferroptosis inducers (erastin, RSL3, artesunate) trigger non-canonical, iron-dependent ferroptosis-like death in eosinophils, reducing their survival and synergizing with glucocorticoids.22 CREB inhibition similarly promotes eosinophil ferroptosis,23 and α-tocopherol promotes ILC2 ferroptosis via an LKB1-dependent mechanism.128 However, in neutrophilic asthma, ferroptosis in neutrophils promotes NET formation, exacerbating Th17/Treg imbalance.129 Ferroptotic eosinophils can also induce epithelial ferroptosis via an ERα-mediated loop,130 while myeloid ApoE deficiency increases macrophage ferroptosis, contributing to chronic type 2 inflammation.131

Environmental Exacerbants, Signaling Amplifiers, and Endotype Specificity

PM2.5 exacerbates asthma by inducing ferroptosis through AHR-HSP90-PKM2-DRP1-mediated mitochondrial fission,111 and its oxidative potential correlates with ferroptotic cytotoxicity.132 PM2.5 components like indenopyrene activate AHR and cPLA2, driving arachidonic acid release and lipid peroxidation.133 Coke oven emissions and plastic derivatives similarly promote ferroptosis via ferritinophagy and iron overload.134,135 The JAK2/STAT3/EPAS1 axis, activated by IL-13, drives ferroptosis and inflammation,136 while eosinophil-derived MBP promotes ferroptosis via mTORC1/PBX1/GABARAPL1,24 and STING upregulates ACSL4 to amplify ferroptosis.137

Importantly, ferroptosis contribution varies across asthma endotypes. In T2-high (eosinophilic) asthma, ferroptosis is driven by IL-13/STAT6/SOCS1 and 15-LOX1/PEBP1, whereas in T2-low (neutrophilic) asthma, HIF-1α/HO-1 activation, ferritinophagy, and pollutant sensitivity predominate.111,117,134,138 This endotype divergence has therapeutic implications: ferroptosis inhibitors like liproxstatin-1 and quercetin show efficacy in neutrophilic models,33,139 while ferroptosis inducers may benefit eosinophilic phenotypes. Bioinformatics has identified ferroptosis-related genes (TIMP1, AKR1C3, S100A16) with diagnostic relevance.140–142 In summary, ferroptosis is deeply woven into asthma pathogenesis through epithelial barrier injury, cytokine amplification, 15-LOX1/ALOX15 enzymatic driving, epigenetic fine-tuning, and cell-type-specific immune effects, establishing it as a central pathological axis and a promising therapeutic frontier, particularly for severe or treatment-resistant phenotypes. Future research must focus on cell-specific modulation and clinical translation.

In summary, ferroptosis contributes to allergic asthma pathogenesis through multiple convergent mechanisms: (1) the depletion of antioxidant defenses (eg, GSH, GPX4); (2) the activation of specific signaling pathways (JAK2/STAT3/EPAS1, mTORC1/PBX1/GABARAPL1, STING-ACSL4) that drive lipid peroxidation and epithelial cell death; and (3) the amplification of inflammation and barrier disruption. These processes are often initiated or exacerbated by asthma-relevant cytokines such as IL-13 and IL-33.24,119,136,137,143,144 Consequently, ferroptosis serves as a critical mechanistic link between allergic inflammation and airway tissue damage, highlighting its potential as a multifaceted therapeutic target for intervening in asthma progression.

In conclusion, ferroptosis is deeply woven into the pathogenic fabric of allergic asthma through a vast, interconnected network of mechanisms. It acts as a key executor of environmental and allergen-induced airway epithelial barrier injury, a process amplified by pro-inflammatory cytokines like IL-6, IL-13, and IL-17A. The 15-LOX1/ALOX15 pathway serves as a major enzymatic driver, while a layer of epigenetic regulation fine-tunes cellular susceptibility. The role of ferroptosis in immune cells is dichotomous, highlighting both a pathogenic mechanism (eg, in NETosing neutrophils) and a therapeutic opportunity (eg, in eosinophils and ILC2s). The convergence of these pathways underscores ferroptosis not as a singular entity but as a dynamic process influenced by genetics, environment, and the immune milieu. This comprehensive understanding establishes ferroptosis as a central pathological axis and a promising, albeit complex, therapeutic frontier for asthma, particularly for severe or treatment-resistant phenotypes. Future research must focus on achieving cell-specific modulation and translating these robust preclinical findings into validated clinical strategies.

However, the contribution of ferroptosis to asthma pathogenesis is unlikely to be uniform across the spectrum of this heterogeneous disease. Asthma comprises multiple endotypes—T2-high (eosinophilic) and T2-low (neutrophilic, pauci-granulocytic, or mixed)—that differ in their underlying immunopathology, response to conventional therapies, and, as emerging evidence suggests, their ferroptosis landscape. In eosinophilic (T2-high) asthma, which is typically steroid-responsive and driven by IL-4, IL-5, and IL-13, epithelial ferroptosis appears to be predominantly triggered by type 2 cytokines (eg, IL-13 via STAT6/SOCS1-mediated SLC7A11 degradation)117 and the 15-LOX1/PEBP1 axis,21,124 with eosinophil-derived mediators further amplifying the ferroptotic cascade.24 By contrast, in neutrophilic (T2-low) asthma—which is often steroid-resistant and associated with IL-17A, IL-8, and neutrophil infiltration—the ferroptosis signature is shaped by distinct molecular drivers, including HIF-1α/HO-1 pathway activation, enhanced ferritinophagy, and heightened sensitivity to environmental pollutants such as PM2.5 and coke oven emissions.111,134,138 This endotype-specific divergence is not merely descriptive; it has direct therapeutic implications, as ferroptosis inhibitors such as liproxstatin-1 and quercetin have shown particular efficacy in neutrophilic asthma models,33,145 whereas ferroptosis inducers that eliminate eosinophils may be more appropriate for eosinophilic phenotypes.22 Furthermore, the role of ferroptosis differs fundamentally between acute inflammatory episodes (where rapid epithelial cell death may drive exacerbations via DAMP release) and chronic disease states (where persistent ferroptotic stress contributes to airway remodeling, smooth muscle hyperplasia, and progressive loss of lung function).24,146 Finally, the biological consequences of ferroptosis are profoundly cell-type dependent: while ferroptosis in airway epithelial cells is uniformly detrimental (compromising barrier integrity, releasing alarmins, and propagating inflammation),18,31,109 its effects on immune cells are context-specific—ferroptosis in eosinophils and ILC2s can be therapeutically harnessed to reduce pathogenic effector populations,22,127,128 whereas ferroptosis in neutrophils may exacerbate disease by promoting NET formation and Th17/Treg imbalance,129 and ferroptosis resistance in ILC2s and Th2 cells may actually sustain pathogenic type 2 immunity.127 These distinctions—between endotypes, disease phases, and cell types—are critical for interpreting experimental observations and for designing rationally targeted therapeutic strategies. Throughout the following subsections, we have explicitly noted the endotype, phase, and cell-type context of the evidence discussed, to avoid inappropriate extrapolation across biologically distinct settings.

