Antioxidant defense systems, such as GPX4, play a critical role in protecting cells from ferroptosis (23, 24). As a selenoprotein, GPX4 catalyzes the reduction of lipid hydroperoxides to non-toxic lipid alcohols, preventing the accumulation of lipid peroxides (25). This enzymatic activity is essential for mitigating oxidative stress and maintaining cell viability, underscoring its importance in cellular homeostasis. In COPD, the pulmonary microenvironment is characterized by severe depletion of reduced glutathione (GSH) (146). Since GSH is a critical cofactor for GPX4, this depletion directly impairs GPX4 activity, rendering airway epithelial cells and alveolar macrophages highly susceptible to ferroptosis following oxidative insults such as CS exposure (26, 27). By converting lipid hydroperoxides into less harmful lipid alcohols, GPX4 helps maintain cellular membrane integrity and protects cells from the detrimental effects of lipid peroxidation.

The cystine/glutamate antiporter System Xc- is a key regulator of cellular redox balance and antioxidant defense (28). Composed of the SLC7A11 (encoding the xCT subunit) and SLC3A2 subunits, it facilitates the import of cystine into cells in exchange for glutamate. Intracellular cystine is rapidly converted to cysteine—the rate-limiting precursor for GSH synthesis (29). GSH, in turn, scavenges ROS and maintains redox homeostasis, critical for protecting against ferroptosis (30). In the context of COPD, CS extract directly inhibits System Xc- activity, depleting intracellular cysteine and GSH pools (31). This disruption primes lung cells for ferroptosis by compromising their antioxidant capacity. By supplying cysteine for GSH synthesis, System Xc^- reinforces cellular defenses against oxidative damage, making it a key target for modulating ferroptosis in COPD.

ACSL4 is a pivotal enzyme in regulating lipid peroxidation and ferroptosis. It catalyzes the conversion of free long-chain fatty acids into acyl-CoA derivatives, facilitating their integration into cell membranes (32). This process, combined with the activity of lipoxygenases (LOXs) and other lipid-metabolizing enzymes, promotes lipid peroxidation and drives ferroptosis (29). ACSL4 preferentially activates polyunsaturated fatty acids (PUFAs), notably arachidonic and adrenic acids, which are highly susceptible to lipid peroxidation (33, 34). Notably, ACSL4 expression is upregulated in the airway epithelium of COPD patients and in experimental models of CS exposure (35). This upregulation suggests a direct link between CS-induced stress and the acquisition of a ferroptosis-sensitive lipid profile in lung cells. Inhibition of ACSL4 has been shown to protect cells from ferroptosis. For instance, Yingxi Wang et al. demonstrated that ACSL4 inhibition mitigated ferroptosis in tubular epithelial cells and reduced interstitial fibrosis (35).

Other molecules involved in lipid and iron metabolism also regulate ferroptosis, including iron-responsive element-binding protein 2 (IRP2) (22). IRP2 is a transcription factor sensitive to intracellular iron levels, modulating the expression of proteins related to iron and lipid metabolism, thus influencing cellular susceptibility to ferroptosis (36). For example, Terzi et al. reported that the iron-sulfur cluster (ISC) could activate IRP2, enhancing sensitivity to ferroptosis through mechanisms independent of IRP1 and FBXL5 (37). Furthermore, other regulators of lipid metabolism, such as various lipases and lipid transporters, have been implicated in regulating lipid metabolism and ferroptosis (38). These components are significant in protecting cells from oxidative stress and lipid peroxidation and have been shown to sensitize cells to ferroptosis induction when depleted or inhibited.

