While iron is required for normal physiological processes, it can become toxic when iron overload occurs, such as in patients with hereditary forms of hemochromatosis or as a result of multiple blood transfusions as seen with sickle cell disease or in patients with β-thalassemia ^[1][12]. The heart is one of the major target organs for iron deposition which can be manifested as iron overload cardiomyopathy (IOC) ^[2][3][103,104]. IOC is the leading cause of morbidity and mortality in patients with primary hemochromatosis and secondary iron overload. These patients exhibit cardiomyopathy as well as life-threatening cardiac arrhythmias. Although IOC remains a global tragedy and significant clinical challenge in the U.S. and internationally, the underlying mechanism(s) involved in IOC iron-associated cardiotoxicity have not been well defined ^[1][3][4][12,104,105].

Ferroptosis has recently been implicated in iron overload-induced cardiac cell death and cardiovascular disease ^[5][6][7][8][34,106,107,108]. Baba et al. have demonstrated that ferric iron-citrate, erastin, and RSL3 readily induce ferroptosis in cultured adult mouse cardiomyocytes, which can be reversed by the ferroptosis inhibitor ferrostatin-1 ^[5][34]. Iron catalyzes the Fenton reaction, resulting in the formation of soluble peroxides or lipid peroxides that then generate toxic hydroxyl or lipid alkoxyl radicals, which can then propagate lipid peroxidation. Baba et al. further demonstrated that the mechanistic target of rapamycin (mTOR) plays an important role in protecting cardiomyocytes against excess iron and ferroptosis, probably by regulating ROS production ^[5][34].

It is well known that mitochondria play an important role in the process of iron metabolism. Iron overload may occur at the cellular as well as mitochondrial level. It should be noted that mitochondrial iron overload may play an important role in causing mitochondrial dysfunction and even ferroptosis ^{[1][9][10][11]}[12,53,109,110]. Iron overload promotes ROS production, depolarizes mitochondrial membrane potential (ΔΨ_m), and disrupts cytosolic Ca dynamics. Cytosolic Ca dysregulation is a recognized hallmark of cardiac dysfunction and heart failure ^[12][111]. The involvement of the mitochondrial permeability transition pore (mPTP) has been suggested as contributing to cytosolic Ca dysregulation ^[13][112]. Kumfu et al. have shown that mCU is involved in mitochondrial dysfunction under iron-loaded conditions ^[10][109]. Iron overload-induced ferroptosis is dependent on the mitochondrial Ca uniporter (mCU) using a conditional mCU KO mouse model created by Kwong et al. ^[14][113]. Supporting the importance of mitochondrial labile iron in the induction of ferroptosis, it has also been reported that overexpression of the iron-storage protein ferritin in mitochondria suppresses erastin-induced ferroptosis ^[15][114]. However, detailed mechanisms for mitochondrial iron metabolism in the regulation of mitochondrial (dys)function and ferroptosis, such as the role of mCU, crosstalk between Ca and iron, compartmentalization of lipid peroxides, etc., are still not well understood. Nevertheless, preventing cellular and mitochondrial iron overload by either reducing iron uptake or increasing iron storage, e.g., via transferrin, may inhibit the occurrence of ferroptosis. Iron chelators have also been widely used to treat IOC ^[1][12].

Doxorubicin (DOX) is a widely used anthracycline anticancer agent. However, its clinical efficacy is limited by cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). The detailed mechanisms for DIC and its therapeutic strategy have yet to be fully elucidated. Previous studies have linked Ca handling abnormalities, mitochondrial iron accumulation, and mitochondrial dysfunction to DIC ^{[16][17][18][19]}[115,116,117,118]. It has also been suggested that several RCDs such as apoptosis, necroptosis, and autophagy are involved in DOX-induced cardiomyocyte death ^{[16][17][20][21][22]}[115,116,119,120,121]. Several recent studies have recently demonstrated that ferroptosis is likely to be the major form of RCD in DOX-induced cardiomyocyte death. Therefore, therapeutics targeting ferroptosis might be a novel preventive strategy for DIC ^{[23][24][25][26][27]}[35,80,122,123,124]. It has been demonstrated that heme oxygenase 1 (Hmox1)-dependent heme degradation and free iron overload promote ferroptosis and DIC ^[23][35]. Furthermore, doxorubicin has been shown to suppress mGPX4 expression thereby inducing excessive lipid peroxidation in mitochondria and might consequently lead to mitochondria-dependent ferroptosis. Furthermore, the overexpression of mGPX4 or iron chelation targeting mitochondrial iron content significantly rescued doxorubicin-induced ferroptosis ^[24][80]. Whether doxorubicin also suppresses the expression or activity of DHODH, another arm of the mitochondrial lipid peroxidation defense system, remains to be studied.

