Introduction

Acute myocardial infarction (AMI) is a disease with high morbidity, disability, and mortality worldwide. It imposes a heavy burden on the health care and economy of the society.¹ Myocardial infarction (MI) is caused by plaque accumulation in the coronary arteries inner lining. This reduces the heart’s blood flow, leading to the death of cardiac cells as a result of an inadequate oxygen supply. Therefore, quick restoration of blood flow to the heart is the primary strategy for treating AMI. Reperfusion therapy following the onset of MI (thrombolysis, coronary artery bypass grafting, percutaneous coronary intervention, and bypass surgery) can effectively improve the heart’s adequate blood supply. However, clinical and experimental studies have proven that restoring sufficient blood flow to the ischemic heart muscle further impairs energy metabolism, electrophysiology, tissue structure, and cardiac function of the damaged myocardium, causing myocardial death and increasing infarct size. This phenomenon is referred to as myocardial ischemia/reperfusion injury (MIRI).² Traditionally, it has been reported that MIRI causes calcium overload, oxidative stress, and inflammatory responses.³ However, given that classic anti-oxidation and anti-inflammatory treatments have not achieved good curative effects, it is speculated that other mechanisms may be involved. Evidence from most studies has demonstrated that MIRI pathogenesis involves ferroptosis, and several ferroptosis indicators significantly influence the prognosis of MIRI.⁴ Recently, numerousin vitroandin vivostudies have shown that ferroptosis has a therapeutic effect on various cardiovascular disorders, including MIRI.⁵ Therefore, investigating the primary mechanism, function, and target of ferroptosis in MIRI may reveal new avenues for treating MIRI.

Myocardial Ischemia/Reperfusion Injury

Overview of Myocardial Ischemia/Reperfusion Injury

Reperfusion-induced myocardial injury may account for nearly half of the final myocardial injuries in AMI.³ Cardiomyocytes are highly differentiated terminal cells that cannot generally divide and proliferate. These cells are permanently lost and do not regenerate once they die, which reduces the number of cardiomyocytes in an adult heart. As a consequence, a reduction in cardiomyocytes causes structural and functional changes in the heart. Therefore, inhibiting myocardial cell death is the key to protecting cardiac function and preventing heart disease.⁶ For this reason, research into the mechanisms of MIRI is a hotspot topic in this field.

Myocardial Ischemia/Reperfusion Injury Mechanism

The pathological pathway of MIRI is complex and completely unclear but mainly includes calcium overload, oxidative stress, inflammatory response, mitochondrial permeability transition pore opening, energy metabolism disorders, and activation of different cell death modes.³ Studies have indicated that MIRI is associated with various modes of cell death, including apoptosis, necrosis, autophagy, and ferroptosis. Ferroptosis is a critical factor in these processes (Figure 1).

Myocardial Ischemia/Reperfusion Injury and Ferroptosis

Overview of Ferroptosis

Ferroptosis is a novel iron-dependent cell death process. Iron homeostasis is essential for cell survival and numerous biological activities. Low, high, or abnormal iron distributions throughout the body affect physiological functions. Ferroptosis is recognized as a regulated cell death (RCD) process promoted by iron overload, which was first presented by Dixon in 2012.⁷ Ferroptosis is a recently discovered type of RCD mainly mediated by reactive oxygen species (ROS) groups and iron ion-mediated lipid peroxidation. The above processes are distinct from those of apoptosis, pyroptosis, necrosis, and autophagy in terms of morphology, biochemistry, genetics, and metabolism.⁸ 1) Morphological features are mainly manifested as mitochondrial abnormalities (a reduction in mitochondrial volume, high mitochondrial membrane density, and fewer or absence of mitochondrial cristae), although the cell membrane is usually complete, with normal nucleus size and unconcentrated chromatin. 2) The biochemical characteristics are iron accumulation, causing lipid peroxidation. 3) The genetic characteristics are regulated by various genes, including ceruloplasmin, transferrin receptor 1 (TFR1), divalent metal-ion transporter-1 (DMT1), glutathione peroxidase 4 (GPX4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenase (LOX). 4) Metabolic characteristics: several metabolic pathways contribute to ferroptosis pathogenesis, including amino acid metabolism, iron metabolism, lipid metabolism, and others (Figure 2).