Mitochondria are critical for energy production, metabolism, and cell death regulation—including ferroptosis (40, 41). They maintain redox balance and iron homeostasis; dysfunction in these processes elevates oxidative stress, triggering ferroptosis (41). Mitochondria generate ATP via oxidative phosphorylation, a process that also produces ROS. Under physiological conditions, mitochondria balance ROS production with antioxidant defenses (42). However, stress (e.g., CS exposure) disrupts this balance, leading to excessive ROS accumulation (43, 44). Elevated ROS levels can trigger lipid peroxidation—an essential event in ferroptosis—by oxidizing PUFAs in cellular membranes, resulting in cellular damage and death. Mitochondrial dysfunction can exacerbate oxidative stress, heightening the risk of ferroptosis (45). Increased lipid peroxidation activates iron-dependent pathways that generate toxic lipid radicals, prompting cell demise. Iron is crucial for mitochondrial function, serving as a necessary component of mitochondrial proteins involved in the ETC and metabolic pathways. Mitochondria regulates both iron metabolism and storage; thus, maintaining optimal iron levels is essential for mitochondrial health. Dysregulation can lead to iron overload, catalyzing lipid peroxidation and oxidative stress, which promotes ferroptosis (46). Mitochondrial ferritin plays a protective role by sequestering excess iron and preventing oxidative damage (47). Peina Wang et al. reported that Mitochondrial ferritin attenuates cerebral ischemia/reperfusion injury by inhibiting ferroptosis (48). However, when mitochondrial ferritin is overwhelmed or dysfunctional, free iron levels may rise, catalyzing the Fenton reaction and exacerbating oxidative damage, further driving ferroptosis. For instance, Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis (49). Mitochondrial morphology, characterized by fission (division) and fusion (joining), significantly influences cellular susceptibility to ferroptosis. Fission can fragment mitochondria, making them more vulnerable to damage and dysfunction, while promoting the release of pro-apoptotic factors that increase cell death likelihood (50). Conversely, mitochondrial fusion maintains organelle integrity and functionality, countering oxidative stress effects (51). The balance between fission and fusion is regulated by specific proteins influenced by cellular signaling pathways in response to stressors. Dysregulation of these processes can tip the balance toward either cell survival or death, including ferroptosis; for example, inhibited fusion may enhance sensitivity to oxidative stress and promote ferroptotic cell death.

Mitochondria interact with other organelles to modulate ferroptosis. For example, mitochondrial dysfunction destabilizes lysosomes, amplifying oxidative stress (52). The ER-mitochondria interaction regulates calcium signaling; excessive ER calcium release disrupts mitochondrial function, promoting ferroptosis (53). Mitophagy—the selective degradation of damaged mitochondria—prevents ROS accumulation and ferroptosis (54); impairment of mitophagy leads to the accumulation of dysfunctional mitochondria, increasing oxidative damage and ferroptosis (55–57). Collectively, mitochondrial dynamics and function are critical regulators of ferroptosis in COPD.

The ER maintains cellular homeostasis through protein synthesis, lipid metabolism, and calcium storage (58). Recent studies highlight its role in ferroptosis regulation, via ER stress responses, lipid biosynthesis, and iron metabolism (59). The ER is the primary site of lipid synthesis, producing phospholipids, cholesterol, and PUFAs—all of which influence membrane susceptibility to lipid peroxidation (60). ER stress—triggered by CS in COPD—escalates lipid peroxidation, activating ferroptosis pathways (61, 62). The ER also regulates redox homeostasis via the unfolded protein response (UPR). The UPR restores homeostasis by enhancing protein-folding capacity and reducing protein load; however, persistent ER stress activates cell death pathways, including ferroptosis (63). Prolonged ER stress increases oxidative stress and lipid peroxide accumulation, sensitizing cells to ferroptosis (64). For example, UPR activation upregulates enzymes involved in lipid metabolism, promoting lipid peroxidation. System Xc^-—localized to the ER membrane—mediates cystine import for GSH synthesis (65). This impairment compromises antioxidant defense, increasing ferroptosis susceptibility. The ER also regulates iron metabolism by synthesizing and modifying ferritin; dysregulation of this process elevates free iron levels, amplifying lipid peroxidation (66). ER-mitochondria interactions are critical for ferroptosis regulation. Mitochondrial dysfunction increases ER stress, while ER calcium release disrupts mitochondrial function (67). In COPD, CS disrupts this crosstalk, exacerbating both ER stress and mitochondrial dysfunction, and amplifying ferroptosis (68). Targeting ER stress-e.g., via chemical chaperones or antioxidants—may inhibit ferroptosis, representing a potential therapeutic strategy for COPD (69).

