Skip to main content
Download PDF

Ferroptosis in cardiovascular diseases: role and mechanism

Cell & Bioscience volume 13, Article number: 226 (2023) Cite this article

Abstract

In multicellular organisms, regulatory cell death is a crucial aspect of growth and development. Ferroptosis, which was postulated roughly ten years ago, is a mode of cell death that differs from apoptosis, autophagy, and pyrodeath. This distinct pattern of cell death is triggered by an imbalance between oxidants and antioxidants and strongly associated with the metabolism of iron, lipids, amino acids, and glutathione. A growing body of research has implicated ferroptosis in the incidence and progression of many organ traumas and degenerative diseases. Recently, ferroptosis has gained attention as a crucial regulatory mechanism underlying the initiation and development of a variety of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiomyopathy, arrhythmia, chemotherapy, and Corona Virus-2-induced cardiac injury. Pharmacological therapies that inhibit ferroptosis have great potential for the management of cardiovascular disorders. This review discusses the prevalence and regulatory mechanisms of ferroptosis, effect of ferroptosis on the immune system, significance of ferroptosis in cardiovascular diseases, and potential therapeutic value of regulating ferroptosis in a variety of heart diseases.

Background

Recent studies have linked various types of controlled cell death to cardiovascular diseases (CVDs) [1,2,3,4]. Ferroptosis is a recently discovered iron-dependent regulated cell death mode that is distinguished from other regulated cell death modes by the accumulation of lipid hydroperoxides and the distinct mechanism [5, 6].

Iron-dependent accumulation of reactive oxygen species (ROS) and consumption of polyunsaturated fatty acids (PUFAs) in biofilms are the mechanisms underlying ferroptosis, which is initiated by inhibitors of glutathione biosynthesis or the glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4). When intracellular lipid ROS levels exceed the antioxidant activity of GPX4, redox homeostasis is broken, which eventually leads to cell death [7]. However, sex hormones can reduce iron decline and ultimately inhibit iron death by modulating MBOAT1 and MBOAT2 expression to reshape cellular phospholipid profiles [8].

CVDs have a significant impact on public health and are the leading cause of death and disability worldwide. A multinational study showed that the CVD burden is increasingly trending towards younger age groups [9]. Moreover, recent studies have found associations between ferroptosis and a variety of CVDs, including ischemia/reperfusion injury (I/R) [10], heart failure (HF) [11], cardiomyopathy [12], and atherosclerosis (AS) [13]. For example, AS involves the toxic accumulation of lipids in vessel walls, and in AS-related cells, such as macrophages, vascular smooth muscle cells, and endothelial cells, GPX levels are low, iron metabolism is dysregulated, and ROS are elevated [13, 14].

In this review, we discuss research on the prevalence and regulatory mechanisms of ferroptosis, the effect of ferroptosis on the immune system, and the significance of ferroptosis in cardiovascular diseases. Finally, we evaluate current therapies for CVD that target ferroptosis to reveal their challenges and prospects.

Overview of ferroptosis

Cell death is a crucial aspect of healthy biological development; however, abnormal cell death is implicated in a wide range of diseases [15]. For a long time, cell death was considered uncontrolled; however, in the 1950s, the concept of “programmed cell death” was suggested and adopted. Today, the concept of “regulated cell death,” which also refers to pyroptosis and necroptosis, is well accepted [16, 17].

Ferroptosis was identified as a new type of cell death since 2012, and it can be prevented by the antioxidant ferrostatin-1 [18]. In addition, different types of cell death connected to iron and oxidative stress have been discussed for years [19]. The connection between glutamate- and cysteine-induced cytotoxicity and cancer cell death may have initially inspired the concept of ferroptosis [20, 21], and research on oxidative stress-induced non-apoptotic cell death in neurons was reported in 2001 [22]. Erastin was reported to cause cancer cells to perish via undetermined mechanisms in 2003 [23]. A number of substances were later identified as having the ability to cause an iron-dependent cell death pattern with features distinct from those of known cell death modes [18, 24, 25]. The term ferroptosis was coined by Dixon et al. in 2012 for this type of iron-dependent cell death [18].

Regulation of ferroptosis

Iron, lipid, and amino acid metabolism governs the ferroptosis process, which is triggered when REDOX imbalance manifests as uncontrolled lipid peroxidation. GPX4 and a variety of antioxidant systems independent of GPX4 regulate ferroptosis. Here, we generalize the oxidation mechanisms and antioxidant mechanisms of ferroptosis (Fig. 1).

Fig. 1
figure 1

Regulatory mechanism of ferroptosis. The unstable iron pool oxidizes the PUFA on the cell membrane through the Fenton reaction and eventually leads to ferroptosis. GPX4 reduces PL-OOH to PL-OH in the presence of GSH and thus inhibits ferroptosis. DHODH in mitochondria and FSP1 reduce PL-OOH to PL-OH by providing CoQH2. GTP directly inhibits PUFA oxidation by increasing BH4

Full size image

Oxidation mechanisms

Lipid peroxidation

Unsaturated fatty acids play a major role in cell membrane lipid peroxidation, which is driven by free radicals, and its products increase during ferroptosis. PUFA peroxidation is crucial for ferroptosis despite the fact that a variety of cell membrane lipids may undergo oxidation [26, 27].

Long-chain-fatty-acid-coenzyme A (CoA) ligase 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) are enzymes that can incorporate PUFAs into the cell membrane. Either an enzymatic catalyst or a non-enzymatic free radical chain reaction can be used to achieve PUFA oxidation [28, 29]. The two major PUFAs that cause ferroptosis are arachidonic acid (AA) and adrenic acid (AdA) [26]. ACSL4, for example, catalyzes CoA to link with AA to create CoA-AA intermediates, which are esterified to phosphatidyl ethanolamine by LPCAT3, resulting in arachidonic acid-phosphatidyl ethanolamine (PE-AA). Both types of PE-AA oxidation, enzymatic (by lipoxygenase) and non-enzymatic (by autooxidation to PE-AA-OOH), eventually result in cell death [18, 30,31,32]. The ability of ACSL4 to effectively link CoA with long-chain PUFAs, such as AA and AdA, allows it to play a part in the process of ferroptosis. These long-chain PUFAs can then be re-esterified in phospholipids by different LPCAT enzymes. Short-chain monounsaturated fatty acyl tails (MUFAs) replace long-chain PUFA tails in phospholipids because of the genetic deletion of ACSL4 [26, 28]. Exogenous MUFA administration, MUFA synthesis upregulation, and ACSL3-dependent MUFA membrane accumulation can all decrease the likelihood of ferroptosis [30, 33, 34]. Therefore, one of the main methods of desensitizing cells to ferroptosis may be inhibiting ACSL4 expression, which is controlled by a number of signalling pathways [35, 36].Conversely, increased ACSL4 expression may contribute to ferroptosis in various pathophysiological settings [37, 38].

Iron metabolism

The Fenton reaction, for which iron is crucial, catalyses the peroxidation of PUFA-phospholipids (PUFA-PLs) through non-enzymatic automatic oxidation [39, 40]. Ferritin autophagy increases susceptibility to ferroptosis by increasing unstable iron pools through ferritin degradation [41,42,43]. Ferritin is recruited by nuclear receptor coactivator 4 (NCOA4) to selective cargo receptors on autophagosomes [44]. Targeting NCOA4 may be an important protocol for regulating unstable iron pools and controlling susceptibility to ferroptosis. The generation of ROS by iron-dependent Fenton reactions and the activation of iron-containing enzymes that regulate lipid peroxidation and redox homeostasis, such as arachidonate 5-lipoxygenase (ALOX), are two methods by which excess iron controls lipid peroxidation [30, 45]. In doxorubicin-induced mouse cardiomyopathy, an iron-deficient diet mitigated doxorubicin-induced myocardial toxicity and led to a higher survival rate by targeting cardiac iron metabolism [46].