Metabolic Pathways of Ferroptosis

The ferroptosis mechanism is very complex and comprises a sequence of signaling and metabolic pathways. Iron, amino acids, and lipid metabolism are vital for ferroptosis pathogenesis. The principal metabolic pathways in these 3 types of ferroptosis are discussed in the following sections (Figure 3).

Iron Metabolism—Iron-Mediated Ferroptosis

Ferroptosis is intricately linked to the presence of iron. Iron, a vital trace element in the human body, is crucial for maintaining normal physiological functions. Thus, any disruption to iron homeostasis, whether due to iron overload or deficiency, can lead to various disorders, eventually causing ferroptosis.⁹

Iron Import

Generally, iron can infiltrate cells in 2 different forms: transferrin-bound iron and non-transferrin-bound iron. Ferric iron (Fe³⁺) is absorbed by transferrin-bound iron. First, the ferroxidase activity of copper-containing glycoprotein ceruloplasmin converts ferrous iron (Fe²⁺) to Fe³⁺.¹⁰ Second, TFR1 allows extracellular Fe³⁺ to enter the cell after binding to transferrin, which is the primary iron uptake pathway.⁸ In addition, non-transferrin-bound iron is primarily absorbed into cells in Fe²⁺ form, increasing the level of cardiac labile iron.⁹ L-type voltage-dependent calcium channel,⁶ T-type voltage-dependent calcium channel, metal transporter SLC39A14,¹¹ DMT1, and zinc transporter are imported into cardiomyocytes. Heat shock protein B1 inhibits TFR1, decreases iron ion concentrations, and inhibits ferroptosis.¹² Overexpression of ubiquitin-specific protease 7, which mediates ferroptosis, activated the p53/TFR1 pathway in rats with MIRI (Figure 3) (Table 1).¹³

Iron Export

Two proteins, ferroportin-1 (FPN1) and prominin 2 (PROM2), are primary mediators of iron export.

The membrane protein FPN1 exports iron from the cell, generating Fe³⁺ from Fe²⁺. Hepcidin, a 25-amino acid protein predominantly secreted from hepatocytes, modulates FPN. Hepcidin stimulates FPN internalization and breakdown, decreasing iron efflux from cardiomyocytes and promoting ferroptosis (Figure 3) (Table 1).¹⁷

Prominin 2 mediates FT export. Brown et al¹⁸ found that PROM2 (a 5-transmembrane glycoprotein) mediates the FT-containing multivesicular bodies as well as exosomes (EXOs) formation. The multivesicular structures and EXOs expel iron from the cells, effectively reducing ferroptosis (Figure 3) (Table 1).

Amino Acid Metabolism: Inhibition of Lipid Peroxidation

System Xc-glutathione-GPX4 Axis–Classic Ferroptosis Suppression Route

System Xc^-/glutathione (GSH)/GPX4 axis is the primary ferroptosis suppression mechanism. This axis contains 2 ferroptosis key regulators, including GSH and GPX4. System Xc^- is a glutamate/cystine antiporter and a heterodimer containing 2 subunits (solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2)), mainly through SLC7A11 (the main active site of erastin). System Xc^- releases glutamate from the cell to the outside at a ratio of 1 : 1 across the cell membrane and also absorbs cystine throughout the cell from outside and is decreased to cysteine in the cell. Glutam, cysteine, and glycine are used to produce GSH. GPX4, a selenoprotein and a vital antioxidant enzyme, inhibits lipoxygenase and cyclooxygenase activity during ferroptosis. GPX4, which relies on GSH, transforms reduced GSH to oxidized glutathione (GSSG) and lowers toxic lipid peroxide (LPO) to non-toxic lipid alcohol. GPX4 removes excess peroxide and hydroxyl radicals secreted during cellular respiration and metabolism. Consequently, GPX4 can precisely and effectively eliminate phospholipid hydroperoxide, suppressing ferroptosis. Suppression of the system Xc⁻ mechanism reduces intracellular GSH levels, decreasing GPX4 activity and ferroptosis. A high extracellular glutamate concentration suppresses the antiporter system Xc⁻ and promotes ferroptosis, which indicates the toxicity of high glutamate accumulation in the nervous system (Figure 3) (Table 1).⁸