Role of Ferroptosis in the Pathogenesis of Atopic Dermatitis

Beyond ferroptosis, another recently characterized form of regulated cell death—cuproptosis—has emerged as a distinct copper-dependent cell death pathway with potential relevance to inflammatory skin disorders. Cuproptosis is triggered by the accumulation of intracellular copper, which directly binds to and destabilizes lipoylated proteins within the tricarboxylic acid (TCA) cycle, particularly dihydrolipoamide S-acetyltransferase (DLAT), leading to the aggregation of lipoylated mitochondrial proteins and the loss of iron–sulfur cluster proteins.139 This process is dependent on mitochondrial respiration and is distinctly different from other forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, in terms of its morphological features, biochemical hallmarks, and molecular regulators.139 The copper chaperone FDX1 has been identified as a key upstream regulator that promotes protein lipoylation and sensitizes cells to cuproptosis, while the copper transporter SLC31A1 (CTR1) controls cellular copper influx, thereby determining cuproptotic sensitivity.139 Importantly, emerging evidence indicates that cuproptosis and ferroptosis are not mutually exclusive but rather interconnected: copper overload can indirectly promote ferroptosis by impairing iron homeostasis, for instance through the transcriptional repression of ferritin heavy chain 1 (FTH1), which leads to labile iron accumulation and subsequent lipid peroxidation.139 This mechanistic crosstalk has been implicated in the pathogenesis of atopic dermatitis (AD), where cuproptosis-driven ferroptosis in keratinocytes exacerbates skin barrier dysfunction and local inflammation.139 The following sections detail the current understanding of how these interconnected cell death pathways contribute to AD pathogenesis.

The study revealed that cuproptosis promotes the pathogenesis of Atopic Dermatitis (AD) by driving ferroptosis through the downregulation of ferritin heavy chain 1 (FTH1)147 (Figure 4). Mechanistically, increased expression of the copper transporter SLC31A1 leads to intracellular copper accumulation, which elevates α-ketoglutarate (α-KG) levels. α-KG activates the lysine demethylase KDM5B, resulting in demethylation of H3K4me3 at the FTH1 promoter and transcriptional suppression of FTH1. Reduced FTH1 impairs iron storage, leading to iron overload, lipid peroxidation, and ferroptotic cell death. Ferroptosis subsequently releases pro-inflammatory signals, amplifies local inflammation, and contributes to AD-like skin lesions, as evidenced by the amelioration of dermatitis upon inhibition of either cuproptosis or ferroptosis in experimental models.147

Figure 4.

Schematic illustration of the mechanisms linking copper transport, ferroptosis, and inflammation in keratinocytes. Increased intracellular copper via SLC31A1 promotes ferroptosis through iron-mediated Fenton reactions, leading to lipid peroxidation (LPO) and reactive oxygen species (ROS) generation. The resulting release of damage-associated molecular patterns (DAMPs), ATP, and alarmins (IL-33, IL-1α) drives local inflammation, recruiting neutrophils and polarizing Th2 responses. Concurrently, iron-dependent histone demethylase KDM5B activity, supported by α-ketoglutarate (α-KG), modulates gene expression, further amplifying inflammatory signaling.

The study primarily revealed the widespread involvement of pyroptosis and ferroptosis in the pathogenesis of several autoimmune diseases at the single-cell transcriptome level.148 In the context of atopic dermatitis (AD), the analysis indicates that while no major differences were observed in ferroptosis-related gene scores in keratinocytes, fibroblasts, or endothelial cells between lesional, non-lesional, and healthy skin, a distinct pyroptosis-sensitive keratinocyte subset was identified.148 Specifically, lesional AD keratinocytes showed elevated expression of GSDMC and GSDMD, suggesting enhanced susceptibility to pyroptosis. The study implies that TNFα-caspase-8-GSDMC signaling may drive keratinocyte pyroptosis, contributing to inflammation and barrier disruption in AD. Ferroptosis, however, does not appear to be prominently altered in AD compared to other autoimmune diseases examined, highlighting a more central role for pyroptosis in AD pathogenesis.148

This section highlights emerging but limited evidence linking ferroptosis to AD. Key findings indicate that cuproptosis-driven ferroptosis, mediated via downregulation of ferritin heavy chain 1 (FTH1), exacerbates skin inflammation and barrier dysfunction. Additionally, single-cell transcriptomic analyses suggest that while pyroptosis is prominent in AD keratinocytes, ferroptosis may not be significantly altered compared to other autoimmune diseases. These insights point to a potential cross-talk between different regulated cell death pathways in AD. However, several unresolved issues remain: the precise contribution of ferroptosis relative to other forms of cell death in AD progression is unclear, and the cell-specific role of ferroptosis in keratinocytes, immune cells, and fibroblasts needs further delineation. Future research should focus on mapping the ferroptosis molecular landscape in human AD samples across different severities and subtypes, elucidating the interplay between cuproptosis, ferroptosis, and pyroptosis, and exploring cell-type-specific ferroptosis modulation as a targeted therapeutic strategy for atopic dermatitis.

It is important to note, however, that the evidence linking ferroptosis to AD pathogenesis remains limited and partly conflicting. While the cuproptosis–ferroptosis axis was demonstrated in one study,147 single-cell transcriptomic analyses have not consistently identified ferroptosis as a dominant pathway in AD keratinocytes or fibroblasts.148 This discrepancy may reflect tissue-specific or disease-stage-dependent differences, as well as methodological variations between bulk and single-cell approaches. Moreover, most current data derive from a single experimental model or dataset, and independent validation across different AD cohorts is lacking. Whether ferroptosis acts as a primary driver or a secondary consequence of inflammation in AD skin remains unresolved. These uncertainties underscore the need for systematic, multi-omics profiling of human AD samples across severity grades and endotypes to clarify the relative contribution of ferroptosis versus other cell death modalities.148

Therapeutic Potential of Ferroptosis Targeting in Allergic Diseases

Building upon the established pathogenic role of ferroptosis in various allergic disorders, significant therapeutic potential lies in its precise pharmacological modulation. This section synthesizes the promising strategies of either inhibiting ferroptosis to protect structural cells and suppress inflammation or inducing ferroptosis to selectively deplete hyperactive immune effector cells. We review the current evidence for ferroptosis-targeting interventions, including small-molecule inhibitors, inducers, and natural compounds, across major allergic conditions such as allergic rhinitis, asthma, and atopic dermatitis. The discussed mechanisms highlight how modulating this cell death pathway can complement existing therapies, potentially offering enhanced efficacy, reduced side effects, and novel solutions for severe or treatment-resistant allergic diseases (Figure 5).

Figure 5.

Schematic illustration of the mechanisms linking pharmacological targeting of ferroptosis to the alleviation of allergic inflammation. This schematic illustrates candidate pharmacological agents (circled, eg, BZYQD, quercetin, polydatin, linarin) that may suppress ferroptosis and allergic inflammation by modulating key nodes within the ferroptosis‑regulatory network. These include pathways such as HIF1A‑TP53‑ROS, Keap1‑Nrf2‑HO‑1, SIRT1, METTL3‑m6A modification, and the ACSL4‑GPX4 axis. The diagram highlights how intervention at these targets could mitigate epithelial dysfunction, oxidative stress, and type 2 inflammation in allergic rhinitis, asthma, and atopic dermatitis.