Lysosomes regulate cellular debris degradation, biomolecule recycling, and iron metabolism—all of which influence ferroptosis (70, 71). Lysosomal membrane integrity is critical for maintaining cellular homeostasis; under ferroptotic conditions, lysosomal leakage releases hydrolytic enzymes and iron-rich contents into the cytosol, amplifying oxidative stress (72). Lysosomes mediate iron turnover via ferritinophagy—the selective degradation of ferritin (the primary iron storage protein) (73). When iron is needed, lysosomes degrade ferritin, releasing iron into the cytosol. Misregulation of this process leads to iron overload, which catalyzes the Fenton reaction and exacerbates lipid peroxidation. In COPD, CS exposure disrupts lysosomal function, increasing ferritinophagy and free iron levels (74, 75). Lysosomes interact with mitochondria and the ER to modulate ferroptosis. Mitochondrial ROS production induces lysosomal biogenesis (76), while impaired lysosomal function compromises mitochondrial health (64). The ER-lysosome interaction facilitates lipid transfer; disruption of this crosstalk disrupts lipid homeostasis, increasing lipid peroxide levels. Targeting lysosomal function-e.g., via lysosomal stabilizers or ferritinophagy inhibitors-may mitigate ferroptosis in COPD (16).

Lipid droplets (LDs) are dynamic organelles serving as storage reservoirs for neutral lipids, playing pivotal roles in cellular energy homeostasis and lipid metabolism (77). Recent studies have revealed their significant involvement in regulating ferroptosis, characterized by iron-dependent lipid peroxidation. LDs influence ferroptosis primarily through lipid metabolism; they are essential for the storage and release of polyunsaturated fatty acids (PUFAs) (78). These fatty acids are particularly susceptible to oxidative damage, and their release from LDs can increase lipid peroxide levels within the cell, promoting ferroptotic cell death (78). Conversely, LDs can also store saturated fatty acids, which are less prone to oxidation, potentially safeguarding cells from ferroptotic insults. Thus, the balance between the types of lipids stored in LDs is a critical determinant of ferroptosis susceptibility. Additionally, LDs can modulate cellular redox status by sequestering ROS and providing a controlled environment for lipid peroxidation. Under conditions of increased cellular stress, LDs enhance the storage of toxic lipids that, upon mobilization, can trigger further oxidative stress and promote ferroptosis. Moreover, lipophagy—the selective degradation of lipid droplets—plays a significant role in these processes. When iron levels rise or oxidative stress increases, the autophagic degradation of LDs can release free fatty acids and accelerate lipid peroxidation, predisposing cells to ferroptosis.

Peroxisomes regulate lipid metabolism and ROS detoxification, influencing ferroptosis (79). They mediate the β-oxidation of long-chain fatty acids, generating lipid-derived signaling molecules that alter membrane composition (80). Imbalances in fatty acid composition—e.g., increased PUFAs—increase ferroptosis susceptibility (41). Peroxisomes also degrade hydrogen peroxide via catalase, peroxisomal dysfunction leads to ROS accumulation, exacerbating lipid peroxidation. Peroxisomes interact with mitochondria to regulate metabolism and ROS dynamics (59). In COPD, CS disrupts peroxisomal function, reducing catalase activity and increasing PUFAs (111). This disruption amplifies ferroptosis, contributing to lung injury. Targeting peroxisomal function—e.g., via catalase activators or fatty acid oxidation modulators—may inhibit ferroptosis in COPD (112).