Glutaminase (GLS1 and GLS2) transforms glutamine to glutamate during ferroptosis, regulating extracellular glutamate concentration. GLS2 is included in the initiation of ferroptosis. Suppression of glutaminase activity can effectively inhibit ferroptosis and alleviate MIRI (Table 1).¹⁹ Studies have demonstrated that GPX4 of mitochondrial-specific overexpression attenuates cardiac malfunction following the onset of ischemia/reperfusion. Suppression of ferroptosis results in suppression of glutaminolysis (a GSH synthesis pathway component), which potentially alleviates cardiac damage caused by I/R.

The tumor suppressor P53 downregulates SLC7A11 and limits cystine absorption by system Xc^-, impacting GPX4 action and diminishing the antioxidant ability of cells. These accumulate lipid ROS, causing ferroptosis (Figure 3) (Table 1).²⁰

YT521-B homology domain family member 2 has the ability to inhibit SLC7A11, which interferes with glutamate and cystine transport and lowers GPX4 production. However, iron excess may result from this. These 2 factors synergize to induce ferroptosis and exacerbate MIRI.²¹

Ubiquitin-specific protease 22 prevents ferroptosis-stimulated cardiac cells death in MIRI by sirtuin-1/p53/SLC7A11 axis (Table 1).²²

Moreover, nicotinamide adenine dinucleotide phosphate (NADPH) further regulates ferroptosis by maintaining GSH in a reduced state (Figure 3).²³

Several compounds and drugs can induce ferroptosis. Currently, ferroptosis promoters are divided into 2 groups according to whether they directly inactivate GPX4. Class 1 ferroptosis promoters suppress the system Xc⁻, whereas class 2 ferroptosis promoters directly suppress GPX4.

Erastin, a class 1 ferroptosis promoter, is one of the principal ferroptosis inducers. Erastin blocks system Xc⁻ and the absorption of cystine into cells. This decreases GSH production and indirectly turns off GPX4, causing LPOs to accumulate to promote ferroptosis. Moreover, Erastin engages and suppresses the voltage-dependent anion channels VDAC2 and VDAC3, causing mitochondrial malfunction and contributing to massive oxide discharge, ultimately triggering iron-mediated cell death.²⁴ More inhibitors of system Xc⁻ include glutamate, sorafenib, sulfasalazine, imidazolone, Istin, interferon-γ, and diarylisoxazole.⁶

Class 2 ferroptosis promoters, including RSL3, directly block GPX4, promote lipid peroxidation, and induce ferroptosis. RSL3 does not affect GPX4 upstream, such as GSH depletion and cysteine uptake. Subsequently, more direct GPX4 inhibitors were identified, such as FINO2, ferroptosis inducing 56, ML162 (DPI7), and ML210 (DPI10). Ferroptosis inducing 56 causes ferroptosis by depleting coenzyme Q10 (CoQ10) and promoting GPX4 degradation.⁶

Ferroptosis Suppressor Protein 1-CoQ10 Axis—An Emerging Pathway to Suppress Ferroptosis

The FSP1-CoQ10 pathway is a GPX4-independent pathway that inhibits ferroptosis and aligns with GPX4 and GSH in inhibiting LPO proliferation and ferroptosis (Figure 3).²⁵

Suppression of ferroptosis via FSP1 is promoted by CoQ10. Myristoylation attracts FSP1 to the plasma membrane, where it acts as an oxidoreductase that decreases CoQ10 with NAD(P)H and forms a lipophilic free radical trapping antioxidant, inhibiting production of LPO (Table 1).