Allergic Rhinitis

Several pharmacological agents have been reported to target ferroptosis in allergic rhinitis, as summarized in Table 1. These interventions either induce ferroptosis in specific immune cells or inhibit the pathway in structural cells to alleviate disease pathology. The pharmacological mechanism of iodine, specifically in the form of lecithin-bound iodine (LBI), in attenuating allergic rhinitis involves the induction of ferroptosis in activated B cells, thereby suppressing the allergic immune response.149 In an ovalbumin (OVA)-induced allergic rhinitis mouse model, LBI supplementation alleviated nasal symptoms, reduced eosinophil infiltration, and decreased OVA-specific IgE levels in the serum. The antiallergic effect was attributed to elevated serum iodine levels rather than changes in thyroid hormone concentrations, indicating an extrathyroidal action of iodine. In vitro studies demonstrated that potassium iodide (KI) treatment induced dose-dependent cell death in activated B cells, characterized by increased reactive oxygen species (ROS), elevated intracellular ferrous iron (Fe²⁺), and loss of plasma membrane integrity.149 This form of cell death was identified as ferroptosis, as it was specifically inhibited by ferrostatin-1 (Fer-1), a ferroptosis inhibitor, but not by inhibitors of apoptosis, necrosis, or pyroptosis. Mechanistically, iodine upregulated the expression of Steap3, a metalloreductase that converts ferric iron to ferrous iron, thereby enhancing the Fenton reaction and promoting lipid peroxidation—a hallmark of ferroptosis. Additionally, iodine may directly interact with ferric iron to facilitate ROS generation.149 In vivo, LBI feeding increased ROS levels in germinal center B cells within draining lymph nodes and reduced the frequency of these cells, along with T follicular helper cells, thereby dampening the germinal center reaction and IgE class-switching. The critical role of ferroptosis was further confirmed by the reversal of LBI’s protective effects upon Fer-1 administration in mice. Thus, dietary iodine alleviates allergic rhinitis by promoting ferroptosis in activated B cells, leading to suppressed allergen-specific IgE production and mitigated inflammatory responses in the upper airway.149

Table 1.

Summary of Pharmacological Agents Targeting Ferroptosis in Allergic Rhinitis

Drug/Extract	Key Mechanism of Action	Effect on Ferroptosis & Allergic Rhinitis Pathology	Level of Evidence	Ref.
Iodine	Induces ferroptosis specifically in activated B cells. Mechanism involves upregulation of Steap3, leading to increased ferrous iron (Fe2⁺), enhanced Fenton reaction, and lipid peroxidation.	Promotes ferroptosis of germinal center B cells and T follicular helper cells in draining lymph nodes. This suppresses the germinal center reaction, reduces allergen-specific IgE production, and alleviates nasal symptoms and eosinophil infiltration.	In vivo (murine OVA-induced AR model); in vitro (activated B cell cultures). No human clinical data available.	[149]
Bu-Zhong-Yi-Qi Decoction (BZYQD)	Multi-component action. Key active flavonoids (eg, naringenin, kaempferol) interact with core ferroptosis regulators (eg, TP53, MAPK1, HIF1A). Modulates pathways related to epithelial proliferation, IL-17 signaling, and Th17 differentiation.	Coordinates a network to inhibit ferroptosis, reducing iron-dependent lipid peroxidation and oxidative stress in nasal epithelial cells. This helps restore epithelial barrier function, reduces release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and mitigates inflammation.	In silico (network pharmacology, molecular docking); in vivo (murine AR models). Requires experimental validation; no clinical evidence.	[150]

Using network pharmacology and molecular docking approaches, the research identifies 182 active components from BZYQD, with key flavonoids such as naringenin, kaempferol, and isorhamnetin showing strong binding affinities to core ferroptosis-related targets including TP53, MAPK1, and HIF1A. These interactions suggest that BZYQD may directly regulate ferroptosis by stabilizing or modulating the expression and activity of these pivotal genes.150 Enrichment analyses further reveal that BZYQD influences biological processes and signaling pathways closely associated with both ferroptosis and AR pathogenesis, such as epithelial cell proliferation, the IL-17 signaling pathway, and Th17 cell differentiation.150 By targeting key ferroptosis regulators, BZYQD is proposed to mitigate the iron-dependent lipid peroxidation and cellular oxidative stress that characterize ferroptosis, thereby reducing nasal epithelial injury and inflammation. This integrative action helps restore epithelial barrier function and modulates immune responses, including the secretion of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α. Thus, BZYQD exerts its therapeutic effects on AR by coordinately intervening in ferroptosis through a network of critical genes and pathways, highlighting its potential as a multi-faceted treatment strategy for ameliorating allergic inflammation and epithelial damage.150

Allergic Asthma

Therapeutically, targeting ferroptosis presents a promising strategy. Table 2 provides a comprehensive summary of the various pharmacological agents that modulate ferroptosis in allergic asthma, including their mechanisms of action and key experimental findings. Notably, the efficacy of some treatments is linked to their anti-ferroptotic effects. For instance, priming mesenchymal stem cells (MSCs) with the ferroptosis inhibitor Liproxstatin-1 enhances their therapeutic potential in alleviating chronic asthma features, likely by protecting the MSCs themselves from lipid peroxidation and improving their anti-inflammatory function via macrophage reprogramming.143 This aligns with the broader observation that inhibiting ferroptosis, whether directly or indirectly, mitigates key asthmatic phenotypes.

Table 2.