Antioxidant mechanisms

GPX4 dependent antioxidant mechanisms

The GPX family includes a number of isoenzymes that are expressed in various subcellular locations and organs. PL hydroperoxide can be reduced to PL alcohol by GPX4 [47, 48]. GPX4 primarily defends against ferroptosis by preventing the production of lipid peroxides in the cell membrane. Compared with solute carrier family 7 member 11 (SLC7A11) knockout mice, GPX4 knockout mice displayed early embryonic pathogenicity [49, 50]. This implies that GPX4 and SLC7A11 may have different functions in the synthesis of lipid peroxides. Selenium and glutathione (GSH) control GPX4 expression and function. GPX4 reduces cytotoxic lipid peroxide to the equivalent alcohol accompanied by oxidation of GSH. GSH is a cysteine-containing tripeptide that functions as an intracellular antioxidant, and its production is mainly dependent on the uptake of cystine and the conversion of cystine to cysteine, which is mediated by the amino acid reverse transport system SLC7A11 [18]. When SLC7A11 is suppressed by erastin, the transsulfuration pathway is upregulated, which could block ferroptosis [51]. GPX4 is inactivated immediately after GSH depletion. Glutamate cysteine ligase inhibitors, such as butylthiamine subfoximine, or system xc− (xc−) cystine-glutamate antiporter inhibitors (erastin), can drive deficiencies of GSH [52]. The active domain of GPX4 is selenocysteine. The form of selenium used during GPX4 synthesis is selenocysteine, which is similar to cysteine but with sulphur substituted by selenium. Selenium can boost the anti-ferroptosis activity of GPX4 via selenocysteine residues at position-46 [53], and exogenous selenium supplementation inhibited ferroptosis in a mouse model of intracerebral haemorrhage [53,54,55].

When GPX4 activity is suppressed, lipid peroxides may build up and induce ferroptosis. Downregulated GPX4 expression increases the susceptibility of cells to ferroptosis, whereas upregulated GPX4 expression has the opposite impact [24]. Cystine starvation leads to GSH depletion and also induces glutamate accumulation, which inactivates GPX4 and ultimately leads to ferroptosis [52]. In addition, SLC7A11 activity is regulated in terms of protein–protein interactions, gene expression, and protein stability [56,57,58,59,60]. In addition to regulating GPX4 function, ferroptosis agonists also degrade GPX4 via autophagy or the ubiquitin–proteasome system [61,62,63]. Notably, GPX4 regulates cell apoptosis, necrosis, and pyrodeath in addition to ferroptosis [64,65,66].

GPX4-independent antioxidant mechanisms

Following the inactivation of GPX4, some cancer cells still remain resistant to ferroptosis [67, 68], implying that there are other ferroptosis defence mechanisms. Ferroptosis suppressor 1 (FSP1) inhibits ferroptosis independently of GPX4 [68, 69]. By reducing CoenzymeQ10 (CoQ), FSP1 prevents lipid peroxidation and suppresses ferroptosis [68, 69]. Similarly, in the mitochondrial inner membrane, dihydro-orotate dehydrogenase (DHODH) converts CoQ to CoQH2. By increasing DHODH activity when GPX4 is inactive, CoQH2 production is significantly increased and lipid peroxidation is neutralized, thereby mitigating ferroptosis in mitochondria [70]. The combination of GPX4 and DHODH in mitochondria inhibits mitochondrial lipid peroxidation. In addition to reducing CoQ, GTP cyclohydrolase-1 (GCH1) could produce tetrahydrobiopterin/dihydrobiopterin (BH4/BH2), thereby antagonizing ferroptosis independent of GPX4 by inhibiting lipid peroxidation [71].

Ferroptosis and immune microenvironment

Regulated cell death is vital for maintaining homeostasis. In the immune system, ferroptosis is essential. The immune system is divided into two parts: inherent immunity and adaptive immunity. Ferroptosis can contribute to the immune process by influencing the quantity and function of immune cells. Additionally, immune cells can detect ferroptosis in non-immune cells and use it to trigger an immune response [72]. CVD is closely related to immune response [73,74,75]. The impact of ferroptosis on macrophages, T cells, and B cells will be covered in next section (Fig. 2).

Fig. 2
figure 2

Interaction between ferroptosis and immune cells. Ferroptosis can promote the proliferation and activation of B cells, T cells, and macrophages. Ferroptosis also promotes the recruitment of macrophages. Macrophages induce ferroptosis by causing iron overload, and T cells induce ferroptosis by secreting IFN-γ

Full size image

Ferroptosis and macrophages

Ferroptosis has a pro-inflammatory impact in macrophages [76] and this process can be blocked by RAS-selective lethal 3 [77]. GPX4 requirements in vivo are not consistent across macrophage subsets and are limited to alternatively activated macrophages whose proliferation or expansion is reduced after GPX4 deletion [78]. Macrophages usually store iron by binding to ferritin. At various stages of macrophage polarization, the expression of genes related to iron also varies. The expression of HAMP and ferritin L and H subunits was higher in M1 macrophages compared to M2 macrophages, while the expression of ferroportin 1 (FPN) and iron regulatory protein 1/2 was lower, suggesting a greater ability to store iron and a stronger resistance to ferroptosis [79, 80]. Iron overload promotes the polarization of M1 macrophages by increasing the levels of M1 markers interleukin-6, tumour necrosis factor, and interleukin-1 and decreasing the levels of M2 marker tissue transglutaminase-2 [81].

Similarly, the malondialdehyde content and Fe2+ load were substantially increased in mice with myocardial infarction, accompanied by ferroptosis of myocardial cells. In heart tissue from myocardial infarction mice, the expression of the M1 marker nitric oxide synthase 2 (NOS2) was substantially upregulated compared with that of the control group, while the expression of the M2 marker interleukin-10 was significantly downregulated [82]. In the context of polycythemia, macrophages can induce iron death by phagocytosis of erythrocytes, thus exacerbating AS [83].

Ferroptosis and T cells

T cells are engaged in adaptive immunity, which includes responses to pathogens, allergens, and tumours [84]. T cell activity and function are regulated by ferroptosis. SLC7A11 is almost completely absent from human naive CD4+ T cells but is markedly increased during the T cell activation process [85]. T cell activation and proliferation require the maintenance of intracellular GSH levels [86]. T cells undergo ferroptosis when the GPX4 level is diminished or lipid peroxidation levels are elevated. T cell mortality induced by the glucocorticoid and diterpene compound Kayadiol entails ferroptosis [87, 88]. In contrast, loss of ACSL4 or overexpression of GPX4 can prevent ferroptosis in T cells [89,90,91,92]. Interestingly, ferroptosis is an important mechanism of T cell activation and immune function [92,93,94]. Vitamin E supplementation is a treatment option for GPX4 insufficiency because it prevents CD4+ or CD8+ T cells from expanding in the event of an acute infection [95].

The acute rejection of transplanted hearts has a negative impact on the therapeutic result. The number of CD3+, CD4+, and CD8+ cells in spleen cells and draining lymph node cells was substantially decreased in tumour necrosis factor-induced protein-8 −/− mice, and CD4+ and CD8+ cells also showed a decreased capacity to produce interferon based on activation of the TANK-binding kinase 1 signalling axis and the upregulation of GPX4. Interferon-γ promotes lipid peroxidation associated with ferroptosis in cardiomyocytes and is inhibited by GPX4 expression. Thus, heart allograft damage is significantly reduced by inhibiting ferroptosis [96]. Ferroptosis has great application potential in the treatment of a variety of diseases via its ability to influence immune response involving T cells.

Ferroptosis and B cells

Hematopoietic stem cells (HSCs) are the source of B cells, which grow through a number of stages before maturing into B cells, including early lymphoid progenitors, common lymphoid progenitors, pre-B cells in bone marrow, and transitional B cells in peripheral lymphoid organs [97]. During B1 and marginal zone B cell development, maintenance, and immunity, GPX4 is necessary to promote ferroptosis. However, GPX4 plays the opposite role in follicular B2 cell development, germinal centre response, and antibody response, which is because B1 and marginal zone B cells are more susceptible to lipid peroxidation and ferroptosis than follicular B2 cells [98]. In chickens, melatonin causes a significant increase in malondialdehyde content and inducible nitric oxide synthase expression and a significant decrease in superoxide dismutase, GSH peroxidase, and total antioxidant capacity, which ultimately promotes B cell proliferation [99]. Interestingly, both inadequate and excessive GPX4 concentrations inhibited B cell proliferation [100]. The impact of GPX4 on B cell proliferation requires additional research. The ferroptosis agonist erastin induces lipid peroxidation that promotes the proliferation and differentiation of human peripheral blood mononuclear cells into B cells and natural killer cells by downregulating the expression of bone morphogenetic protein family members [101]. B cells produce antibodies that interfere with cardiomyocyte function, recruit a variety of immune cells, and play an important role in heart failure [102]. Interestingly, regulatory B cells reduce the expression of C–C motif chemokine receptor 2 (CCR2) in monocytes, thereby inhibiting the mobilization of pro-inflammatory monocytes and ultimately limiting ventricular remodelling after myocardial infarction [103].

