Ferroptosis is a newly identified form of cell death that depends on iron ions and lipid peroxidation (20). Current research on its mechanisms relies on the detection of key biomarkers, such as the lipid peroxidation-related molecules Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) and Arachidonate 15-Lipoxygenase, as well as the dynamic changes in the lipid peroxidation products 4-Hydroxy-2-Nonenal (4-HNE) and malondialdehyde (17, 18). Lipid peroxidation involves two mechanisms: (1) the active site of lipoxygenase contains Fe³⁺, which catalyzes the oxidation of polyunsaturated fatty acids (PUFAs), and (2) polyunsaturated fatty acids undergo oxidation reactions with reactive oxygen species (ROS) and Fe²⁺. Both these processes can generate lipid hydroperoxides (LOOH), which ultimately participate in ferroptosis, The hallmark of ferroptosis is the inhibition of glutathione peroxidase 4 (GPX4), which can reduce LOOH to maintain cellular homeostasis (21). Additionally, ferroptosis suppressor protein 1 (FSP1) selectively inhibits ferroptosis by targeting the plasma membrane, thereby exerting a protective effect (20). These core regulatory mechanisms focus on the role of the lipid metabolism network in the maintenance of plasma membrane integrity. As the molecular mechanisms of ferroptosis are further elucidated, therapeutic strategies targeting this process may open new avenues for the treatment of related diseases.

Maintaining Copper (Cu) ion homeostasis is crucial for human health. Cu can primarily exist in two oxidative states: Cu⁺, which accounts for 95% of the total intracellular Cu content, and Cu²⁺, which constitutes 5% of extracellular Cu. The reduction of Cu²⁺ in the gut to Cu⁺ by metal reductases is followed by Cu uptake in a Ctr1-dependent manner. Notably, the form of Cu(copper complex or copper ions) also affects the accumulation efficiency (41, 42). Following absorption, Cu is exported into the bloodstream via the P-type ATPases ATP7A and ATP7B (43). Cu⁺ in the blood is easily oxidized to Cu²⁺, which can bind with plasma proteins, among which Ceruloplasmin (CP) transports Cu²⁺ to various organs. However, Intracellular Cu⁺ is delivered to specific targets by chaperones such as antioxidant 1 copper chaperone (Atox1), cytochrome c oxidase copper chaperone (Cox17), and copper chaperone for superoxide dismutase (CCS), or it can be stored in metallothionein (44). Dysregulated Cu metabolism has been implicated in metabolic disorders, providing a rationale for targeting Cu homeostasis in therapies (14, 45). Even before the formal concept of cuproptosis was proposed, studies showed that Cu imbalance could suppress cytochrome c oxidase (COX) activity, impair mitochondrial membrane potential, reduce energy production, activate the AMP-activated protein kinase (AMPK) pathway, shift cellular metabolism toward glycolysis, and inhibit cell growth (46, 47). In 2022, researchers discovered that Cu ions, when delivered by carriers such as elesclomol, bind to lipoylated proteins in the tricarboxylic acid (TCA) cycle. The intracellular reductase FDX1 promotes the synthesis of lipoic acid synthase (LIAS), which regulates lipoylation. Under Cu overload conditions, reduced FDX1 specifically interacts with the Cu ionophore elesclomol or elesclomol-Cu(II), facilitating the conversion of excess Cu²⁺ into more toxic Cu⁺ (48, 49). The released Cu⁺ subsequently binds to lipoylated proteins, inducing proteotoxic stress and ultimately leading to cell death (50). This process, termed cuproptosis, is accompanied by the loss of Fe-S cluster proteins. This form of cell death is uniquely reversible by Cu chelators, distinguishing it from other regulated cell death pathways (Table 2).

In PH, ferroptosis often exacerbates disease progression, primarily through a lipid peroxidation imbalance, which disrupts the redox equilibrium in pulmonary vascular endothelial and smooth muscle cells. In the vascular endothelium, promotion of the binding of SLC3A2 to ubiquitin induces ferroptosis, thereby causing endothelial injury. Similarly, PAH endothelial cells often exhibit pro-ferroptotic phenotypes. For instance, the overexpression of ACSL4, which is involved in lipid peroxidation, in PAECs induces ferroptosis, leading to an inflammatory pulmonary vascular burden, triggering PAH and subsequently inducing right ventricular dysfunction (10, 76). Additionally, peroxiredoxin 3 (PRDX3) serves as a crucial antioxidant protein. After peroxidation, it translocates from the mitochondria to the plasma membrane, where it triggers ferroptosis by inhibiting cystine uptake (77). Based on this, Liao et al. (78) found that peroxiredoxin 6, which belongs to the same family as that of PRDX3, can prevent the release of high-mobility group box 1 (HMGB1) induced by ferroptosis in PAECs and inhibit the TLR4/NLRP3 inflammasome pathway, thereby alleviating inflammatory responses and reversing PH. Similarly, Xie et al. (79) demonstrated that Fer-1 can also alleviate ferroptosis, which inhibits the release of HMGB1 and the subsequent inflammatory response, thus exerting a protective effect in PH. The ROS generated by ferroptosis can regulate the expression of endothelial to mesenchymal transition (EndMT)-related genes via the ROS-TGF-β axis, thereby endowing endothelial cells with the characteristics of mesenchymal cell migration and invasion capabilities, and thus promoting vascular remodeling (80).