The Golgi apparatus is a vital organelle involved in the post-translational modification, sorting, and trafficking of proteins and lipids within the cell (81). Recent discoveries indicate its significant role in regulating ferroptosis, characterized by iron-dependent lipid peroxidation. One mechanism by which the Golgi apparatus influences ferroptosis is through lipid modification, particularly phospholipid synthesis, which determines membrane integrity (82). By controlling lipid composition, the Golgi can affect cellular membranes’ susceptibility to oxidative damage. Additionally, it transports enzymes necessary for lipid metabolism, affecting the availability of PUFAs that are prone to oxidation (83). Furthermore, Golgi dysfunction can lead to the accumulation of misfolded proteins and increased oxidative stress, triggering signaling pathways that promote ferroptosis (84). Understanding the Golgi apparatus’s role in lipid and protein processing yields valuable insights into the mechanisms regulating ferroptosis and has implications for therapeutic strategies addressing diseases characterized by oxidative stress. In COPD, dysfunction in Golgi-mediated lipid trafficking could potentially contribute to ferroptotic sensitivity by altering the membrane composition of pulmonary cells.

Collectively, the dysfunction of key organelles—including mitochondria, endoplasmic reticulum, lysosomes, lipid droplets, peroxisomes, and the Golgi apparatus—synergistically amplifies ferroptosis susceptibility in COPD. Mitochondrial fission and ROS overproduction, ER stress-induced lipid peroxidation, lysosomal iron release via ferritinophagy, and altered lipid metabolism collectively disrupt cellular redox homeostasis. This organelle-centric vulnerability is further exacerbated by cigarette smoke, which perturbs inter-organelle communication and creates a pro-ferroptotic microenvironment. These subcellular alterations not only directly damage structural cells (e.g., airway epithelium) but also release damage-associated molecular patterns (DAMPs) and oxidized lipids that activate and recruit immune cells (85). Thus, the stage is set for a vicious cycle wherein organelle-driven ferroptosis and immune cell-mediated inflammation mutually reinforce each other, driving COPD progression. This interplay forms the foundation for exploring the role of immune cells in ferroptosis regulation, as detailed in the following section.

Macrophages are abundant in lung tissue and exist in two primary phenotypes: M1 (pro-inflammatory) and M2 (anti-inflammatory). In COPD, there is a shift toward M1 phenotype (121). M1 macrophages are activated by CS, bacterial products, and DAMPs, and secrete pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) (87). These cytokines recruit additional immune cells, amplifying inflammation and tissue damage. M1 macrophages exhibit dysregulated iron metabolism, with increased expression of hepcidin (Hamp) and ferritin heavy/light chains (FTH/FTL), and reduced expression of ferroportin (FPN) and IRP1/2 (88). This dysregulation increases iron storage, promoting M1 polarization (89). Iron overload enhances glycolysis—supporting the M1 phenotype-and increases ROS production and p53 acetylation, further driving M1 polarization. M1 macrophages also promote ferroptosis in neighboring structural cells (e.g., airway epithelial cells) by secreting cytokines that downregulate GPX4 and SLC7A11 (90). This crosstalk creates a self-perpetuating cycle: inflammation induces ferroptosis, while ferroptotic cells release DAMPs that activate more M1 macrophages (91, 92). In COPD, M1 macrophage function is dysregulated via multiple pathways. The nuclear factor-kappa B (NF-κB) pathway-critical for inflammation—is hyperactivated in M1 macrophages, leading to sustained cytokine production (93, 94). The peroxisome proliferator-activated receptor gamma (PPARγ) pathway-which regulates macrophage polarization—is suppressed, further favoring M1 polarization (95, 96). M1 macrophages also contribute to airway remodeling by releasing proteases (e.g., matrix metalloproteinases) and growth factors, exacerbating airflow limitation (97). Targeting M1 macrophages—e.g., via NF-κB inhibitors or PPARγ agonists—may reduce inflammation and ferroptosis in COPD (98).

Th17 cells—a subset of CD4⁺ T cells that secrete IL-17 and interferon-gamma (IFN-γ)-play a critical role in COPD inflammation (99). Th17 cells are recruited to the lungs in response to CS, where they activate macrophages and neutrophils (100). IL-17 enhances neutrophil recruitment and ROS production, amplifying oxidative stress and ferroptosis (101). In COPD, Th17 cell numbers are increased, and their activity correlates with disease severity (102). Th17 cells promote ferroptosis by secreting cytokines that disrupt antioxidant defenses. For example, IL-17 downregulates SLC7A11 expression, reducing cystine uptake and GSH synthesis (103). This impairment increases lipid peroxidation and ferroptosis in lung structural cells. Th17 cells also activate neutrophils, which release ROS and proteases, further exacerbating ferroptosis. Targeting Th17 cells—e.g., via IL-17 inhibitors—may mitigate inflammation and ferroptosis in COPD.