Summary of Pharmacological Agents Targeting Ferroptosis in Allergic Asthma

Drug/Extract	Pharmacological Mechanism of Action (in the Context of Asthma)	Level of Evidence	Ref
Gentisic acid	Modulates the Nrf2/HO-1 and NF-κB signaling pathways, reducing oxidative stress, lipid peroxidation, and iron accumulation, thereby inhibiting ferroptosis and airway inflammation.	In vivo (murine OVA-induced asthma model); in vitro (airway epithelial cell lines). No human data.	[151]
Xiaoqinglong Decoction (XQLD)	Ameliorates neutrophilic asthma by upregulating GPX4 and downregulating ACSL3, thereby inhibiting iron-dependent lipid peroxidation and ferroptosis.	In vivo (murine neutrophilic asthma model); proteomic analysis. No clinical evidence.	[152]
Linarin	Binds to and stabilizes ALDH2, initiating the ALDH2/MAOA axis to inhibit mitochondrial fission, oxidative stress, and subsequent airway epithelial ferroptosis.	In vivo (murine asthma model); in vitro (bronchial epithelial cells). No human data.	[153]
Rhizoma Dioscoreae Nipponicae (RDN)	Induces ferroptosis in eosinophils by inhibiting the p38 MAPK pathway (downregulating p-p38 and GPX4, upregulating ACSL4), reducing eosinophil viability and airway inflammation.	In vivo (murine asthma model); in vitro (eosinophil cultures). No clinical evidence.	[154]
Quzhou Aurantii Fructus extract (QAFA)	Inhibits TRPV1-mediated Ca2⁺ influx, leading to downregulation of pro-ferroptotic proteins (TFR1, ACSL4) and upregulation of anti-ferroptotic factors (GPX4, SLC7A11).	In vivo (murine OVA-induced asthma model); in vitro (IL-4-stimulated bronchial epithelial cells). No human data.	[155]
Wuwei Shaji Powder (WSP)	Alleviates asthma via S-sulfhydration of Keap1, which activates Nrf2 and upregulates GPX4, thereby protecting bronchial epithelial cells from ferroptosis.	In vivo (murine OVA-induced asthma model); in vitro (bronchial epithelial cells). No clinical evidence.	[156]
Yanghe Pingchuan granules (YPG)	Induces ferroptosis in airway smooth muscle cells (ASMCs) via the METTL3/p53/SLC7A11 axis, depleting glutathione and promoting lipid peroxidation to counteract airway remodeling.	In vivo (murine asthma model); in vitro (ASMC cultures). No human data.	[146]
α-Tocopherol	Promotes ferroptosis in group 2 innate lymphoid cells (ILC2s) via an LKB1-dependent mechanism (downregulating SCARB1, inhibiting LKB1-AMPK/mTOR, and suppressing GPX4 via KLF4).	In vivo (murine asthma model); in vitro (ILC2 cultures). No clinical evidence.	[128]
Fermented and aged ginseng sprouts (FAGS)/Compound K (CK)	Suppress ferroptosis, inflammation, and ER stress by restoring SLC7A11 and GPX4 expression, reducing lipid peroxidation markers (MDA, 4-HNE), and mitigating oxidative stress.	In vivo (murine OVA-induced asthma model); in vitro (cell lines). No human data.	[157]
Ferrostatin-1 (Ferr-1)	Inhibits ferroptosis by reducing iron deposition and lipid peroxidation, restoring GPX4 activity, and enhancing antioxidant defense.	In vivo (murine asthma model); in vitro (BEAS-2B cells). No human data; used as a pharmacological tool.	[158]
Liproxstatin-1	Inhibits ferroptosis in bronchial epithelial cells by upregulating GPX4 and SLC7A11 while downregulating PTGS2, reducing lipid ROS and mitochondrial damage, and suppressing inflammation.	In vivo (murine neutrophilic asthma model); in vitro (LPS/IL-13-challenged bronchial epithelial cells). No human data.	[33]
Quercetin	Inhibits ferroptosis and M1 macrophage polarization by upregulating GPX4 and SLC7A11, reducing lipid peroxidation markers (MDA, 4-HNE), and modulating macrophage phenotype.	In vivo (murine neutrophilic asthma model); in vitro (macrophage and epithelial cell cultures). No human data.	[145]
Quercetin	Inhibits ferroptosis by activating the SIRT1/Nrf2/HO-1 signaling pathway, reducing ROS and MDA, increasing SOD, and mitigating iron overload.	In vivo (murine asthma model); in vitro (cell lines). No human data.	[159]
Scorpio and centipede (SC)	Ameliorates asthma by inhibiting the crosstalk between ferroptosis and inflammation in airway epithelial cells, upregulating FTH1 and GPX4, and reducing MDA and Fe3⁺.	In vivo (murine asthma model); in vitro (epithelial cells). No clinical evidence.	[160]
Genkwanin (GKA)	Inhibits ferroptosis in airway epithelial cells by suppressing DYRK1A, promoting TFE3 nuclear translocation, enhancing autophagy, and subsequently downregulating ferroptosis markers.	In vivo (murine asthma model); in vitro (bronchial epithelial cells). No human data.	[161]
Polydatin	Inhibits ferroptosis by suppressing NCOA4-mediated ferritinophagy, reducing Fe2⁺ overload, decreasing lipid peroxidation (MDA, 4-HNE), and upregulating GPX4 and SLC7A11.	In vivo (rat OVA-induced asthma model); in vitro (cell lines). No human data.	[162]
β-glucan nanoparticles (BG-NPs)	Suppress ferroptosis by reducing iron deposition, upregulating GPX4 expression/activity, and enhancing overall antioxidant defense (increasing GSH, SOD, CAT, GPx; reducing MDA).	In vivo (murine OVA-induced asthma model); in vitro (cell lines). No human data.	[163]
Chicoric acid (CA)	Acts as an ALOX15 inhibitor to prevent ferroptosis, reducing lipid peroxidation and Fe2⁺ accumulation, and modulating ferroptosis-related proteins (GPX4, SLC7A11, ACSL4).	In vivo (murine HDM/LPS-induced asthma models); in vitro (molecular docking, cell cultures). No clinical evidence.	[126]
Isoimperatorin (ISO)	Exerts prophylactic effects via mTOR-dependent modulation, activating the Nrf2/GPX4 axis, regulating iron homeostasis (upregulating PCBP1, SLC40A1), and suppressing inflammation/oxidative stress.	In vivo (murine LPS-ALI model, asthma models); in vitro (cell lines). No human data.	[164]
Ferroptosis-inducing agents (FINs: erastin, RSL3, artesunate)	Trigger non-canonical, iron-dependent ferroptosis-like death in eosinophils (via cytosolic ROS), reducing eosinophil survival and synergizing with glucocorticoids to alleviate inflammation.	In vivo (murine allergic airway inflammation models); in vitro (eosinophil cultures). Artesunate has clinical use for malaria, but not specifically validated as a ferroptosis-inducer in human asthma.	[22]

Gentisic acid exerts its anti-asthmatic effects by modulating the Nrf2/HO-1 and NF-κB signaling pathways, thereby regulating ferroptosis in asthma. It activates Nrf2, likely by binding to Keap1, which enhances the expression of antioxidant enzymes like HO-1, GPx, and CAT, reducing oxidative stress and lipid peroxidation. Simultaneously, GA suppresses NF-κB activation, lowering inflammatory cytokine production and immune cell infiltration. By decreasing iron accumulation and lipid peroxide formation—key features of ferroptosis—GA mitigates airway inflammation, oxidative damage, and iron-dependent cell death, ultimately alleviating asthma pathology.151

Xiaoqinglong Decoction (XQLD) ameliorates neutrophilic asthma by modulating the ferroptosis pathway, as revealed by proteomic analysis.152 XQLD treatment significantly upregulates the expression of GPX4, a key antioxidant enzyme that reduces lipid peroxides and protects against ferroptosis.152 Concurrently, XQLD downregulates ACSL3, a protein involved in fatty acid metabolism that promotes ferroptosis when overexpressed. By restoring the balance between GPX4 and ACSL3, XQLD inhibits iron-dependent lipid peroxidation and cell death in lung tissues, thereby alleviating airway inflammation, oxidative stress, and tissue damage associated with asthma.152 This ferroptosis regulation, along with the inhibition of pro-inflammatory genes such as ARG1, MMP12, and SPP1, contributes to the therapeutic effects of XQLD in asthma.152