Moreover, maintaining an appropriate level of Coenzyme Q10 (CoQ10) is crucial for protecting pulmonary cells. FSP1 synergizes with GPX4 to inhibit ferroptosis (20). Chen et al. (81) showed in aortic vessels that blocking the FSP1-CoQ10 pathway reduces cell viability and increases lipid peroxidation levels associated with ferroptosis in smooth muscle cells, exacerbating inflammatory damage, suggesting that the FSP1-CoQ10 pathway's role in counteracting ferroptosis may be significant in pulmonary vascular pathology. Rutin, a naturally occurring flavonoid, protects PAH rats from ferroptosis damage by directly interacting with protein kinase C (PKC)α and altering its structure and activity (82), highlighting the therapeutic potential of small and large molecule interactions. These findings not only provide new insights into PH pathogenesis but also offer potential interventions and therapeutic targets (Figure 1).

Cu, an essential trace element, may exacerbate PAH progression, with metabolic factors likely playing a dominant role. Cu affects vascular endothelium and smooth muscle, is associated with vascular aging, and participates in energy metabolism, signal transduction, and biomolecule synthesis (83, 84). Endothelial cell-derived nitric oxide (NO) diffuses to pulmonary smooth muscle cells (PSMCs) to induce vasodilation and oppose vascular remodeling. Cu contributes to NO synthesis and release, and restoring NO levels can prevent EndMT in PAECs, thereby counteracting the endothelial-to-mesenchymal transition that promotes a proliferative phenotype (85). Thus, inhaled nitric oxide (iNO) therapy effectively reduces PVR but is less effective in advanced stages, which are often accompanied by right heart failure (86). Moreover, a recent report showed that in children with PH who experienced in-hospital cardiac arrest, iNO treatment was associated with a lower uncorrected return of spontaneous circulation rate than that in controls (56), highlighting the need for further investigation of PH treatment.

Animal studies have shown that Cu overload induces mitochondrial abnormalities and inhibits angiogenesis, ultimately leading to Cuproptosis. Mo et al. (87) demonstrated that chelator-mediated reduction of Cu²⁺ in rat cerebral vessels inhibited cuproptosis, improved blood perfusion, and alleviated mitochondrial damage. Additionally, data from Phase II clinical trials indicated that the Cu ion chelator triethanolamine reduces Cu²⁺ toxicity on mitochondrial function and energy metabolism, significantly improving left ventricular systolic function (88). This also implies the potential involvement of cuproptosis in the pulmonary vasculature. However, direct studies linking cuproptosis to PH are lacking, although evidence suggests that PH severity correlates with elevated Cu ion levels in pulmonary vascular cells, possibly because of hypoxia or other factors upregulating Cu transporters (89). Excessive Cu accumulation may exacerbate PH progression by promoting cell death. Cu chelators have been shown to inhibit PAEC proliferation in patients with idiopathic pulmonary arterial hypertension (IPAH) by activating Apoptosis-Inducing Factor protein and triggering a non-caspase-dependent apoptotic pathway (90). Moreover, a diet deficient in Cu will not cause further damage to the right atrium (90, 91). These findings suggest that the role of Cuproptosis in PH and the activation or inhibition of associated signaling pathways in pulmonary vascular cells represent crucial directions for future research (Figure 2).