Guanosine triphosphate cyclohydrolase 1- Tetrahydrobiopterin/Dihydrobiopterin (BH4/BH2)-Phospholipid Axis—An Emerging Pathway to Suppress Ferroptosis

GCH1-BH4/BH2 is another GPX4-independent pathway that suppresses ferroptosis. Using a CRISPR-mediated genome-wide activation screen, Kraft et al²⁶ revealed that GCH1 and its metabolic products BH4/BH2 are essential for gradual resistance of ferroptosis (Figure 3).

GCH1 is the rate-limiting enzyme in BH4 production. Upregulation or silencing of GCH1 causes corresponding resistance or sensitivity of cells to ferroptosis through modulating the antioxidant BH4 endogenous production, which is mechanistically capable of selectively preventing tailed phospholipid autooxidation and CoQ10 production. In turn, CoQ10 confers BH4 with an emerging lipophilic free radical trapping antioxidant that requires dihydrofolate reductase (Table 1).

Lipid Metabolism: Lipid Peroxide Lead to Ferroptosis

The key factors causing ferroptosis include LPO accumulation, specifically the transformation of PUFAs into LPO through oxidation. Arachidonoyl (AA) containing PUFA and adrenoyl phospholipids are major components of biofilms, and the primary substrates for ferroptosis lipid peroxidation are PUFA-containing phospholipids (Figure 3).²⁷

So far, 3 enzymes involved in phospholipid metabolism have been identified to participate in ferroptosis. These enzymes contain acyl-CoA synthetase long-chain family member 4 (ACSL4), LPCAT3, and LOX, which are involved in the biosynthesis, remodeling, and oxidation of phosphatidylethanolamine (PE), respectively (Figure 3).²⁷

PUFA is acylated as a result of the catalysis of ACSL4 to generate PUFA acyl-coenzyme A (PUFA-CoA).²⁷ PUFA-CoA subsequently combines with PE via LPCAT3 to form PUFA-PE. Polyunsaturated fatty acid-phosphatidylethanolamine is oxidized by LOX to lipid hydroperoxides, which initiates ferroptosis. The production of intracellular LPO substrates decreases with the downregulation of ACSL4, LPCTA3, and LOX, preventing ferroptosis. ACSL4 in the above process is considered more effective than LPCTA3. Lipid peroxidation and ferroptosis are fundamentally influenced by the lipoxygenase family (LOXs), iron-containing enzymes which catalyze the PUFA dioxygenation), particularly 12/15-LOX.^4,27 Lipoxygenase stimulates ferroptosis by modulating the oxidation of AA and adrenal-esterified phosphatidylethanolamine throughout the endoplasmic reticulum. The small scaffold protein phosphatidylethanolamine-binding protein 1, a suppressor of the protein kinase cascade, binds to 15-LOX to promote ferroptosis (Figure 3) (Table 1).²⁸

A member of the E3 ubiquitin ligase family, neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), plays a critical role in the emergence of numerous disorders by aiding in the ubiquitination of its target proteins. Studies have demonstrated that NEDD4L regulates the pathogenesis of various cardiovascular disorders. The Hippo pathway’s essential component is the yes-associated protein (YAP). To reduce ferroptosis during MIRI, YAP transcriptionally activated NEDD4L to cause the ubiquitination and destruction of ACSL4.²⁹

Regulators Related to the Ferroptosis Metabolic Pathway

The processes included in ferroptosis involve the metabolism of iron, amino acids, and lipids. Related positive and negative regulators participate in ferroptosis through various pathways. Genes that play essential roles are listed in Table 1.