Ferroptosis and cardiovascular diseases

In this section, we summarize the relationship between ferroptosis and various CVDs. Patients with hereditary hemochromatosis often have iron overload, myocardial hypertrophy, and decreased left ventricular ejection fraction [104]. An increasing body of research has implicated ferroptosis in a number of CVDs, including myocardial I/R injury, cardiomyopathy, arrhythmia, chemotherapy, and heart injury caused by Corona Virus-2 (CoV-2) (Fig. 3).

Fig. 3
figure 3

Ferroptosis-related cardiovascular diseases and potential treatment reagents. Ferroptosis is involved in the occurrence and progression of ischemia perfusion injury, atrial fibrillation, chemotherapy-related cardiomyopathy, diabetes-related cardiomyopathy, myocardial hypertrophy, and COVID-19-related cardiomyopathy. Molecules and drugs targeting ferroptosis may ameliorate these ferroptosis-related heart diseases, and they include SMI, SSYXC, melatonin, curcumin, ferrostatin-1, and deferoxamine

Full size image

Ischemia reperfusion (I/R)

The leading cause of death and disability globally is acute myocardial infarction (MI). The best method of reducing acute myocardial ischemia injury and decreasing the size of myocardial infarction is through prompt and efficient myocardial reperfusion. However, I/R can cause myocardial reperfusion injury, which results in myocardial cell death [5]. Ferroptosis occurs in the early stages of I/R injury and represents the dominant form of cell death during prolonged reperfusion [105]. Ischemia triggers redox reaction between PUFAs and phospholipids in cardiomyocytes, which results in powerful oxidative damage during the reperfusion stage [106]. Therefore, ferroptosis plays an important role in I/R injury [107]. Iron chelating agents can protect cardiomyocytes from cardiac iron deposition during I/R [10]. Oxidation of phosphatidylcholine during reperfusion produces phosphatidylcholine oxide (OxPC), which disrupts mitochondrial biological function and calcium transport and induces ferroptosis, leading to widespread cell death. However, cell death during reperfusion is prevented by neutralizing OxPC. OxPC produced during reperfusion injury is a potent inducer of cardiomyocyte death [108]. In I/R, bone marrow stromal cell exo-culture demonstrated increased cell proliferation and GSH content and decreased iron concentration, ROS levels, and iron death marker protein levels. As a result, ferroptosis of cardiomyocytes was inhibited, I/R-induced cardiac injury was reduced, and cardiac function was enhanced [109]. Another study showed that the levels of the non-coding RNA miR-199a-5p were increased in I/R [110]. Cardiomyocyte mortality after ferroptosis can be improved by inhibitors of ferroptosis. MiR-199a-5p blocks the signalling cascade involving Akt serine/threonine kinase and endothelial nitric oxide synthase; thus, it is a key player in promoting iron damage-induced cardiomyocyte death during ischemia/hypoxia injury [110]. Similarly, blocking miR-122, which specifically targets GPX4, can produce protective effects against I/R injury in vitro [111]. Compared with animals lacking the cardiomyocyte-specific hypoxia-inducible factor-1 (HIF-1), control mice with I/R injury presented increased frataxin expression in their hearts. Frataxin can preserve mitochondrial membrane integrity and normal cardiomyocyte function by reducing ROS generation and iron overload in the mitochondria, and it may be an iron-storing protein [112].

Thus, the above findings indicate that ferroptosis is a potential therapeutic target for myocardial I/R injury. In I/R rats, resveratrol reduced oxidative stress levels and Fe2+ content and increased GPX4 expression, thereby inhibiting ferroptosis. Additionally, resveratrol prevents ferroptosis by controlling ubiquitin-specific peptidase 19-Beclin1 autophagy. Thus, resveratrol may be a potential drug for preventing myocardial I/R damage [113]. The nuclear factor erythroid 2-related factor 2 (NRF2)/System xc-/GPX4 pathway is regulated by naringenin, which can prevent ferroptosis, and erastin reversed the naringenin-mediated protective effects of cardiomyocytes. Therefore, maringenin regulates the Nrf2/System Xc-/GPX4 axis to suppress ferroptosis, which reduces myocardial I/R injury [114]. Shenmai injection can also reduce cardiac I/R injury by activating the Nrf2/GPX4 signalling pathway [115]. In addition, dapagliflozin can reduce MI-reperfusion injury via inhibiting ferroptosis by modulating MAPK signalling pathways [116].

Atrial fibrillation

Atrial fibrillation (AF), a prevalent arrhythmia in clinical settings, is linked to high clinical mortality rates. Patients with AF usually die not from AF but from its concomitant complications, such as heart failure (HF), MI, venous thromboembolism (VTE), and stroke. According to data from the Framingham Heart Study, the incidence of AF has quadrupled over the past 50 years [117]. The occurrence of AF is related to many pathological factors; for example, frequent and excessive alcohol consumption can activate ferroptosis and increase the incidence of AF. However, ferroptosis inhibitors can reduce the susceptibility to AF [118]. Therefore, ferroptosis may contribute to the development of AF. Ferroptosis activation was later discovered to significantly increase the susceptibility to AF in rat models of endotoxemia, canine rapid atrial pacing, and chronic iron overload mice, whereas ferroptosis inhibition was found to reverse this change [119,120,121]. Due to cardiac iron deposition, beta-thalassemia patients have a higher risk factor for developing AF [122]. In these patients, iron chelators might help prevent AF. Taken together, ferroptosis inhibitors may be promising therapeutic targets for the prevention and treatment of AF in a range of pathological situations. Shensong Yangxin capsule can reduce the susceptibility of AF and inhibit electrical and structural remodelling in patients with metabolic syndrome by upregulating FPN and inhibiting ferroptosis. This indicates that the Shensong Yangxin capsule may be a potential drug to treat AF caused by metabolic syndrome [123].

COVID-19-related cardiomyopathy

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), sparked a global pandemic. Either the acute or late acute phase of COVID-19 may induce cardiovascular complications, such as palpitations, chest pain, stress cardiomyopathy, myocarditis, postural tachycardia, arrhythmias, and MI [124,125,126,127,128,129]. In patients with COVID-19, SARS-CoV-2 can inhibit the expression of a specific set of selenoprotein mRNAs and suppress GPX4 activity [130]. In addition, SARS-CoV-2 ORF3a promotes NRF2 degradation through the recruitment of Keap1, thus weakening the resistance of cells to oxidative stress and promoting ferroptosis [131]. In addition, coronavirus can induce ferroptosis via ACLS4. Interestingly, by inhibiting ACLS4, coronavirus replication is reduced [132]. Thus, ferroptosis has been suggested as a possible therapeutic target for the treatment of COVID-19. Following SARS-CoV-2 infection, sinoatrial node cells in the heart develop ferroptosis and exhibit dysfunction. Iron chelators deferoxamine and lactoferrin and the tyrosine kinase inhibitor imatinib prevent viral infection and ferroptosis-associated injury [133, 134].

Diabetes-associated cardiomyopathy

Diabetes is very prevalent in patients with CVDs. Myocardial fibrosis, hypertrophy, and cardiac diastolic dysfunction are characteristics of diabetic cardiomyopathy, which is distinct from coronary artery disease and hypertension and eventually results in HF. Diabetic cardiomyopathy is primarily caused by insulin resistance, type 2 diabetes, and the resulting hyperinsulinemia [135]. The progression of the illness is mediated by a number of mechanisms, including oxidative stress [136]. In diabetic retinopathy, where autophagy serves a protective role, ferroptosis has been implicated in the death of pigment epithelial cells [137]. Similarly, ferroptosis inhibitors prevent high-glucose-induced cardiomyocyte dysfunction in diabetes-induced cardiomyopathy, suggesting that ferroptosis may play an essential part in the development of diabetic cardiomyopathy [12].