Aberrant Cu and Fe metabolism has been implicated in the pathogenesis of cardiovascular diseases (92). In the context of pulmonary vascular remodeling, exploring the interplay between these two forms of cell death may offer a more effective strategy for mitigating PH progression. However, current research on the synergistic effects of ferroptosis and cuproptosis remains largely limited to preclinical studies, with nanotechnology showing promising results. For instance, the MitCuOHA nanozyme has been shown to deplete cysteine (Cys), release Cu ions, and induce lipoylated protein aggregation, thereby simultaneously triggering cuproptosis and ferroptosis both in vitro and in vivo, resulting in enhanced tumor growth suppression (93). Similarly, Erastin and Cu—conjugated nanoparticles deplete glutathione (GSH), increase lipid peroxidation, inhibit the TCA cycle, and promote T-cell infiltration (16, 94). A nanocarrier system responsive to GSH via disulfide bonds (-S-S-) was also found to inhibit GPX4 and induce DLAT oligomerization, ultimately activating both cuproptosis and ferroptosis in tumors (95). Moreover, in treating myelodysplastic syndromes, combining the ferroptosis inducer imidazole ketone erastin (IKE) with Elesclomol-Cu (ES-Cu) induces severe mitochondrial damage, elevates ROS levels, and enhances lipoylation-dependent DLAT oligomerization, resulting in more pronounced cell death and greater inhibition of proliferation compared to monotherapy (96). Likewise, compared to the toxic effects of Cu chelation therapy, the traditional Chinese medicine curcumin has demonstrated marked efficacy in Wilson's disease by lowering intracellular Cu levels, inhibiting ferroptosis, and promoting the expression of oxidative stress-related markers such as GPX4, heme oxygenase 1 (HO-1), and Nrf2 (97). These findings underscore the therapeutic potential of co-targeting ferroptosis and cuproptosis in disease treatment. Nevertheless, clinical reports on the combined induction of these two forms of cell death remain scarce.

Although research on the interplay between cuproptosis and ferroptosis has primarily focused on cancer, a notable gap remains in cardiovascular research. Cancer cells often exhibit a Warburg (glycolytic) phenotype to meet excessive growth demands. In mouse models of early-stage PH, reduced activity of electron transport chain complexes in pulmonary endothelial cells elevates mitochondrial ROS, which upregulates hypoxia-inducible factor-1 alpha (HIF-1α) and enhances glycolysis. This results in a metabolic profile resembling that of cancer cells—albeit without invasion or metastasis—ultimately contributing to vascular remodeling (98, 99). These observations suggest that insights from cancer research on the interaction between cuproptosis and ferroptosis may also be relevant to pulmonary vascular remodeling.

PH associated with chronic pulmonary disease often exhibits unique pathological characteristics, primarily involving the loss of small pulmonary vessels, leading to vascular remodeling and increased mortality. However, the efficacy of conventional pharmacological treatments for PH remains limited (109), highlighting the urgent need for further research.

PAH is a vascular dysfunction associated with inflammatory infiltration and is closely related to mitochondrial dysfunction (139). For instance, studies have shown that serum ceruloplasmin (CP) levels are significantly elevated in patients with systemic sclerosis-associated PAH and PAH mouse models (140). CP is a vital protein responsible for binding Cu and transporting it to target organs. It relies on ferroxidase (FOX) activity to oxidize Fe2 + to Fe3+, thereby facilitating Fe transport. Excess Cu in the liver promotes FOX synthesis, potentially enhancing Fe absorption (141). Elevated Cu levels in the body can also induce oxidative stress and vascular dysfunction, both of which are detrimental to cardiovascular health (142).

When superoxide exacerbates endothelial injury, it contributes to the pathogenesis of PAH, as evidenced by the decreased levels of the antioxidant enzyme superoxide dismutase (SOD) in idiopathic PAH (143). Additionally, cohort studies have suggested that this disease is closely linked to autoimmunity, characterized by abnormal immune cell infiltration (144), including increased regulatory T-cell (Treg) concentrations and B cell frequencies. In hereditary PAH (HPAH) patients, the severity of pulmonary vascular lesions is associated with TIM-3-positive T cells (92). Although immune inflammation is a common feature of this disease, the precise relationship between immunity and IPAH remains unclear. Cuproptosis induces immunogenic cell death, thereby activating numerous immune cells (145). Similarly, Fe accumulation activates immune cells (146), both of which contribute to inflammatory responses. Cheng et al. (57) reported that lung cancer exhibits pulmonary vascular remodeling features of PH, possibly because of tumor cell-induced inflammation affecting the pulmonary vessels. Therefore, the immune effects of cuproptosis and ferroptosis may provide new perspectives for treating PH.