Linarin exerts its anti-asthma effects by directly binding to and stabilizing aldehyde dehydrogenase 2 (ALDH2), initiating a key ALDH2/MAOA regulatory axis. This action downregulates monoamine oxidase A (MAOA), thereby inhibiting excessive mitochondrial fission and oxidative stress.153 The preservation of mitochondrial integrity prevents mitochondrial DNA leakage and subsequent activation of the cGAS-STING inflammatory pathway. Concurrently, this mechanism inhibits airway epithelial ferroptosis by restoring the expression of crucial regulators like glutathione peroxidase 4 (GPX4) and reducing iron accumulation and lipid peroxidation. Thus, Linarin coordinately suppresses mitochondrial dysfunction, inflammation, and ferroptosis via the ALDH2/MAOA axis to alleviate asthma pathology.153

Rhizoma Dioscoreae Nipponicae (RDN) alleviates asthma primarily by inducing ferroptosis in eosinophils through inhibition of the p38 MAPK signaling pathway. RDN treatment downregulates phosphorylated p38 (p-p38) and the ferroptosis suppressor GPX4, while upregulating the ferroptosis promoter ACSL4, leading to increased ROS levels and reduced eosinophil viability.154 This targeted induction of eosinophil ferroptosis decreases eosinophil infiltration in the airways and reduces key markers of airway inflammation and remodeling, such as collagen I, FN1, and α-SMA. The study further confirms that pharmacological inhibition of p38 MAPK mimics RDN’s effects, whereas its activation counteracts them, establishing that RDN’s anti-asthmatic action is mediated by p38 MAPK suppression to drive eosinophil ferroptosis.154

The aqueous extract of Quzhou Aurantii Fructus (QAFA) alleviates asthma by modulating ferroptosis primarily through TRPV1 channel mediation. QAFA inhibits TRPV1 activation, thereby reducing Ca²⁺ influx, which is linked to ferroptosis induction.155 In ovalbumin-induced asthmatic mice, QAFA downregulates pro-ferroptotic proteins (TFR1 and ACSL4) and upregulates anti-ferroptotic factors (GPX4 and SLC7A11). In IL-4-stimulated bronchial epithelial cells, QAFA prevents glutathione depletion and restores GPX4 expression, confirming its anti-ferroptotic role via TRPV1. Thus, QAFA mitigates asthma by suppressing TRPV1-mediated ferroptosis, reducing oxidative stress and airway inflammation.155

Wuwei Shaji Powder alleviates allergic asthma primarily by inhibiting ferroptosis in bronchial epithelial cells through the Keap1/Nrf2/GPX4 pathway.156 WSP induces S-sulfhydration of Keap1, which disrupts its interaction with Nrf2, leading to Nrf2 nuclear translocation and subsequent upregulation of antioxidant genes, including GPX4. This enhances cellular resistance to lipid peroxidation and iron accumulation, key drivers of ferroptosis. By protecting epithelial cells from ferroptosis, WSP helps maintain airway integrity, reduces inflammation, and mitigates asthma pathology without the immunosuppressive effects associated with conventional steroids.156

Yanghe Pingchuan granules (YPG) treat asthma by inducing ferroptosis specifically in airway smooth muscle cells (ASMCs).146 YPG upregulates the RNA methyltransferase METTL3, which enhances m6A methylation and stability of p53 mRNA. The increased p53 protein then transcriptionally represses SLC7A11, a key component of the cystine/glutamate antiporter. This inhibition depletes glutathione, inactivates GPX4, and leads to the accumulation of lipid peroxides and iron (evidenced by increased Fe²⁺ and PTGS2). This deliberate induction of ferroptosis in hyper-proliferative ASMCs counteracts airway remodeling, a core pathological feature of asthma.146

α-Tocopherol alleviates allergic asthma by promoting ferroptosis specifically in group 2 innate lymphoid cells (ILC2s) through an LKB1-dependent mechanism.128 It downregulates SCARB1 and inhibits the LKB1-AMPK/mTOR pathway. LKB1 deficiency upregulates KLF4, which interacts with and likely suppresses GPX4, leading to increased lipid peroxidation and Fe²⁺ accumulation in ILC2s. This ILC2 ferroptosis reduces their production of type 2 cytokines (IL-5, IL-13), thereby dampening eosinophil infiltration and airway inflammation, offering a targeted dietary immunomodulatory approach for asthma management.128

Fermented and aged ginseng sprouts (FAGS) and its main component Compound K (CK) alleviate allergic asthma by suppressing ferroptosis alongside inflammation and ER stress.157 In OVA-induced asthmatic mice, FAGS and CK treatment significantly reduced lipid peroxidation markers (MDA, 4-HNE) and iron accumulation in lung tissue, while restoring the expression of key anti-ferroptotic proteins SLC7A11 and GPX4. This inhibition of ferroptosis was accompanied by decreased oxidative stress (ROS), apoptosis, and ER stress signals. By concurrently mitigating these interconnected pathways, FAGS and CK effectively ameliorated hallmark asthmatic features such as airway hyperresponsiveness, Th2 inflammation, and mucus hypersecretion, positioning them as potential therapeutic agents targeting ferroptosis in asthma.157

Ferrostatin-1 (Ferr-1) and 3-methyladenine (3-MA) ameliorate asthma by inhibiting ferroptosis, an iron-dependent cell death process exacerbated in asthma models. Ferr-1 acts primarily as a ferroptosis inhibitor by reducing iron deposition and lipid peroxidation, thereby restoring glutathione peroxidase 4 (GPX4) activity and enhancing antioxidant defense. 3-MA, an autophagy inhibitor, suppresses ferritinophagy-mediated iron release and downregulates ferroptosis-related proteins such as NCOA4, TFR1, and DMT-1. Both drugs attenuate inflammatory cytokine production (eg, IL-1β, IL-6, TNF-α) and oxidative stress markers (ROS, MDA), while promoting SOD activity. Together, they mitigate airway inflammation and epithelial damage by targeting distinct yet complementary pathways in ferroptosis regulation.158

Liproxstatin-1 exerts its therapeutic effects in neutrophilic asthma primarily by inhibiting ferroptosis in bronchial epithelial cells. It upregulates key anti-ferroptotic regulators GPX4 and SLC7A11, while downregulating the ferroptosis marker PTGS2.33 This reduces lipid reactive oxygen species (ROS) accumulation and mitochondrial damage, thereby preserving cell viability. Concurrently, Liproxstatin-1 suppresses the release of pro-inflammatory cytokines (eg, IL-33, TSLP, IL-8, IL-6, HMGB1) from epithelial cells and in lung tissue, mitigating airway inflammation, neutrophil infiltration, and mucus hypersecretion. Thus, by targeting the ferroptosis pathway, Liproxstatin-1 alleviates both cellular injury and inflammatory responses characteristic of neutrophilic asthma.33