Neutrophils are the most abundant granulocytes and serve as first responders in COPD (104). They are recruited to the lungs in response to cytokines from M1 macrophages and Th17 cells. Activated neutrophils release ROS, proteases (e.g., neutrophil elastase), and neutrophil extracellular traps (NETs), contributing to tissue damage and mucus hypersecretion (105). Neutrophilic inflammation is a hallmark of COPD exacerbations, worsening symptoms and lung function (106). Neutrophils directly induce ferroptosis by releasing excessive ROS, overwhelming cellular antioxidant defenses (107). They also secrete LOXs, which catalyze PUFA oxidation and lipid peroxidation. Conversely, ferroptotic cells release DAMPs that activate neutrophils, amplifying inflammation (108). In COPD, neutrophil function is dysregulated: CS impairs neutrophil apoptosis, prolonging their survival and inflammation. Neutrophils also exhibit increased NET formation, which contributes to tissue damage and ferroptosis (109). Targeting neutrophils—e.g., via neutrophil elastase inhibitors or NET inhibitors—may reduce inflammation and ferroptosis in COPD. For example, sivelestat (a neutrophil elastase inhibitor) has been shown to reduce lung injury in COPD models (110). However, further research is needed to evaluate the efficacy of these strategies in clinical settings.

M2 macrophages are recognized for their anti-inflammatory properties and their capacity to facilitate tissue repair. They facilitate wound healing by secreting anti-inflammatory cytokines and growth factors that help resolve inflammation after an acute immune response. However, in the context of chronic COPD, the function of M2 macrophages may be impaired, leading to an imbalance with M1 macrophages (112). This impairment leads to persistent inflammation and ongoing tissue damage, ultimately affecting ferroptosis regulation. Enhancing M2 macrophage activity could help mitigate chronic inflammation and ferroptosis responses, creating a more favorable environment for repair. Promoting M2 polarization or functionality could potentially reduce the incidence of ferroptosis in lung tissue, thereby alleviating damage (113, 114).

Modulating macrophage polarization, inhibiting pro-inflammatory signaling pathways, and promoting tissue repair mechanisms are potential approaches for attenuating inflammation, reducing tissue damage, and improving lung function in individuals with COPD. Pharmacological agents, such as corticosteroids, PPARγ agonists, and NF-κB inhibitors, have been investigated for their ability to modulate macrophage function and polarization in COPD (115). In addition to pharmacological interventions, cell-based therapies, such as macrophage transplantation or mesenchymal stem cell therapy, hold promises for modulating the inflammatory response and promoting tissue repair in COPD. These approaches aim to restore the balance between pro-inflammatory and anti-inflammatory macrophages, enhance the resolution of inflammation, and support lung regeneration. Further research is needed to optimize the efficacy and safety of these therapeutic strategies and to translate preclinical findings into clinical applications for individuals with COPD (116).

Tregs maintain immune homeostasis suppressing excessive inflammation (117). They secrete anti-inflammatory cytokines (e.g., IL-10, TGF-β) and inhibit pro-inflammatory cell activation (118). In COPD, Treg function is compromised, leading to uncontrolled inflammation (119). Treg depletion increases Th17 cell activity and neutrophil recruitment, amplifying ferroptosis. Tregs regulate ferroptosis by maintaining redox balance. They secrete GSH precursors (e.g., cysteine), enhancing antioxidant defenses in neighboring cells (120). Tregs also inhibit ROS production by pro-inflammatory cells, reducing oxidative stress and ferroptosis (121). Enhancing Treg function—e.g., via IL-2 administration or Treg adoptive transfer—may mitigate inflammation and ferroptosis in COPD (122). For example, IL-2 treatment has been shown to increase Treg numbers and reduce inflammation in COPD models (123).