Ferroptosis was activated in a diabetic rabbit model. Curcumin can reduce cardiac injury caused by ferroptosis and enhance cardiac performance by increasing Nrf2 nuclear translocation and GPX4 and haem oxygenase-1 (HO-1) expression [138]. The activation of HO-1, a mitochondrial enzyme that catalyses the degradation of haem to generate ferrous iron, results in increased mitochondrial iron, thereby upregulating ferroptosis [139, 140]. Curcumin might also regulate ferroptosis by upregulating ferritin and SLC7A11 levels; moreover, NRF2 stimulation prevents ferroptosis [141]. Non-coding RNAs are also crucial in the development of diabetic cardiomyopathy. lncRNA-ZFAS1 can promote the progression of diabetic cardiomyopathy by downregulating cyclin-D2, thereby facilitating ferroptosis. These findings suggest a potential strategy for treating and preventing diabetic cardiomyopathy by targeting lncRNA-ZFAS1 [142].

Patients with diabetes are more likely to develop coronary heart disease. The optimum treatment for acute MI is prompt revascularization. Revascularization may lead to I/R injury, thereby impairing clinical benefit [143]. Activation of ferroptosis in diabetic patients increases the vulnerability of the heart after I/R. The NRF2/FPN1 signalling pathway can inhibit ferroptosis by regulating iron metabolism homeostasis, which partially alleviates myocardial reperfusion injury in diabetes mellitus [144]. One effective strategy for the prevention and management of diabetic myocardial I/R injury may be to inhibit ferroptosis by controlling iron metabolism.

Chemotherapy-related cardiomyopathy

One of the major side effects of applying doxorubicin is potentially fatal cardiovascular toxicity, such as congestive HF and cardiomyopathy [145]. Doxorubicin can inhibit GPX4 and NRF2 production, thereby causing lipid peroxidation and ultimately ferroptosis. However, GPX4 upregulation or Fe2+ chelation in mitochondria prevents doxorubicin-induced mitochondrial ferroptosis [146, 147]. In addition, the FoxO4/ectonucleotide pyrophosphatase/phosphodiesterase family member 2 axis and the TRIM21/NRF2 axis can inhibit ferroptosis, thereby alleviating doxorubicin-induced cardiotoxicity. These findings suggest an effective treatment for doxorubicin cardiotoxicity [148, 149].

Melatonin and empagliflozin can inhibit ferroptosis and protect against doxorubicin-induced cardiotoxicity. Melatonin reverses the doxorubicin-induced upregulation of ACSL4 and downregulation of GPX4 and yes-associated protein 1 (YAP1). By participating in NLRP3 and NF-kB related signalling pathways, empagliflozin, a new hypoglycaemic drug that can improve the prognosis of CVDs, can attenuate ferroptosis, fibrosis, apoptosis, and inflammation in doxorubicin-treated mice and significantly improve cardiac function, thereby opening up a new avenue for the treatment of doxorubicin-related cardiotoxicity [150, 151]. Nevertheless, myocardial ferroptosis can be exacerbated by inducing a histamine deficit or pharmacologically inhibiting the histamine H1 receptor. Disruption of the histamine/histamine H1 receptor signalling axis regulates the signal transducer and activator of transcription 3 (STAT3)-SLC7A11 pathway, which may exacerbate doxorubicin-related cardiotoxicity [152]. This finding suggests possible adverse effects of antihistamines in patients treated with doxorubicin.

Hypertrophic cardiomyopathy

In the heart, high blood pressure and aortic stenosis often lead to hypertrophic cardiomyopathy, fibrosis and eventually HF. Cardiac hypertrophy and decreased left ventricular ejection fraction have been observed in patients with hereditary hemochromatosis [104], among whom heart damage caused by iron overload is the leading cause of death. Age-related increases in cardiac iron levels were observed in a hemochromatosis mouse model, which suggests that iron deposition and elevated levels of oxidative stress occurred [153]. Thus, ferroptosis may be involved in heart hypertrophy in hemochromatosis patients.

A high-iron diet causes decreased GSH levels and increased lipid peroxidation, which lead to significant heart damage and hypertrophic cardiomyopathy. These changes were reversed by ferrostatin-1, thus providing solid evidence that ferroptosis contributes to ventricular hypertrophy [154]. Cardiomyocytes treated with angiotensin II underwent hypertrophy due to the decrease of xCT mRNA and protein levels. Knocking out xCT can exacerbate cardiac hypertrophy and dysfunction. Similarly, ferrostatin-1 and Elabela may reduce heart remodelling by inhibiting ferroptosis [155, 156]. Cardiac hypertrophy is associated with abnormal cardiac microvascular function [157]. SLC7A11 transcription is downregulated and ferroptosis is promoted when interferon regulatory factor 3 (IRF3) is inhibited. However, when docosahexaenoic acid is applied, IRF3 expression is increased and the endothelial system is protected from pressure overload. This finding implies that up-regulating IRF3 may offer possible therapeutic approaches for the management of HF and cardiac hypertrophy [158]. In human and mouse hypertrophic heart models and mice injected with apelin-13, cardiac mitochondrial iron deposition was significantly increased and NCOA4 and sideroflexin 1 (SFXN1) expression was elevated. Apelin-13-induced mitochondrial iron excess is reversed by inhibiting SFXN1 and NCOA4 expression, which it also mitigates cardiac hypertrophy. Furthermore, NCOA4 suppression prevented the rise in SFXN1 expression brought on by apelin-13. This indicates that NCOA4 functions upstream of SFXN1 and implicates NCOA4-mediated autophagy and ferroptosis in the development of cardiac hypertrophy [159, 160]. The expression of ATP-binding cassette subfamily B member 7 and mitochondrial oxidative phosphorylation enzymes were significantly downregulated in rats with left ventricular hypertrophy, while lipid metabolites, iron, ROS, and autophagy-associated proteins were upregulated in the cytoplasm and mitochondria. However, by interacting with mitochondrial complexes IV and V, ATP-binding cassette subfamily B member 7 reverses the above process when it is overexpressed [161].

Puerarin has been found to ameliorate HF in the clinic, and its anti-cardiomyocyte cell death function has been confirmed by animal studies. Puerarin can inhibit cardiac ferroptosis and protect cardiac function in HF mice with over-afterload. This suggests that puerarin may be a potential treatment strategy for HF [162]. Mice receiving intravenous iron supplementation showed increased iron deposition in lung tissue, increased pulmonary artery resistance, and right heart hypertrophy. Losartan, an angiotensin II-1 receptor blocker, prevents iron overload-induced vascular remodelling, pulmonary hypertension, and right ventricular hypertrophy [163].

Ferroptosis-associated therapeutic opportunities

Ferroptosis is linked to the occurrence and progression of a number of heart illnesses, including myocardial I/R injury, AF, hypertensive heart disease, diabetic heart disease. There are novel opportunities for the treatment of these diseases based on the involvement of ferroptosis (Table 1). In myocardial I/R damage, iron-chelating agents can be protective [102]. Exosomes and non-coding RNA are also implicated in the induction of iron death, and their inhibitors could be used as potential therapeutic targets [109,110,111]. Resveratrol, naringenin and Shenmai injection have shown protective effects on reperfusion of myocardium [113,114,115]. The likelihood of AF can be decreased by iron-chelating medications [122], and it may also be reduced by Shensong Yangxin capsules by inhibiting the ferroptosis pathway [123]. Imatinib, the iron-chelating agent deferoxamine, and lactoferrin all showed protective effects in ferroptosis-induced cardiac dysfunction induced by COVID-19 [133, 134]. In diabetic cardiomyopathy, non-coding RNA may be involved in disease progression by inducing ferroptosis. Therefore, specific non-coding RNA inhibitors can play a protective role [142]. In addition, curcumin has been shown to inhibit ferroptosis and play a cardioprotective role [138]. Doxorubicin treatment-related heart damage is a long-term clinical concern, although studies have found that melatonin and empagliflozin may have a heart-protective effect by inhibiting ferroptosis. In addition, empagliflozin is frequently used to manage diabetes [150, 151]. Losartan and puerarin can inhibit ventricular hypertrophy by inhibiting ferroptosis. Losartan has been used in the clinic, and puerarin is a potential therapeutic target [162, 163].

Table 1 Cardiovascular disease treatment strategies involving ferroptosis
Full size table

In ferroptosis-related heart disease, a variety of effectors have been identified that play a cardioprotective role either by inhibiting oxidation mechanisms or by regulating antioxidant mechanisms, including the ferroptosis pathway. However, further research is needed before these agents can be used in the clinic.