Cuproptosis, ferroptosis, and metabolism are closely linked to mitochondrial damage and cellular respiration (147). NFU1, a mitochondrial Fe-S scaffold protein, assembles and transfers Fe-S clusters to target proteins such as complex II and LIAS. Mutations in NFU1 impair these electron transport proteins, weaken mitochondrial respiration, and promote pulmonary artery smooth muscle cell proliferation (148). Accordingly, humanized NFU1 mutations leading to mitochondrial dysfunction are closely associated with pulmonary vascular remodeling, with a marked NFU1 deficiency observed in patients with IPAH. Supplementation of the downstream target LA in PAECs from patients with PAH has been shown to improve mitochondrial function (149). High Cu concentrations can also compromise the mitochondrial membrane (150). LA is a component of the PDH complex, and lipoyltransferase 1 (LIPT1), a recently identified cuproptosis-related gene, transfers LA from glycine cleavage system protein H to the E2 subunit of lipoylated substrates, thereby influencing PDH activity, as observed in cancer and metabolic studies (151–153). Further investigation revealed that elevated Fe levels may bind to pyruvate dehydrogenase kinase (PDK) 3, inhibiting PDH complex activity (154). Clinically, a 4-month trial demonstrated that administration of the PDK inhibitor dichloroacetate to patients with IPAH activated PDH, reduced PVR, and improved lung function (155). Conversely, another study found that PDK4-mediated inhibition of PDH could reduce pyruvate oxidation, thereby decreasing ROS generation in the TCA cycle, limiting lipid peroxidation, and mitigating ferroptosis (29). Thus, targeting mitochondrial ROS reduction may alleviate PDH-mediated ferroptotic damage and curb abnormal PASMC proliferation. Additionally, LIPT1 participates in the lipoylation of the mitochondrial enzymes PDH and KGDH. Studies on fibroblasts from patients with LIPT1 mutations have shown markedly reduced activity of these enzymes and intracellular Fe accumulation. In this setting, α-LA, an Fe chelator, inhibits ferroptosis and modulates PDH activity (85, 156). Consequently, suppressed PDH by iron metabolism may contribute to both cuproptosis and the inflammatory response, leading to adverse pathological outcomes.

In left heart disease, the loss of cardiac function leads to reduced myocardial contractility, ultimately resulting in heart failure (HF). This condition increases PVR and decreases pulmonary arterial compliance, thereby inducing postcapillary pulmonary hypertension (pcPH). HF is the primary cause of pcPH, with ischemic heart disease (IHF) being a major contributor to HF. IHF results from insufficient coronary blood supply, which initially damages the left ventricular cells (157, 158). Excessive Cu ion levels in patients with HF induce oxidative stress and severe cardiac injury (159). Furthermore, cuproptosis has been implicated in IHF and is characterized by the oligomerization of PDH complex proteins. In response, the body initiates a self-defense mechanism by downregulating FDX1 expression. Moreover, a strong positive correlation has been observed between cuproptosis-related genes and Treg cells, which can promote cardiac remodeling in IHF through inflammatory pathways (160). In hepatocellular carcinoma studies, ferroptosis inducers have been shown to inhibit FDX1 degradation while reducing the Cu chelator GSH, leading to the accumulation of lipoylated proteins (161) and, ultimately, cuproptosis. Ferroptosis is widely associated with various cardiac diseases (162). CoQ10, a core electron carrier in the mitochondrial respiratory chain, exerts its antioxidant effects by inhibiting lipid/DNA oxidation, thereby suppressing ferroptosis. Clinical trials have demonstrated that high-dose CoQ10 improves hepatic steatosis and enhances cardiovascular function (163). In a study by Sharp et al., patients with PAH treated with CoQ10 exhibited increased hemoglobin and mean corpuscular hemoglobin levels, along with improved right and left ventricular function (164). Therefore, ferroptosis regulated by CoQ10 may play a significant role in left-sided heart disease. Thus, FDX1 may serve as a hub for these two types of cell death. However, this requires further investigation.

CTEPH often develops in patients following pulmonary embolism. Despite at least 3 months of anticoagulation therapy, thrombi in the pulmonary artery become organized and resistant to conventional anticoagulation, resulting in vascular obstruction, impaired blood flow, and elevated pulmonary arterial pressure, typically presenting as dyspnea (165). Increased erythrophagocytosis in pulmonary microvascular endothelial cells enhances procoagulant activity by inducing ferroptosis, thereby contributing to thrombotic vascular remodeling (166). PAEC dysfunction caused by thrombi represents a key pathological feature of CTEPH. Experimental studies have demonstrated impaired autophagic activity in PAECs of CTEPH rats, as indicated by the reduced expression of microtubule-associated protein 1 light chain 3 (LC3B), a protein involved in autophagosome formation (167). Forkhead box O1 (FOXO1), a member of the FOXO family, interacts with LC3 to regulate autophagy. FOXO1, a glucose regulator, has been shown to activate hepatic hepcidin transcription (168), thereby reducing Fe release. Bioinformatic data from studies on FOXO signaling indicate that glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway, is central to cellular processes in lung cancer tissues (169). During PH progression, G6PD mutations drive metabolic reprogramming and inflammation, thereby promoting pulmonary arterial remodeling (170). Animal studies have revealed that under conditions of Cu overload, G6PD binds to FDX1, reducing its stability and downregulating NADPH and GSH levels, thereby enhancing cuproptosis (171). Cu chelators also reduce lipid peroxidation levels; therefore, FOXO1 and G6PD may mediate the interaction between Cu and ferroptosis in CTEPH, which requires further study using CTEPH models. In summary, future research on cuproptosis and ferroptosis may offer valuable insights into improving patient survival.