Quercetin alleviates neutrophilic asthma by inhibiting ferroptosis through multiple mechanisms. It upregulates key anti-ferroptotic proteins GPX4 and SLC7A11, thereby enhancing cellular antioxidant defense.145 Concurrently, quercetin reduces lipid peroxidation, as evidenced by decreased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and ameliorates mitochondrial damage. Furthermore, it suppresses the release of pro-inflammatory cytokines (eg, TNF-α, IL-6, IL-1β) and inhibits the polarization of macrophages towards the pro-inflammatory M1 phenotype, a process closely linked to ferroptosis. By targeting both the ferroptosis pathway and associated inflammatory responses, quercetin mitigates airway inflammation, neutrophil infiltration, and tissue injury in neutrophilic asthma.145

Quercetin alleviates asthma by inhibiting ferroptosis primarily through activating the SIRT1/Nrf2/HO-1 signaling pathway. It enhances the expression of SIRT1, which in turn promotes the nuclear translocation and activity of the transcription factor Nrf2. Activated Nrf2 upregulates the expression of the antioxidant protein HO-1. This coordinated pathway activation combats oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, while increasing superoxide dismutase (SOD) activity. Crucially, it also mitigates iron overload, a key driver of ferroptosis. Consequently, quercetin reduces lipid peroxidation, protects airway epithelial cells from ferroptosis, and attenuates the associated airway inflammation and pathological changes in asthmatic mice.159

Scorpio and centipede (SC), a traditional Chinese medicinal combination, ameliorates asthma by suppressing ferroptosis in airway epithelial cells.160 SC treatment upregulates the expression of key ferroptosis inhibitors, ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4), while reducing malondialdehyde (MDA) and Fe³⁺ levels, indicating attenuated lipid peroxidation and iron overload. Concurrently, SC decreases pro-inflammatory cytokines such as TNF-α and IL-1β. The reversal of SC’s protective effects by the ferroptosis inducer erastin confirms that its anti-asthmatic mechanism involves inhibiting the crosstalk between ferroptosis and inflammation, thereby preserving epithelial integrity and reducing airway hyperresponsiveness.160

Genkwanin (GKA) alleviates asthma by inhibiting ferroptosis in airway epithelial cells through a DYRK1A/TFE3/autophagy signaling axis. GKA binds to and suppresses the kinase activity of DYRK1A, which reduces the phosphorylation of the transcription factor TFE3 at serine 321.161 This decrease in phosphorylation prevents TFE3 cytosolic retention and promotes its nuclear translocation. Once in the nucleus, TFE3 activates the transcription of autophagy-related genes, such as LC3B and ATG5, thereby enhancing autophagic flux.161 This TFE3-mediated autophagy subsequently suppresses key ferroptosis markers: it reduces intracellular Fe²⁺ accumulation, lipid peroxidation (MDA), and reactive oxygen species (ROS), while upregulating the expression of ferroptosis inhibitors GPX4 and SLC7A11. Consequently, GKA mitigates airway epithelial cell damage and asthma pathology.161

Polydatin ameliorates asthma by inhibiting ferroptosis through suppressing NCOA4-mediated ferritinophagy (ferroautophagy).162 It downregulates the expression of NCOA4 and Beclin1 while upregulating ferritin heavy chain 1 (FTH1) and P62. This action weakens the interaction between NCOA4 and FTH1, thereby reducing the autophagic degradation of ferritin and the subsequent release of free Fe²⁺. Consequently, polydatin alleviates intracellular Fe²⁺ overload, decreases levels of lipid peroxidation markers (MDA, 4-HNE), increases glutathione (GSH), and upregulates key anti-ferroptotic proteins GPX4 and SLC7A11. By blocking this ferritinophagy-ferroptosis axis, polydatin mitigates airway inflammation, improves lung function, and alleviates asthma symptoms in a rat model.162

β-glucan nanoparticles (BG-NPs) alleviate asthma by suppressing ferroptosis through a dual mechanism of antioxidant reinforcement and iron homeostasis modulation.163 In an OVA-induced murine asthma model, BG-NPs significantly reduce iron deposition in lung tissues, as evidenced by decreased total iron content and Prussian blue staining. Concurrently, BG-NPs upregulate the expression and activity of glutathione peroxidase 4 (GPX4), a central inhibitor of ferroptosis. Furthermore, BG-NPs enhance the overall antioxidant defense system by increasing levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), while reducing lipid peroxidation marker malondialdehyde (MDA).163 By mitigating oxidative stress, reducing cytotoxic iron accumulation, and boosting GPX4-mediated protection, BG-NPs effectively inhibit ferroptosis-driven airway epithelial cell death, thereby attenuating airway inflammation and hyperresponsiveness in asthma.163

Chicoric acid (CA) exerts its therapeutic effect in asthma primarily by targeting and inhibiting ALOX15, a key regulator of ferroptosis. Through molecular docking and dynamics simulations, CA demonstrates stable binding to ALOX15, thereby suppressing its activity.126 In both in vitro and in vivo asthma models induced by HDM and LPS, CA treatment reduces lipid peroxidation, decreases Fe²⁺ accumulation, and modulates the expression of ferroptosis-related proteins such as GPX4, SLC7A11, and ACSL4. By inhibiting ALOX15-mediated ferroptosis, CA alleviates airway inflammation, epithelial damage, and asthma-like symptoms, highlighting its potential as a natural ferroptosis inhibitor for asthma therapy.126

Prophylactic isoimperatorin (ISO) exerts its therapeutic effects against asthma primarily through mTOR-dependent modulation of ferroptosis-related pathways.164 ISO activates the Nrf2/GPX4 antioxidant axis, enhancing glutathione peroxidase 4 (GPX4) expression and activity, which mitigates lipid peroxidation—a key driver of ferroptosis. Concurrently, ISO regulates iron homeostasis by upregulating PCBP1 and SLC40A1, reducing intracellular iron accumulation and oxidative stress. By suppressing mTORC1 signaling, ISO further inhibits inflammatory cascades (eg, TLR4/NF-κB/NLRP3) and oxidative damage, thereby attenuating airway inflammation and ferroptosis-associated lung injury in asthma models.164

The pharmacological agents, namely ferroptosis-inducing agents (FINs) such as erastin, RSL3, and artesunate (ART), trigger a non-canonical, iron-dependent form of cell death in eosinophils characterized by cytosolic ROS accumulation rather than lipid peroxidation.22 This ferroptosis-like death reduces eosinophil survival, thereby alleviating eosinophilic airway inflammation in asthma models. Importantly, FINs synergize with glucocorticoids like dexamethasone, which promote eosinophil apoptosis, through complementary cell death pathways. The combination enhances therapeutic efficacy and may allow lower steroid doses, offering a novel strategy to resolve allergic inflammation with reduced side effects.22

While the agents listed above demonstrate robust efficacy in preclinical asthma models, their relative potency, target selectivity, and safety profiles vary considerably and are rarely compared head-to-head. For example, liproxstatin-1 and ferrostatin-1 directly block lipid peroxidation with high specificity, but their poor aqueous solubility and rapid metabolism limit systemic bioavailability.33,158 In contrast, natural compounds such as quercetin and polydatin exert broader antioxidant and anti-inflammatory effects via Nrf2 or autophagy modulation, which may confer additional benefits but also increase off-target risks and complicate dose-response relationships.159,162 Furthermore, the ferroptosis-inducing agents (erastin, RSL3, artesunate) efficiently eliminate eosinophils in vitro and synergize with glucocorticoids, yet their systemic use risks triggering unwanted ferroptosis in airway epithelium or other organs, as evidenced by the dose-dependent cytotoxicity observed in non-target cells.22 Notably, most studies use single-dose or short-term protocols, leaving chronic safety, pharmacokinetics, and potential resistance mechanisms (eg, upregulation of FSP1 or GCH1) largely unexplored.81,93 Therefore, direct translational extrapolation from these experimental results remains premature, and future work should prioritise comparative efficacy studies in clinically relevant endotypes (eg, neutrophilic vs eosinophilic asthma) and the development of cell-targeted delivery systems to mitigate off-target ferroptosis.