Conclusions and perspectives

One of the main threats to human life and health is CVD. To improve patient quality of life and save lives, advances in the treatment of CVD are desperately needed. Ferroptosis has recently been identified as a regulated mode of cell death, and a growing number of studies have demonstrated that ferroptosis is closely related to the occurrence and development of various CVDs. Studies have revealed the role of ferroptosis in heart disease and its regulatory mechanisms and thus have provided mechanistic insights into CVDs and novel treatment options. However, the role of ferroptosis in this field is not sufficiently understood to develop an efficient treatment strategy.

The field of ferroptosis is being actively studied. More research is needed to refine our understanding of the regulatory mechanisms of ferroptosis. In addition, the inducers and inhibitors of ferroptosis need to be further clarified so that more substances with stronger application potential can be screened to serve as treatments. There are many modes of regulated cell death, and they are not completely independent of each other. Thus, further research is needed to determine the relationship between different regulated cell death modes and reveal how they interact with each other. Such work would provide a deeper understanding of the occurrence and development of living processes and may reveal better disease treatment strategies.

Availability of data and materials

Not applicable.

Abbreviations

CVD:

Cardiovascular disease

ROS:

Reactive oxygen species

PUFAs:

Polyunsaturated fatty acids

GPX4:

Glutathione peroxidase 4

AS:

Atherosclerosis

ACSL4:

Long-chain-fatty-acid-CoA ligase 4

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

AdA:

Adrenic acid

MUFAs:

Monounsaturated fatty acyl tails

NCOA4:

Nuclear Receptor Coactivator 4

SLC7A11:

Solute carrier family 7 member 11

GSH:

Glutathione

FSP1:

Ferroptosis suppressor 1

NOS2:

Nitric oxide synthase 2

HSCs:

Hematopoietic stem cells

MI:

Myocardial infarction

HIF-1:

Hypoxia-inducible factor-1

NRF2:

Nuclear factor erythroid 2-related factor 2

AF:

Atrial fibrillation

HF:

Heart failure

VTE:

Venous thromboembolism

COVID-19:

Coronavirus disease 2019

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus type 2

HO-1:

Haem oxygenase-1

YAP1:

Yes-associated protein 1

STAT3:

Signal transducer and activator of transcription 3

IRF3:

Interferon regulatory factor 3

SFXN1:

Sideroflexin 1

References

  1. Yarovinsky TO, Su M, Chen C, Xiang Y, Tang WH, Hwa J. Pyroptosis in cardiovascular diseases: pumping gasdermin on the fire. Semin Immunol. 2023;69: 101809.

    Article  CAS  PubMed  Google Scholar 

  2. Yang L, Yang P, Lip GYH, Ren J. Copper homeostasis and cuproptosis in cardiovascular disease therapeutics. Trends Pharmacol Sci. 2023;44(9):573–85.

    Article  CAS  PubMed  Google Scholar 

  3. Linkermann A, Green DR. Necroptosis. N Engl J Med. 2014;370(5):455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jose Corbalan J, Vatner DE, Vatner SF. Myocardial apoptosis in heart disease: does the emperor have clothes? Basic Res Cardiol. 2016;111(3):31.

    Article  CAS  PubMed  Google Scholar 

  5. Wu X, Li Y, Zhang S, Zhou X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics. 2021;11(7):3052–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Xie LH, Fefelova N, Pamarthi SH, Gwathmey JK. Molecular mechanisms of ferroptosis and relevance to cardiovascular disease. Cells. 2022;11(17):2726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhou RP, Chen Y, Wei X, Yu B, Xiong ZG, Lu C, et al. Novel insights into ferroptosis: implications for age-related diseases. Theranostics. 2020;10(26):11976–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liang D, Feng Y, Zandkarimi F, Wang H, Zhang Z, Kim J, et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell. 2023;186(13):2748-64.e22.

    Article  CAS  PubMed  Google Scholar 

  9. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982–3021.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pucheu S, Coudray C, Tresallet N, Favier A, de Leiris J. Effect of iron overload in the isolated ischemic and reperfused rat heart. Cardiovasc Drugs Ther. 1993;7(4):701–11.

    Article  CAS  PubMed  Google Scholar 

  11. Chen Y, Guo X, Zeng Y, Mo X, Hong S, He H, et al. Ferroptosis contributes to catecholamine-induced cardiotoxicity and pathological remodeling. Free Radic Biol Med. 2023;207:227–38.

    Article  CAS  PubMed  Google Scholar 

  12. Chen L, Yin Z, Qin X, Zhu X, Chen X, Ding G, et al. CD74 ablation rescues type 2 diabetes mellitus-induced cardiac remodeling and contractile dysfunction through pyroptosis-evoked regulation of ferroptosis. Pharmacol Res. 2022;176: 106086.

    Article  CAS  PubMed  Google Scholar 

  13. Ouyang S, You J, Zhi C, Li P, Lin X, Tan X, et al. Ferroptosis: the potential value target in atherosclerosis. Cell Death Dis. 2021;12(8):782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guo Y, Lu C, Hu K, Cai C, Wang W. Ferroptosis in cardiovascular diseases: current status, challenges, and future perspectives. Biomolecules. 2022;12(3):390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011;147(4):742–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yuan Q, Sun Y, Yang F, Yan D, Shen M, Jin Z, et al. CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes. Signal Transduct Target Ther. 2023;8(1):99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gao P, Cao M, Jiang X, Wang X, Zhang G, Tang X, et al. Cannabinoid receptor 2-centric molecular feedback loop drives necroptosis in diabetic heart injuries. Circulation. 2023;147(2):158–74.

    Article  CAS  PubMed  Google Scholar 

  18. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eaton JW, Qian M. Molecular bases of cellular iron toxicity. Free Radic Biol Med. 2002;32(9):833–40.

    Article  CAS  PubMed  Google Scholar 

  20. Eagle H. Nutrition needs of mammalian cells in tissue culture. Science. 1955;122(3168):501–14.

    Article  CAS  PubMed  Google Scholar 

  21. Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron. 1989;2(6):1547–58.

    Article  CAS  PubMed  Google Scholar 

  22. Tan S, Schubert D, Maher P. Oxytosis: a novel form of programmed cell death. Curr Top Med Chem. 2001;1(6):497–506.

    Article  CAS  PubMed  Google Scholar 

  23. Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003;3(3):285–96.

    Article  CAS  PubMed  Google Scholar 

  24. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15(3):234–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447(7146):864–8.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81–90.

    Article  CAS  PubMed  Google Scholar 

  27. Wenzel SE, Tyurina YY, Zhao J, St Croix CM, Dar HH, Mao G, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell. 2017;171(3):628-41.e26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91–8.

    Article  CAS  PubMed  Google Scholar 

  29. Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10(7):1604–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A. 2016;113(34):E4966–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hishikawa D, Shindou H, Kobayashi S, Nakanishi H, Taguchi R, Shimizu T. Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity. Proc Natl Acad Sci U S A. 2008;105(8):2830–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Küch EM, Vellaramkalayil R, Zhang I, Lehnen D, Brügger B, Sreemmel W, et al. Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol. Biochim Biophys Acta. 2014;1841(2):227–39.

    Article  PubMed  Google Scholar 

  33. Magtanong L, Ko PJ, To M, Cao JY, Forcina GC, Tarangelo A, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol. 2019;26(3):420-32.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tesfay L, Paul BT, Konstorum A, Deng Z, Cox AO, Lee J, et al. Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 2019;79(20):5355–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brown CW, Amante JJ, Goel HL, Mercurio AM. The α6β4 integrin promotes resistance to ferroptosis. J Cell Biol. 2017;216(12):4287–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu J, Minikes AM, Gao M, Bian H, Li Y, Stockwell BR, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature. 2019;572(7769):402–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 2019;26(11):2284–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lei G, Zhang Y, Koppula P, Liu X, Zhang J, Lin SH, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 2020;30(2):146–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol. 2019;15(12):1137–47.

    Article  CAS  PubMed  Google Scholar 

  40. Shah R, Shchepinov MS, Pratt DA. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent Sci. 2018;4(3):387–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59(2):298–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26(9):1021–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12(8):1425–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014;509(7498):105–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fang X, Wang H, Han D, Xie E, Yang X, Wei J, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A. 2019;116(7):2672–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med. 2019;133:144–52.