Nuclear Factor Erythroid 2-Related Factor 2

Nuclear Factor Erythroid 2-Related Factor 2 triggers the activation of numerous essential target genes included in modulating ferroptosis through regulating amino acid metabolism, iron metabolism, lipid metabolism, and mitochondrial function (Table 1).⁶

Nuclear Factor Erythroid 2-Related Factor 2 is a protein that has a significant function in iron homeostasis, regulating several genes included in iron metabolism [FTH, FTL, transferrin, FPN, and heme oxygenase-1 (HO-1)].^17,30

Moreover, Nrf2 regulates amino acid metabolism in ferroptosis. Nuclear Factor Erythroid 2-Related Factor 2, a transcription factor, serves as a pivotal regulator of cellular antioxidant responses. Under stimulation of oxidative stress, Nrf2 translocates to the nucleus and forms a heterodimer with Maf protein, after which it starts the target gene transcription that has antioxidant response elements. Subsequently, superoxide dismutase, glutathione peroxidase, and catalase production are initiated, lowering oxidative stress, the inflammatory response, and ferroptosis. Studies have indicated that Nrf2 suppresses ferroptosis by modulating SLC7A11 and HO-1 expression.³¹

Heme Oxygenase-1

The HO-1 effect on ferroptosis remains to be validated. Heme Oxygenase-1 is a crucial enzyme in heme catabolism that catalyzes heme degradation into Fe²⁺, carbon monoxide (CO), and biliverdin. The overactivity of HO-1 increases LIP, subsequently triggering ferroptosis.³² However, moderate overexpression of HO-1 protects the cells because of its antioxidant activity. HO-1 and metabolites of heme metabolism (biliverdin and CO) have antioxidant capabilities. Heme Oxygenase-1 activation can reduce oxidative stress and exert anti-apoptotic and anti-inflammatory characteristics, enhancing myocardial resistance to I/R injury. Preconditioning of donor rats using inhaled CO prevents I/R injury after heart transplantation.¹⁷

CDGSH Iron-Sulfur Domains 1 and CDGSH Iron-Sulfur Domains 2 (CISD2)

Ferroptosis is negatively regulated by the mitochondrial iron regulators CISD1 and CISD2. The inhibition of CISD1 or CISD2 contributes to ferroptosis (Table 1).^33,34

Ferroptosis in Myocardial Ischemia/Reperfusion Injury

The cardiotoxic effects of iron, coupled with its correlation to reperfused MI in individuals with iron overload in the peri-infarct region, underscore the importance of investigating ferroptosis in MIRI. Numerous studies have revealed that excess iron is related to the pathophysiology of MIRI. For instance, myocardial I/R activates hypoxia-inducible factor 1 signaling and upregulates TFR1 expression to promote iron absorption and increase iron content.¹⁴ In a 30-minute occlusion experiment for I/R damage in a mice model, the left anterior descending coronary artery (LAD) was not perfused by blood. This resulted in FT accumulation in the myocardial scar region and increased cardiac cytosolic iron levels in I/R due to the mobilization of high iron levels into the coronary blood stream after extended ischemia.³⁵ Similarly, mice with MIRI had elevated mitochondrial iron.¹⁴ In an experiment of the ischemic area of the heart, scarce alterations in iron, GPX4, ACSL4, or malondialdehyde (MDA) were detected. However, in a reperfusion mouse model, iron, ACSL4, and MDA contents were increased, and GPX4 expression was downregulated.³⁶ The above findings suggest that ferroptosis occurs during myocardial reperfusion, not during ischemia. This implies it could be a novel approach for therapeutic intervention in MIRI.

Ferroptosis Treatment in Myocardial Ischemia/Reperfusion Injury

Ferroptosis have a vital function in the pathogenesis of MIRI, consequently, ferroptosis inhibition is a possible MIRI therapeutic target.⁴

Ferroptosis inhibitors mainly consist of iron chelators [deferoxamine (DFO), deferiprone (DFP), and dexrazoxane (DXZ) etc.] and lipid peroxidation inhibitors [e.g., ferrostatin-1, liproxstatin-1, vitamin E, N-acetylcysteine (NAC), CoQ10, and XJB-5-131]. The effects and mechanisms underlying some ferroptosis inhibitors in MIRI are summarized below.