The PD-1/PD-L1 axis is critical for regulating immune responses during chronic inflammation characteristic of COPD (126). PD-L1 expression on antigen-presenting cells inhibits T cell activation, contributing to immune tolerance or exhaustion. In COPD, this inhibition poses challenges since robust immune responses against damaging environmental factors are crucial. Notably, the PD-1/PD-L1 axis may influence ferroptosis; suppressed T cell activity can hinder the clearance of damaged cells, fostering an inflammatory environment rich in oxidative stress that triggers ferroptosis in surrounding lung tissue (127). Targeting the PD-1/PD-L1 pathway could potentially restore T cell functionality, enhance immune responses, and ameliorate ferroptosis.

TIM-3 is another checkpoint that negatively regulates T cell responses. Its upregulation in chronic inflammatory conditions, such as COPD, may contribute to T cell exhaustion and ineffective immune responses (128–130). Recent studies suggest that TIM-3 may interact with ferroptosis signaling pathways, as chronic inflammation can induce senescence and ferroptosis in T cells, further compromising the immune response (131, 132). Developing therapeutic strategies to inhibit TIM-3 signaling could restore T cell activity and enhance immune efficacy against the inflammation and tissue damage characteristic of COPD (133). A comprehensive understanding of immune cell interactions—considering pro-inflammatory mediators, anti-inflammatory resolvers, immune checkpoints, and their relationships with ferroptosis—provides valuable insights into the underlying mechanisms of COPD. By addressing ferroptosis in both pro-inflammatory and anti-inflammatory contexts, new therapeutic strategies may be developed. Continued research into these pathways is essential for informing targeted therapies aimed at improving clinical outcomes and quality of life for individuals affected by this debilitating disease. Targeting both inflammation and ferroptosis could yield a multifaceted treatment approach that mitigates lung damage and promotes healing in COPD patients.

The distinct yet interconnected roles of immune cells—from the pro-ferroptotic actions of M1 macrophages, neutrophils, and Th17 cells to the protective efforts of M2 macrophages and Tregs—collectively establish a complex immunological landscape in COPD. However, these cell-specific effects do not occur in isolation. Instead, they form a dynamic, self-perpetuating network of crosstalk with ferroptotic lung cells, wherein immune-derived signals amplify lipid peroxidation, and ferroptosis-derived DAMPs further fuel inflammation. This intricate reciprocity underscores the necessity to move beyond a cell-centric view and toward a holistic understanding of the pathological circuit. Thus, we now explore the integrated ferroptosis-immune-metabolic axis, where dysregulated iron metabolism, immunomodulation, and metabolic rewiring converge to drive COPD progression.

Classical ferroptosis pathways primarily involve GPX4, System Xc-, and lipid peroxidation. Under normal conditions, GPX4 reduces lipid peroxides, preventing ferroptosis. However, compromised GPX4 activity—due to genetic mutations, post-translational modifications, or decreased expression—renders cells vulnerable to ferroptosis. Similarly, dysregulation of System Xc- limits cysteine availability, impairing glutathione synthesis and escalating oxidative stress. This cascade promotes increased lipid peroxidation, ultimately leading to ferroptotic cell death (144). In COPD, environmental stressors, particularly cigarette smoke, significantly influence the activation of classical pathways. These stressors can damage cellular components, trigger ROS production, and induce ferroptosis by overwhelming antioxidant defenses mediated by GPX4, as well as disrupting the cysteine-glutathione axis via System Xc- (145).

In contrast, non-classical ferroptosis pathways involve additional regulatory elements that diverge from classical mechanisms. Emerging studies indicate alternative pathways that utilize various signaling molecules and metabolic processes to modulate ferroptosis independently of GPX4 and System Xc-. For example, signaling through the hepcidin-ferroportin axis can influence cellular iron availability and metabolism. Disruption of iron homeostasis plays a significant role in COPD pathogenesis, exacerbating both lipid peroxidation and oxidative stress (146). Furthermore, long non-coding RNAs (lncRNAs) have come under scrutiny for their roles in regulating ferroptosis. These lncRNAs modulate the expression of ferroptosis-related proteins and may exhibit distinct roles across different cell types within the lungs of COPD patients (147–149). Understanding these non-classical regulatory factors is crucial for advancing targeted therapeutics aimed at the specific mechanisms underlying ferroptosis in COPD (150).