    Article  CAS  PubMed  Google Scholar 

  48. Ursini F, Maiorino M, Valente M, Ferri L, Gregolin C. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochim Biophys Acta. 1982;710(2):197–211.

    Article  CAS  PubMed  Google Scholar 

  49. Imai H, Hirao F, Sakamoto T, Sekine K, Mizukura Y, Saito M, et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun. 2003;305(2):278–86.

    Article  CAS  PubMed  Google Scholar 

  50. Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003;34(4):496–502.

    Article  CAS  PubMed  Google Scholar 

  51. Hayano M, Yang WS, Corn CK, Pagano NC, Stockwell BR. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ. 2016;23(2):270–8.

    Article  CAS  PubMed  Google Scholar 

  52. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172(3):409-22.e21.

    Article  CAS  PubMed  Google Scholar 

  54. Alim I, Caulfield JT, Chen Y, Swarup V, Geschwind DH, Ivanova E, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell. 2019;177(5):1262-79.e25.

    Article  CAS  PubMed  Google Scholar 

  55. Friedmann Angeli JP, Conrad M. Selenium and GPX4, a vital symbiosis. Free Radic Biol Med. 2018;127:153–9.

    Article  CAS  PubMed  Google Scholar 

  56. Song X, Zhu S, Chen P, Hou W, Wen Q, Liu J, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system X(c)(-) activity. Curr Biol. 2018;28(15):2388-99.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Liu T, Jiang L, Tavana O, Gu W. The Deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 2019;79(8):1913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chen D, Tavana O, Chu B, Erber L, Chen Y, Baer R, et al. NRF2 is a major target of ARF in p53-independent tumor suppression. Mol Cell. 2017;68(1):224-32.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520(7545):57–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018;20(10):1181–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Liu Y, Wang Y, Liu J, Kang R, Tang D. Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death. Cancer Gene Ther. 2021;28(1–2):55–63.

    Article  CAS  PubMed  Google Scholar 

  62. Wu Z, Geng Y, Lu X, Shi Y, Wu G, Zhang M, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A. 2019;116(8):2996–3005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhu S, Zhang Q, Sun X, Zeh HJ 3rd, Lotze MT, Kang R, et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 2017;77(8):2064–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ran Q, Van Remmen H, Gu M, Qi W, Roberts LJ 2nd, Prolla T, et al. Embryonic fibroblasts from Gpx4+/- mice: a novel model for studying the role of membrane peroxidation in biological processes. Free Radic Biol Med. 2003;35(9):1101–9.

    Article  CAS  PubMed  Google Scholar 

  65. Canli Ö, Alankuş YB, Grootjans S, Vegi N, Hültner L, Hoppe PS, et al. Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood. 2016;127(1):139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kang R, Zeng L, Zhu S, Xie Y, Liu J, Wen Q, et al. Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host Microbe. 2018;24(1):97-108.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547(7664):453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–8.

    Article  CAS  PubMed  Google Scholar 

  70. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593(7860):586–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent Sci. 2020;6(1):41–53.

    Article  CAS  PubMed  Google Scholar 

  72. Chen X, Kang R, Kroemer G, Tang D. Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021;218(6): e20210518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med. 2019;25(10):1576–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rurik JG, Aghajanian H, Epstein JA. Immune cells and immunotherapy for cardiac injury and repair. Circ Res. 2021;128(11):1766–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Roy P, Orecchioni M, Ley K. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol. 2022;22(4):251–65.

    Article  CAS  PubMed  Google Scholar 

  76. Yang Y, Wang Y, Guo L, Gao W, Tang TL, Yan M. Interaction between macrophages and ferroptosis. Cell Death Dis. 2022;13(4):355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cui Y, Zhang Z, Zhou X, Zhao Z, Zhao R, Xu X, et al. Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression. J Neuroinflamm. 2021;18(1):249.

    Article  CAS  Google Scholar 

  78. Piattini F, Matsushita M, Muri J, Bretscher P, Feng X, Freigang S, et al. Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis. Eur J Immunol. 2021;51(10):2417–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Marques L, Negre-Salvayre A, Costa L, Canonne-Hergaux F. Iron gene expression profile in atherogenic Mox macrophages. Biochim Biophys Acta. 2016;1862(6):1137–46.

    Article  CAS  PubMed  Google Scholar 

  80. Kapralov AA, Yang Q, Dar HH, Tyurina YY, Anthonymuthu TS, Kim R, et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol. 2020;16(3):278–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Handa P, Thomas S, Morgan-Stevenson V, Maliken BD, Gochanour E, Boukhar S, et al. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J Leukoc Biol. 2019;105(5):1015–26.

    Article  CAS  PubMed  Google Scholar 

  82. Sun S, Wu Y, Maimaitijiang A, Huang Q, Chen Q. Ferroptotic cardiomyocyte-derived exosomes promote cardiac macrophage M1 polarization during myocardial infarction. PeerJ. 2022;10: e13717.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Liu W, Östberg N, Yalcinkaya M, Dou H, Endo-Umeda K, Tang Y, et al. Erythroid lineage Jak2V617F expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis. J Clin Invest. 2022;132(13): e155724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kumar BV, Connors TJ, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018;48(2):202–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Levring TB, Hansen AK, Nielsen BL, Kongsbak M, von Essen MR, Woetmann A, et al. Activated human CD4+ T cells express transporters for both cysteine and cystine. Sci Rep. 2012;2:266.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Pruett SB, Obiri N, Kiel JL. Involvement and relative importance of at least two distinct mechanisms in the effects of 2-mercaptoethanol on murine lymphocytes in culture. J Cell Physiol. 1989;141(1):40–5.

    Article  CAS  PubMed  Google Scholar 

  87. Miao W, He L, Zhang Y, Zhu X, Jiang Y, Liu P, et al. Ferroptosis is partially responsible for dexamethasone-induced T cell ablation, but not osteoporosis in larval zebrafish. Ecotoxicol Environ Saf. 2022;242: 113872.

    Article  CAS  PubMed  Google Scholar 

  88. He C, Wang C, Liu H, Shan B. Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells. BMC Cancer. 2022;22(1):724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yao Y, Chen Z, Zhang H, Chen C, Zeng M, Yunis J, et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol. 2021;22(9):1127–39.

    Article  CAS  PubMed  Google Scholar 

  90. Xu C, Sun S, Johnson T, Qi R, Zhang S, Zhang J, et al. The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity. Cell Rep. 2021;35(11): 109235.

    Article  CAS  PubMed  Google Scholar 

  91. Wang Y, Tian Q, Hao Y, Yao W, Lu J, Chen C, et al. The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4(+) T cells by preventing ferroptosis. Nat Immunol. 2022;23(2):303–17.

    Article  PubMed  Google Scholar 

  92. Luoqian J, Yang W, Ding X, Tuo QZ, Xiang Z, Zheng Z, et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis. Cell Mol Immunol. 2022;19(8):913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. 2022;40(4):365-78.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Friedmann Angeli JP, Xavier da Silva TN, Schilling B. CD8(+) T cells PUF(A)ing the flames of cancer ferroptotic cell death. Cancer Cell. 2022;40(4):346–8.

    Article  CAS  PubMed  Google Scholar 

  95. Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm GW, Kopf M. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015;212(4):555–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang Y, Ma Y, Yu S, Lin Z, Yan C, Wang Y, et al. TIPE2 knockout reduces myocardial cell damage by inhibiting IFN-γ-mediated ferroptosis. Biochim Biophys Acta Mol Basis Dis. 2023;1869(1): 166566.

    Article  CAS  PubMed  Google Scholar 

  97. Hua Z, Hou B. TLR signaling in B-cell development and activation. Cell Mol Immunol. 2013;10(2):103–6.

    Article  CAS  PubMed  Google Scholar 

  98. Muri J, Thut H, Bornkamm GW, Kopf M. B1 and marginal zone B cells but not follicular B2 cells require Gpx4 to prevent lipid peroxidation and ferroptosis. Cell Rep. 2019;29(9):2731-44.e4.

    Article  CAS  PubMed  Google Scholar 

  99. Li J, Cao J, Wang Z, Dong Y, Chen Y. Melatonin plays a critical role in inducing B lymphocyte proliferation of the bursa of Fabricius in broilers via monochromatic lights. J Photochem Photobiol B. 2015;142:29–34.