Despite the promising preclinical landscape, several caveats warrant emphasis. First, the vast majority of evidence comes from murine models or in vitro cell lines, and translation to human asthma remains untested. The complex, multifactorial nature of human asthma—encompassing diverse endotypes (T2-high, T2-low, neutrophilic, paucigranulocytic)—may profoundly influence ferroptosis sensitivity and the efficacy of targeted interventions, yet systematic endotype-stratified analyses are lacking. Second, conflicting observations exist regarding the net effect of ferroptosis modulation. For instance, while inhibition of ferroptosis protects epithelial barriers in most models,33,155 genetic or pharmacological suppression of GPX4 in certain immune contexts has been shown to limit pathogenic ILC2 expansion,127 suggesting that systemic ferroptosis inhibition could inadvertently promote allergic inflammation by preserving these effector cells. Conversely, ferroptosis induction in eosinophils reduces airway inflammation,22 but the same agents may trigger ferroptosis in structural cells if delivered non-selectively, potentially exacerbating tissue injury. Third, the long-term safety of chronic ferroptosis modulation—particularly concerning systemic iron homeostasis, hematopoiesis, and neurodegenerative risks—has not been evaluated. These uncertainties highlight the critical need for cell-targeted delivery systems and rigorous pharmacokinetic and toxicological studies before clinical translation.

This section synthesizes compelling preclinical evidence that modulating ferroptosis—either by inhibiting it in structural airway cells or inducing it in specific immune cells—effectively alleviates key features of allergic asthma in animal models. A diverse array of agents, including natural compounds (eg, quercetin, gentisic acid), traditional Chinese medicine formulations (eg, Xiaoqinglong Decoction, Wuwei Shaji Powder), and synthetic inhibitors (eg, ferrostatin-1, liproxstatin-1), exert therapeutic effects by restoring the redox balance. Their mechanisms primarily involve upregulating antioxidant defenses (eg, GPX4, SLC7A11 via Nrf2 activation) to protect epithelial barriers or, conversely, promoting pro-ferroptotic pathways (eg, via ACSL4, p53) to deplete pathogenic eosinophils or ILC2s. A significant finding is the synergistic potential of combining ferroptosis inducers with glucocorticoids, offering a strategy to enhance efficacy and reduce steroid doses.

However, critical gaps remain before clinical translation. Most evidence is preclinical, lacking validation in human asthma patients. The dual role of ferroptosis necessitates highly cell-selective modulators to avoid detrimental off-target effects—inhibiting ferroptosis systemically could potentially protect harmful immune cells, while inducing it might damage healthy epithelium. The long-term safety and pharmacokinetics of these modulators, especially natural compounds and their formulated mixtures, are undefined. Furthermore, the heterogeneity of asthma endotypes (eg, T2-high vs T2-low, neutrophilic) likely influences ferroptosis’s role and the optimal therapeutic strategy, which is underexplored.

Future research should prioritize: 1) conducting human cohort studies to validate ferroptosis markers correlated with asthma severity and subphenotypes; 2) developing targeted delivery systems (eg, nanoparticles, antibody conjugates) to precisely modulate ferroptosis in specific lung cell populations; 3) launching well-designed clinical trials to evaluate the safety and efficacy of lead ferroptosis modulators, alone and in combination with standard therapies; and 4) elucidating the crosstalk between ferroptosis and other inflammatory pathways (eg, autophagy, cGAS-STING) in asthma to identify novel combinatorial nodes for intervention.

Atopic Dermatitis

This study elucidates the pharmacological mechanism by which Sodium Propionate (SP), a short-chain fatty acid, alleviates Atopic Dermatitis (AD) through the inhibition of ferroptosis. SP exerts its therapeutic effects primarily by activating the LTBP2/FABP4 signaling pathway.32 Bioinformatics and in vitro analyses reveal that SP upregulates the expression of LTBP2 and FABP4, which are identified as key regulatory genes in AD pathogenesis. Functionally, SP modulates ferroptosis by increasing the expression of ferroptosis suppressor genes (GPX4 and SLC7A11) and decreasing the expression of ferroptosis driver genes (PTGS2 and ACSL4).32 Concurrently, SP reduces oxidative stress indicators, including reactive oxygen species (ROS) and lipid peroxidation (LPO), which are hallmark features of ferroptosis. Furthermore, SP treatment downregulates pro-inflammatory cytokines (IL-4, IL-13, TNF-α, TSLP) and upregulates skin barrier proteins (loricrin and filaggrin), thereby mitigating inflammation and restoring epidermal integrity.32 Collectively, SP ameliorates AD by inhibiting ferroptosis-driven oxidative damage and inflammation via the LTBP2/FABP4 axis, positioning it as a promising therapeutic agent for AD management.32

While the preclinical evidence summarized above highlights ferroptosis as a promising pathogenic and therapeutic axis in allergic diseases, several fundamental limitations must be critically acknowledged before any translational conclusions can be drawn. First, nearly all studies reviewed are based on transformed cell lines and acute murine models (mostly OVA or HDM challenge), which, although valuable for mechanistic dissection, do not fully recapitulate the chronic, relapsing, and heterogeneous nature of human allergic diseases. The reproducibility of ferroptosis markers across different mouse strains, allergen doses, and exposure protocols has not been systematically tested, and many reports rely on a single or a few indirect markers—such as GPX4 downregulation, MDA elevation, or iron accumulation—without confirming the complete ferroptotic signature (eg, concomitant ACSL4 dependency, lipidomic profiling of oxidised PUFA-PE species, and rescue by multiple specific inhibitors like ferrostatin-1 and liproxstatin-1). This raises the concern that some studies may be capturing oxidative stress or general lipid peroxidation rather than bona fide ferroptosis. Second, the absence of validated, non-invasive biomarkers of ferroptosis in human allergic tissues (eg, circulating oxidised phospholipids, exhaled volatile organic compounds, or specific urinary metabolites) makes it impossible to assess whether ferroptosis is active in patients, correlates with disease severity, or responds to therapy. Third, the causal role of ferroptosis in allergic pathogenesis remains highly uncertain: in most experimental settings, ferroptosis is induced by exogenous triggers (pollutants, allergens, or pharmacological agents) under artificial conditions, and it is not yet clear whether spontaneous ferroptosis occurs endogenously at sufficient levels to drive human disease. The observed changes in ferroptosis-related molecules could equally reflect secondary metabolic adaptations to inflammation, hypoxia, or cellular stress, rather than a primary cell-death program. This ambiguity is particularly pronounced in atopic dermatitis, where the available data are scant and conflicting; the single study linking cuproptosis to ferroptosis via FTH1 downregulation is intriguing but preliminary, and other single-cell analyses have not identified a prominent ferroptosis signature in AD lesions. Therefore, the field currently lacks definitive evidence to distinguish whether ferroptosis acts as an upstream initiator, a downstream amplifier, or an epiphenomenon of allergic inflammation—and in some contexts, it might even represent a protective attempt to remove damaged cells or limit pathogen spread. Finally, the therapeutic translation is hampered by the lack of cell-type-specific delivery systems; systemic inhibition of ferroptosis could inadvertently protect pathogenic immune cells, while systemic induction might damage healthy epithelial barriers. Given these caveats, we emphasize that the current evidence, though mechanistically compelling, should be interpreted with caution. Future studies must prioritise the development of robust human biomarkers, the use of genetic lineage-tracing and conditional knockout models to establish causality in a cell-autonomous manner, and the design of well-controlled longitudinal clinical trials with validated ferroptosis-specific readouts. Until then, ferroptosis remains a promising but unproven target in allergic diseases, and our review aims to provide a balanced synthesis of the existing preclinical landscape while clearly delineating its boundaries and uncertainties.