The intricate interplay between ferroptosis, inflammation, and cellular dysfunction underscores the pathophysiological complexity of COPD. There is increasing evidence linking ferroptosis to key processes driving the illness, highlighting its dual role as a contributor to inflammation and a mediator of tissue damage. The knowledge gained about the classical and non-classical pathways of ferroptosis elucidates potential targets for interventions aimed at ameliorating COPD pathology (Figure 4). Future research should focus on unraveling these mechanisms further, providing opportunities for developing novel therapeutic strategies that can mitigate ferroptosis and improve outcomes for individuals affected by COPD.

CS generates excessive ROS, including superoxide anion, hydrogen peroxide, and hydroxyl radicals (135, 163). These ROS deplete GSH and inhibit GPX4, impairing lipid peroxide clearance. CS also activates NADPH oxidase (NOX) enzymes, further increasing ROS production (164). This oxidative stress triggers lipid peroxidation, the hallmark of ferroptosis.

CS directly inhibits SLC7A11, the key subunit of System Xc^-. This inhibition reduces cystine uptake, limiting GSH synthesis. CS also downregulates SLC7A11 expression via NF-κB activation (90). The resulting GSH depletion impairs GPX4 activity, increasing ferroptosis susceptibility.

Cigarette smoke (CS) perturbs systemic and cellular iron homeostasis through several interconnected mechanisms: (1) Hepcidin Upregulation: CS exposure elevates hepcidin expression, which subsequently downregulates the iron exporter ferroportin (FPN). This impairs iron efflux from pulmonary macrophages, resulting in intracellular iron accumulation (165). (2) Activation of Ferritinophagy: CS promotes NCOA4-mediated ferritinophagy, the selective autophagic degradation of ferritin. This process liberates stored iron, elevating labile iron pools and potentiating Fenton reaction-derived oxidative damage (166). (3) Heme Oxygenase-1 (HO-1) Induction: CS upregulates HO-1, accelerating heme catabolism and subsequent iron release. Iron overload further exacerbates lipid peroxidation, contributing to ferroptotic cell death (167).

CS also impairs the function of critical organelles central to ferroptosis regulation: (1) Mitochondrial Damage: CS stimulates DRP1-dependent mitochondrial fission, resulting in fragmented, dysfunctional mitochondria that overproduce reactive oxygen species (ROS). This enhances lipid peroxidation and promotes ferroptosis (168). (2) Endoplasmic Reticulum Stress: CS induces ER stress and activates the unfolded protein response (UPR). Sustained ER stress contributes to oxidative lipid damage and facilitates ferroptotic signaling (169). (3) Lysosomal Destabilization: CS compromises lysosomal membrane integrity, leading to the leakage of iron ions and hydrolytic enzymes into the cytosol. This aggravates oxidative stress and accelerates ferroptosis (41). CS-induced ferroptosis is especially prominent in cell types critically involved in COPD pathology, including airway epithelial cells, alveolar macrophages, and vascular endothelial cells (170). For instance, airway epithelial cells subjected to CS exhibit marked lipid peroxidation and ferroptotic damage (98). Therapeutic strategies aimed at inhibiting ferroptosis—such as employing antioxidants or iron chelators—represent promising avenues for attenuating COPD progression. Having elucidated the ferroptosis-immune-metabolism axis as a key self-sustaining mechanism in COPD pathogenesis, these insights provide a foundation for novel therapeutic interventions. The complex interplay among lipid peroxidation, chronic inflammation, and metabolic reprogramming reveals multiple targetable pathways for therapeutic exploitation. In the following section, we translate these mechanistic findings into clinical applications, evaluating emerging strategies—including ferroptosis inhibitors, iron chelation therapies, and biomarker-driven approaches—designed to disrupt this pathological cycle and modify the progression of COPD.