    Article  CAS  PubMed  Google Scholar 

  100. Vega L, Rodríguez-Sosa M, García-Montalvo EA, Del Razo LM, Elizondo G. Non-optimal levels of dietary selenomethionine alter splenocyte response and modify oxidative stress markers in female mice. Food Chem Toxicol. 2007;45(7):1147–53.

    Article  CAS  PubMed  Google Scholar 

  101. Wang D, Xie N, Gao W, Kang R, Tang D. The ferroptosis inducer erastin promotes proliferation and differentiation in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2018;503(3):1689–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. García-Rivas G, Castillo EC, Gonzalez-Gil AM, Maravillas-Montero JL, Brunck M, Torres-Quintanilla A, et al. The role of B cells in heart failure and implications for future immunomodulatory treatment strategies. ESC Heart Fail. 2020;7(4):1387–99.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Jiao J, He S, Wang Y, Lu Y, Gu M, Li D, et al. Regulatory B cells improve ventricular remodeling after myocardial infarction by modulating monocyte migration. Basic Res Cardiol. 2021;116(1):46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rozwadowska K, Raczak G, Sikorska K, Fijałkowski M, Kozłowski D, Daniłowicz-Szymanowicz L. Influence of hereditary haemochromatosis on left ventricular wall thickness: does iron overload exacerbate cardiac hypertrophy? Folia Morphol (Warsz). 2019;78(4):746–53.

    Article  CAS  PubMed  Google Scholar 

  105. Cai W, Liu L, Shi X, Liu Y, Wang J, Fang X, et al. Alox15/15-HpETE aggravates myocardial ischemia-reperfusion injury by promoting cardiomyocyte ferroptosis. Circulation. 2023;147(19):1444–60.

    Article  CAS  PubMed  Google Scholar 

  106. Ma XH, Liu JH, Liu CY, Sun WY, Duan WJ, Wang G, et al. ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage. Signal Transduct Target Ther. 2022;7(1):288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lillo-Moya J, Rojas-Solé C, Muñoz-Salamanca D, Panieri E, Saso L, Rodrigo R. Targeting ferroptosis against ischemia/reperfusion cardiac injury. Antioxidants (Basel). 2021;10(5):667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Stamenkovic A, O’Hara KA, Nelson DC, Maddaford TG, Edel AL, Maddaford G, et al. Oxidized phosphatidylcholines trigger ferroptosis in cardiomyocytes during ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2021;320(3):H1170–84.

    Article  CAS  PubMed  Google Scholar 

  109. Zhang JK, Zhang Z, Guo ZA, Fu Y, Chen XJ, Chen WJ, et al. The BMSC-derived exosomal lncRNA Mir9-3hg suppresses cardiomyocyte ferroptosis in ischemia-reperfusion mice via the Pum2/PRDX6 axis. Nutr Metab Cardiovasc Dis. 2022;32(2):515–27.

    Article  CAS  PubMed  Google Scholar 

  110. Zhang GY, Gao Y, Guo XY, Wang GH, Guo CX. MiR-199a-5p promotes ferroptosis-induced cardiomyocyte death responding to oxygen-glucose deprivation/reperfusion injury via inhibiting Akt/eNOS signaling pathway. Kaohsiung J Med Sci. 2022;38(11):1093–102.

    Article  CAS  PubMed  Google Scholar 

  111. Li G, Jin J, Liu S, Ding K, Qian C. Inhibition of miR-1224 suppresses hypoxia/reoxygenation-induced oxidative stress and apoptosis in cardiomyocytes through targeting GPX4. Exp Mol Pathol. 2021;121: 104645.

    Article  CAS  PubMed  Google Scholar 

  112. Nanayakkara G, Alasmari A, Mouli S, Eldoumani H, Quindry J, McGinnis G, et al. Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2015;309(5):H867–79.

    Article  CAS  PubMed  Google Scholar 

  113. Li T, Tan Y, Ouyang S, He J, Liu L. Resveratrol protects against myocardial ischemia-reperfusion injury via attenuating ferroptosis. Gene. 2022;808: 145968.

    Article  CAS  PubMed  Google Scholar 

  114. Xu S, Wu B, Zhong B, Lin L, Ding Y, Jin X, et al. Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) /System xc-/ glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis. Bioengineered. 2021;12(2):10924–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mei SL, Xia ZY, Qiu Z, Jia YF, Zhou JJ, Zhou B. Shenmai injection attenuates myocardial ischemia/reperfusion injury by targeting Nrf2/GPX4 signalling-mediated ferroptosis. Chin J Integr Med. 2022;28(11):983–91.

    Article  CAS  PubMed  Google Scholar 

  116. Chen W, Zhang Y, Wang Z, Tan M, Lin J, Qian X, et al. Dapagliflozin alleviates myocardial ischemia/reperfusion injury by reducing ferroptosis via MAPK signaling inhibition. Front Pharmacol. 2023;14:1078205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Schnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet. 2015;386(9989):154–62.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Dai C, Kong B, Qin T, Xiao Z, Fang J, Gong Y, et al. Inhibition of ferroptosis reduces susceptibility to frequent excessive alcohol consumption-induced atrial fibrillation. Toxicology. 2022;465: 153055.

    Article  CAS  PubMed  Google Scholar 

  119. Rose RA, Sellan M, Simpson JA, Izaddoustdar F, Cifelli C, Panama BK, et al. Iron overload decreases CaV13-dependent L-type Ca2+ currents leading to bradycardia, altered electrical conduction, and atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4(5):733–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fang J, Kong B, Shuai W, Xiao Z, Dai C, Qin T, et al. Ferroportin-mediated ferroptosis involved in new-onset atrial fibrillation with LPS-induced endotoxemia. Eur J Pharmacol. 2021;913: 174622.

    Article  CAS  PubMed  Google Scholar 

  121. Liu D, Yang M, Yao Y, He S, Wang Y, Cao Z, et al. Cardiac fibroblasts promote ferroptosis in atrial fibrillation by secreting exo-miR-23a-3p targeting SLC7A11. Oxid Med Cell Longev. 2022;2022:3961495.

    PubMed  PubMed Central  Google Scholar 

  122. Russo V, Rago A, Pannone B, Di Meo F, Papa AA, Mayer MC, et al. Early electrocardiographic evaluation of atrial fibrillation risk in beta-thalassemia major patients. Int J Hematol. 2011;93(4):446–51.

    Article  PubMed  Google Scholar 

  123. Yang HJ, Kong B, Shuai W, Zhang JJ, Huang H. Shensong Yangxin attenuates metabolic syndrome-induced atrial fibrillation via inhibition of ferroportin-mediated intracellular iron overload. Phytomedicine. 2022;101: 154086.

    Article  CAS  PubMed  Google Scholar 

  124. Merad M, Blish CA, Sallusto F, Iwasaki A. The immunology and immunopathology of COVID-19. Science. 2022;375(6585):1122–7.

    Article  CAS  PubMed  Google Scholar 

  125. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022;43(11):1157–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Katsoularis I, Fonseca-Rodríguez O, Farrington P, Lindmark K, Fors Connolly AM. Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study. Lancet. 2021;398(10300):599–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Xie Y, Bowe B, Maddukuri G, Al-Aly Z. Comparative evaluation of clinical manifestations and risk of death in patients admitted to hospital with covid-19 and seasonal influenza: cohort study. BMJ. 2020;371: m4677.

    Article  PubMed  Google Scholar 

  130. Wang Y, Huang J, Sun Y, Stubbs D, He J, Li W, et al. SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, endoplasmic reticulum stress and DNA synthesis. Food Chem Toxicol. 2021;153: 112286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Liu L, Du J, Yang S, Zheng B, Shen J, Huang J, et al. SARS-CoV-2 ORF3a sensitizes cells to ferroptosis via Keap1-NRF2 axis. Redox Biol. 2023;63: 102752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kung YA, Chiang HJ, Li ML, Gong YN, Chiu HP, Hung CT, et al. Acyl-coenzyme a synthetase long-chain family member 4 is involved in viral replication organelle formation and facilitates virus replication via ferroptosis. MBio. 2022;13(1): e0271721.