Conclusions and Perspectives

The burgeoning field of ferroptosis research has enriched our understanding of allergic disease pathogenesis, adding a potentially important axis of iron-dependent, lipid peroxidation-driven cellular demise to the classical type 2 immunity paradigm. As synthesized in this review, ferroptosis is not a mere bystander but an active and dynamic player in the pathophysiology of allergic rhinitis, asthma, and atopic dermatitis, operating at the crucial interface between epithelial barrier integrity and immune cell function. In structural cells, aberrant ferroptosis disrupts physical barriers, releases DAMPs (eg, HMGB1, IL-33), and fuels type 2 inflammation; conversely, targeted ferroptosis in effector cells like eosinophils and ILC2s offers a promising strategy to quell inflammation. The core molecular machinery—centered on the GPX4/GSH axis, iron metabolism, and PUFA peroxidation catalyzed by enzymes such as 15-LOX1/ALOX15—is extensively dysregulated in allergic tissues, and environmental triggers like PM2.5 and allergens push this machinery toward a pro-ferroptotic state via oxidative stress, ferritinophagy, and specific signaling pathways (eg, IL-13/STAT6/SOCS1, AhR).

The therapeutic promise of modulating ferroptosis is particularly compelling due to its dual nature: inhibition protects epithelial barriers, while selective induction depletes pathogenic immune cells, with synergy between ferroptosis inducers and glucocorticoids offering a path to enhanced efficacy and reduced steroid requirements. However, translating this promise into clinical reality faces substantial hurdles. First, the cell-type and context-specific outcomes demand extreme precision—an intervention designed to eliminate eosinophils must not inadvertently trigger ferroptosis in epithelial cells, which would worsen disease. Second, the redundancy in ferroptosis defense systems (GPX4, FSP1, GCH1, DHODH) suggests that resistance may develop, necessitating combination approaches. Third, the current evidence is almost entirely preclinical; the safety and efficacy of chronic ferroptosis modulation in humans, particularly with systemic administration, remain unknown, and potential off-target effects on systemic iron homeostasis and other tissues pose significant risks. Fourth, the lack of validated, non-invasive biomarkers to monitor ferroptosis activity in patients hampers patient stratification and clinical trial design. Fifth, while numerous natural compounds and traditional medicine formulations show promising effects in models, their complex compositions, variable bioavailability, and precise molecular targets require rigorous pharmacological validation before any clinical application can be contemplated.~~ Sixth, the heterogeneity of human allergic diseases-encompassing diverse endotypes (T2-high, T2-low, neutrophilic, paucigranulocytic)-may profoundly influence ferroptosis sensitivity and the efficacy of targeted interventions, yet systematic endotype-stratified analyses are lacking. Finally, conflicting observations exist regarding the net effect of ferroptosis modulation: while inhibition of ferroptosis protects epithelial barriers in most models, genetic or pharmacological suppression of GPX4 in certain immune contexts has been shown to limit pathogenic ILC2 expansion, suggesting that systemic ferroptosis inhibition could inadvertently promote allergic inflammation by preserving these effector cells. These uncertainties collectively underscore that ferroptosis modulation in allergic diseases remains an experimental concept rather than a clinically actionable strategy.

Looking forward, several key directions will define the next decade of research. The development of cell- or tissue-targeted ferroptosis modulators, leveraging nanotechnology-based delivery systems, is paramount to achieve spatial precision and avoid off-target toxicity. Systematic efforts to identify and validate non-invasive biomarkers—such as specific lipid peroxidation products (eg, 15-HpETE-PE, 4-HNE adducts) in exhaled breath condensate, sputum, or serum—are essential for patient stratification and treatment monitoring. The interplay between ferroptosis and other cell death pathways (apoptosis, pyroptosis) and immune processes in the allergic milieu needs further elucidation to design rational combination strategies. Moreover, the impact of the microbiome and metabolic cues on cellular ferroptosis sensitivity represents a fascinating frontier for intervention. Finally, well-designed early-phase clinical trials are urgently needed to test the safety of repurposed ferroptosis-active drugs (eg, sulfasalazine, artesunate in non-malarial doses) or novel inhibitors in allergic patients, with careful attention to endotype-specific responses.

In conclusion, ferroptosis is increasingly recognized as a process that may link cellular metabolism, redox biology, and inflammation in allergic diseases, though proof in human pathology is still awaited. Targeting this pathway could represent a step towards mechanism-based, precise immunomodulation, but its clinical impact remains to be established. While substantial challenges exist, the strategic inhibition or induction of ferroptosis holds immense potential to revolutionize the management of severe, chronic, or refractory allergic conditions, offering hope for therapies that not only suppress symptoms but also modify the underlying cellular pathology. The journey from mechanistic insight to bedside application will require a concerted, interdisciplinary effort, and whether it leads to a new class of effective anti-allergic therapeutics remains an open but exciting question.

Funding Statement

This work was supported in part by the Key Scientific and Technological Innovation Demonstration Project of Inner Mongolia Autonomous Region (No.2026ZDSF0002), Inner Mongolia Autonomous Region science and technology plan project (No. 2025YFSH0151), Inner Mongolia Autonomous Region Innovation Platform Construction Plan(No.2025KYPT0143), and Hohhot Municipal Health Commission Science and Technology Plan Project (No.2024-Hu WS-02).

Declaration of Generative AI in Scientific Writing

During the preparation of this work the authors used Deepseek (V4.1) in order to improve readability and language of the work. After using this tool/service, the author(s) reviewed and edited the content as needed and take full responsibility for the content of the publication. Authors confirm the originality and accuracy of all manuscript content and take full responsibility for the integrity of the whole content, including the accuracy of references.

Data Sharing Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Disclosure

The authors have no competing interests for this work.