Iron chelators decrease iron levels, preventing ferroptosis in vivo and in vitro. In most cases, DFO (which binds to free iron, treats iron overload, and stops ferroptosis caused by lipid peroxidation) is a harmless iron chelator. Studies have revealed that DFO prevents I/R injury in isolated hearts. Another study demonstrated that DFO administration prior to reperfusion via primary percutaneous coronary intervention significantly decreased oxidative stress but did not diminish infarct size.³⁷ Paraskevaidis et al³⁸ demonstrated that intravenous infusion of DFO during coronary artery bypass grafting prevented reperfusion damage of the myocardium and decreased lipid peroxidation.

Deferoxamine (DFP) targets hemorrhagic iron in I/R injury and provides cardioprotective benefits in AMI via attenuating intramyocardial bleeding and cardiac hypertrophy.³⁹ In addition, DFP monotherapy is more cardioprotective than treatment with DFO only and subcutaneous DFO therapy.⁶

Dexrazoxane prevented doxorubicin-induced ferroptosis in mice, reducing fatal cardiac injury (infarct size) and myocardial dysfunction after I/R.³⁵

Although iron chelating agents have achieved certain results in treating myocardial I/R injury, there are also some unsatisfactory aspects. The positive therapeutic effect of iron chelators on MIRI is not evident in some experimental animals, which may be attributed to the species specificity of iron chelators.¹⁴

P22077 (a suppressor of ubiquitin-specific protease 7) has been demonstrated to prevent MIRI via suppressing ferroptosis by p53 overexpression and TFR1 downregulation.⁴⁰

The dark red pigment echinochrome A (found in sea urchin shells and spines) is lipophilic and membrane permeable. A water-soluble version of echinochrome A, known as histochrome, exhibits potent iron-chelating and antioxidant properties. Histochrome therapy chelated intracellular iron, significantly caused overexpression of GPX4 and free GSH, and downregulated cyclooxygenase 2 expression to confer cardioprotection against MIRI.⁴¹

Polydopamine nanoparticles (PDA NPs) inhibited Fe²⁺ accumulation and restored mitochondrial function in H9c2 cells. Polydopamine nanoparticles efficiently decreased Fe²⁺ deposition and lipid peroxidation in a mouse model of MIRI. Furthermore, PDA NPs treatment reduced MIRI throughout the mouse model, manifested diminished infarct size, and promoted cardiac function. The current investigation demonstrated the therapeutic effect of PDA NPs on MIRI by stopping ferroptosis.⁴²

In a previous study, ponatinib and DFO suppressed ferroptosis and necroptosis in myocardial I/R, and their incorporation significantly lowered myocardial infarct size.⁴³ In another recent study, DXZ and ponatinib were shown to decrease ferroptosis during MIRI. Combining the above 2 drugs significantly reduced MI scar size. These results suggest that a combined therapy targeting distinct forms of cell death modalities is an efficient treatment approach for MIRI.

Lip-1 prevents I/R injury in mouse cardiac muscles. Lip-1 administration after ischemia can lower MI size. Lip-1 suppresses ferroptosis via upregulating GPX4, reducing ROS, lowering VDAC1 expression, and supporting mitochondrial structure and function following myocardial I/R.⁴⁴

In a mouse model of MIRI, the glutaminolysis inhibitor compound 968 inhibited ferroptosis, reduced MI size, and improved cardiac function.¹⁹

Cysteine has been acetylated to become NAC. N-acetylcysteine is a GSH donor and exhibits antioxidant effects. GSH is a substrate used by enzymes to reduce other compounds as part of the endogenous antioxidant system. In addition, GSH functions directly as an antioxidant. As a result, the above medication may be utilized to augment antioxidant therapy when GSH levels are decreased in a hyperoxidative condition.⁴⁵

Pretreatment with either Fer-1 or DXZ lessens MI severity by preventing myocardial enzyme elevations resulting from I/R.³⁵