    Article  PubMed  Google Scholar 

  133. Han Y, Zhu J, Yang L, Nilsson-Payant BE, Hurtado R, Lacko LA, et al. SARS-CoV-2 infection induces ferroptosis of sinoatrial node pacemaker cells. Circ Res. 2022;130(7):963–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Habib HM, Ibrahim S, Zaim A, Ibrahim WH. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed Pharmacother. 2021;136: 111228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2016;12(3):144–53.

    Article  CAS  PubMed  Google Scholar 

  136. Ritchie RH, Abel ED. Basic mechanisms of diabetic heart disease. Circ Res. 2020;126(11):1501–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Liu C, Sun W, Zhu T, Shi S, Zhang J, Wang J, et al. Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early diabetic retinopathy. Redox Biol. 2022;52: 102292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wei Z, Shaohuan Q, Pinfang K, Chao S. Curcumin attenuates ferroptosis-induced myocardial injury in diabetic cardiomyopathy through the Nrf2 pathway. Cardiovasc Ther. 2022;2022:3159717.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Kwon MY, Park E, Lee SJ, Chung SW. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget. 2015;6(27):24393–403.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Chang LC, Chiang SK, Chen SE, Yu YL, Chou RH, Chang WC. Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis. Cancer Lett. 2018;416:124–37.

    Article  CAS  PubMed  Google Scholar 

  141. Wang X, Chen X, Zhou W, Men H, Bao T, Sun Y, et al. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B. 2022;12(2):708–22.

    Article  PubMed  Google Scholar 

  142. Ni T, Huang X, Pan S, Lu Z. Inhibition of the long non-coding RNA ZFAS1 attenuates ferroptosis by sponging miR-150-5p and activates CCND2 against diabetic cardiomyopathy. J Cell Mol Med. 2021;25(21):9995–10007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wang K, Li Y, Qiang T, Chen J, Wang X. Role of epigenetic regulation in myocardial ischemia/reperfusion injury. Pharmacol Res. 2021;170: 105743.

    Article  CAS  PubMed  Google Scholar 

  144. Tian H, Xiong Y, Zhang Y, Leng Y, Tao J, Li L, et al. Activation of NRF2/FPN1 pathway attenuates myocardial ischemia-reperfusion injury in diabetic rats by regulating iron homeostasis and ferroptosis. Cell Stress Chaperones. 2021;27(2):149–64.

    Article  PubMed  Google Scholar 

  145. Kalyanaraman B. Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree? Redox Biol. 2020;29: 101394.

    Article  CAS  PubMed  Google Scholar 

  146. Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight. 2020;5(9): e132747.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Li X, Liang J, Qu L, Liu S, Qin A, Liu H, et al. Exploring the role of ferroptosis in the doxorubicin-induced chronic cardiotoxicity using a murine model. Chem Biol Interact. 2022;363: 110008.

    Article  CAS  PubMed  Google Scholar 

  148. He L, Yang Y, Chen J, Zou P, Li J. Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin-induced toxicity. Mol Med Rep. 2021;24(3):668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Hou K, Shen J, Yan J, Zhai C, Zhang J, Pan JA, et al. Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin. EBioMedicine. 2021;69: 103456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sun X, Sun P, Zhen D, Xu X, Yang L, Fu D, et al. Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression. Toxicol Appl Pharmacol. 2022;437: 115902.

    Article  CAS  PubMed  Google Scholar 

  151. Quagliariello V, De Laurentiis M, Rea D, Barbieri A, Monti MG, Carbone A, et al. The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin. Cardiovasc Diabetol. 2021;20(1):150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zhu X, Wang X, Zhu B, Ding S, Shi H, Yang X. Disruption of histamine/H(1)R-STAT3-SLC7A11 axis exacerbates doxorubicin-induced cardiac ferroptosis. Free Radic Biol Med. 2022;192:98–114.

    Article  CAS  PubMed  Google Scholar 

  153. Sukumaran A, Chang J, Han M, Mintri S, Khaw BA, Kim J. Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis. Sci Rep. 2017;7(1):5756.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Fang X, Cai Z, Wang H, Han D, Cheng Q, Zhang P, et al. Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis. Circ Res. 2020;127(4):486–501.

    Article  CAS  PubMed  Google Scholar 

  155. Zhang X, Zheng C, Gao Z, Chen H, Li K, Wang L, et al. SLC7A11/xCT prevents cardiac hypertrophy by inhibiting ferroptosis. Cardiovasc Drugs Ther. 2022;36(3):437–47.

    Article  CAS  PubMed  Google Scholar 

  156. Zhang Z, Tang J, Song J, Xie M, Liu Y, Dong Z, et al. Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling. Free Radic Biol Med. 2022;181:130–42.

    Article  CAS  PubMed  Google Scholar 

  157. Wang Y, Yang X, Jiang A, Wang W, Li J, Wen J. Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. Faseb j. 2019;33(12):13145–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Shi P, Song C, Qi H, Ren J, Ren P, Wu J, et al. Up-regulation of IRF3 is required for docosahexaenoic acid suppressing ferroptosis of cardiac microvascular endothelial cells in cardiac hypertrophy rat. J Nutr Biochem. 2022;104: 108972.

    Article  CAS  PubMed  Google Scholar 

  159. Tang M, Huang Z, Luo X, Liu M, Wang L, Qi Z, et al. Ferritinophagy activation and sideroflexin1-dependent mitochondria iron overload is involved in apelin-13-induced cardiomyocytes hypertrophy. Free Radic Biol Med. 2019;134:445–57.

    Article  CAS  PubMed  Google Scholar 

  160. Chen X, Xu S, Zhao C, Liu B. Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure. Biochem Biophys Res Commun. 2019;516(1):37–43.

    Article  CAS  PubMed  Google Scholar 

  161. Kumar V, Aneesh Kumar A, Sanawar R, Jaleel A, Santhosh Kumar TR, Kartha CC. Chronic pressure overload results in deficiency of mitochondrial membrane transporter ABCB7 which contributes to iron overload, mitochondrial dysfunction, metabolic shift and worsens cardiac function. Sci Rep. 2019;9(1):13170.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Liu B, Zhao C, Li H, Chen X, Ding Y, Xu S. Puerarin protects against heart failure induced by pressure overload through mitigation of ferroptosis. Biochem Biophys Res Commun. 2018;497(1):233–40.

    Article  CAS  PubMed  Google Scholar 

  163. Bertoli SR, Marques VB, Rossi EM, Krause M, Carneiro M, Simões MR, et al. Chronic iron overload induces vascular dysfunction in resistance pulmonary arteries associated with right ventricular remodeling in rats. Toxicol Lett. 2018;295:296–306.

    Article  CAS  PubMed  Google Scholar 

  164. Conche C, Finkelmeier F, Pešić M, Nicolas AM, Böttger TW, Kennel KB, et al. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut. 2023;72:1774–82.

    Article  CAS  PubMed  Google Scholar 

  165. Huang L, Shi Y, Gong B, Jiang L, Zhang Z, Liu X, et al. Dynamic blood single-cell immune responses in patients with COVID-19. Signal Transduct Target Ther. 2021;6(1):110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (81903000), Natural Science Foundation of Sichuan Province (2023NSFSC1846), Sichuan Science and Technology Program (2022YFS0636-B4, 2022YFS0636-C4), Foundation of Southwest Medical University (00031742, 2021ZKQN093).

Author information

Author notes

  1. Qi Zhang and Yuhao Luo contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

    Qi Zhang, Xi Rong, Yingxue Liu, Jiafu Li & Jing Luo

  2. Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China

    Yuhao Luo

  3. Department of Bone and Joint Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China

    Lin Peng

  4. Collaborative Innovation Centre for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, China

    Jiafu Li & Jing Luo

Authors
  1. Qi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuhao Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xi Rong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingxue Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiafu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QZ and YHL conceived and wrote the manuscript; LP, XR and YXL contributed to collect the data and draw the figures; JFL and JL provided the guidance throughout the revision of this manuscript; and all authors approved the final manuscript.

Corresponding authors

Correspondence to Jiafu Li or Jing Luo.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Q., Luo, Y., Peng, L. et al. Ferroptosis in cardiovascular diseases: role and mechanism. Cell Biosci 13, 226 (2023). https://doi.org/10.1186/s13578-023-01169-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13578-023-01169-2

Keywords

Cell & Bioscience

ISSN: 2045-3701

Contact us