MIRI significantly affects heart transplantation. I/R injury in heart transplantation can result in considerable sterile inflammation, causing primary graft malfunction in patients and significantly increasing the mortality rate. Investigation of the correlation between ferroptosis and cardiac transplantation-associated I/R injury demonstrated that ferroptosis attracts neutrophils to the damaged myocardium when damage-associated molecular patterns are released. Fer-1 decreases cardiomyocyte mortality through a mechanism involving damage-associated molecular patterns and prevents neutrophil attraction to damaged cardiomyocytes after heart transplantation.⁴⁶ Therefore, focusing on ferroptosis suppression offers a therapeutic avenue for treating individuals at high risk of developing MIRI after coronary blood flow fixation after a heart transplant. Suppressing ferroptosis in the donor heart before surgery may also reduce MIRI and improve the prognosis.

Etomidate inhibits ferroptosis in MIRI model by upregulating Nrf2 and HO-1 expression.⁴⁷

Dexmedetomidine (Dex) significantly attenuates MI, improves cardiac function, and reduces hypoxia/reoxygenation-induced Fe²⁺ accumulation and lipid peroxidation in cardiomyocytes. Dexmedetomidine substantially suppressed ferroptosis via upregulation of Nrf2, SLC7A11, and GPX4 expression.⁴⁸

Ferroptosis is inhibited by XJB-5-131 (a synthetic antioxidant derived from nitrogen oxides), which directs mitochondria and creates ROS and electron scavenging capabilities.⁴⁹

Activation of endoplasmic reticulum stress (ERS) exacerbates cardiomyocyte ferroptosis. A study in MIRI model (generated by ligating the LAD in diabetic rats) demonstrated that infusion of Fer-1 into the tail vein ameliorated ERS-induced cardiomyocyte ferroptosis. Furthermore, salubrinal (an inhibitor of ERS) alleviated cardiomyocyte ferroptosis.⁵⁰

Conclusion and Outlook

Myocardial ischemia/reperfusion injury is one of the crucial reasons for morbidity, disability and mortality globally. Understanding the pathological process of cardiomyocyte injury is critical for establishing cardioprotective strategies. Ferroptosis is associated with MIRI and modulates MIRI by amino acid metabolism, iron metabolism, lipid metabolism, ERS, and autophagy-dependent ferroptosis mechanisms.

Many challenges underlying the mechanism and treatment of MIRI are yet to be investigated. The majority of current research on suppressing ferroptosis to alleviate MIRI shed light on the animal model and cell culture, with limited estimation for its clinical effectiveness. Therefore, a transition towards clinical research is necessary. In addition to ferroptosis, MIRI involves numerous different mechanisms in the cell death pathway. Detailed investigations of ferroptosis and different modes of RCDs have revealed a comprehensive link between ferroptosis and other RCDs. However, the predominant kind of cell death in MIRI remains to be validated. Consequently, more investigations are necessary to determine the function of distinct cell death pathways in developing MIRI. As MIRI worsens because of numerous different types of cell death, combining therapies that target distinct cell death types may be the best way to prevent MIRI progression. Studies have demonstrated that the incidence of iron death varies at various stages of MIRI, but the exact stage at which iron death occurs has not been clarified. Cell-secreted EXOs have become a hotspot area due to their immunogenic defects. Therefore, the interaction between EXOs and ferroptosis is a future research hotspot.

In conclusion, ferroptosis showed the potential to an efficient therapeutic target for MIRI. However, further investigation is required to fully uncover its molecular mechanism and potential role in this condition.

Footnotes

Peer-review: Externally peer-reviewed.

Author Contributions: Conceptualization – M.G. and Y.D.; Investigation – Q.C., T.W. and R.L.; Data curation – J.G., Y.W., J.Z.; Writing: original draft preparation – Y.D.; review and editing – Y.D., M.G., S.W., T.W.; Supervision – M.G.; Funding acquisition – M.G., Y.D., T.W. All authors have read and agreed to the published version of the manuscript.

Declaration of Interests: The authors have no conflict of interest to declare.

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