It has been observed that myocardial injury may lead to the release and accumulation of local iron ^[28][125]. Previous studies have suggested that mitochondrial iron is involved in cardiac ischemic events ^[29][126]. Iron regulatory proteins such as transferrin receptor 1 ^[30][127] and ferroportin ^[31][128] have been shown to be associated with myocardial I/R injury. Furthermore, the overexpression of GPX4 in mitochondria suppresses I/R injury and reduces lipid peroxidation ^[32][129], suggesting a potential association to ferroptosis. A number of very recent studies have further revealed cardiac I/R injury may cause the disruption (expression and activation) of the GPX4 system as well as trigger the accumulation of lipid peroxidation (such as oxidized phosphatidylcholines), thereby inducing cardiomyocyte ferroptosis ^{[23][33][34][35][36][37]}[35,39,130,131,132,133]. In addition, the level of NOX2 (thus generation of ROS) has been shown to also be increased during myocardial I/R injury ^[38][134]. Moreover, it has been demonstrated that the Nrf2 pathway contributes to ferroptosis in I/R injury ^[39][135]. Administration of Fer-1 reduced infarct size caused by I/R injury and showed a long-term improvement in cardiac function ^[40][136]. Therefore, ferroptosis is associated with cardiac I/R injury as a significant form of cell death in cardiomyocytes, although it should be noted that apoptosis and necroptosis have also been observed in I/R injury.

Heart failure (HF) is a serious condition characterized by significantly reduced cardiac output and cardiomyocyte cell death ^[12][111]. Recent studies have linked ferroptosis to HF induced by genetic manipulation in addition to receiving a diet high in iron content and the presence of pressure overload. Fang et al. ^[41][36] has demonstrated that the iron storage protein ferritin H (Fth) plays a central role in mediating cardiac iron homeostasis and protecting against cardiac ferroptosis and subsequent cardiomyopathy (even HF) induced by a diet with a high iron content. Fth-deficient mice showed increased ROS production and developed HF at 6 months of age with a high-iron diet. HF could have been ameliorated by either Fer-1 or by overexpression of x_c⁻ (SLC7A11), which increased GSH levels and suppressed ferroptosis. Furthermore, ferroptosis was found to play an important role in a rat HF model induced by transverse aortic constriction (TAC) ^[42][64]. Knocking-down Toll-like receptor 4 (TLR4) or NOX4 remarkably reduced the incidence of ferroptosis and improved heart function, suggesting that TLR4-NOX4 might be a potential therapeutic target for HF at least partly through inhibiting ferroptosis-mediated cell death. Moreover, in a TAC-induced rat HF model, Liu et al. ^[43][137] suggested that puerarin, an isoflavone, may protect against HF induced by pressure overload by decreasing lipid peroxidation and mitigating ferroptosis.

Atherosclerosis is a chronic inflammatory disease of arteries characterized by disorders of lipid metabolism. It has been previously realized that GPX4 and lipid peroxidation play significant roles in atherosclerosis. For example, Guo et al. ^[44][138] demonstrated that overexpression of GPX4 decreased lipid peroxidation and alleviated atherosclerotic lesions in the aorta of ApoE-deficient mice. Considering that reduced GPX4 expression and/or activation and increased lipid peroxidation are the main features of ferroptosis, recent studies ^[45][139] have explored the potential association between ferroptosis and atherosclerosis.

Bai et al. found that Fer-1 partially reduced iron accumulation, lipid peroxidation, and reversed the expressions of SLC7A11 and GPX4 in aortic endothelial cells in high fat diet-fed ApoE(−/−) mice ^[45][139]. Fer-1 reduced high fat diet-induced atherosclerotic lesions in ApoE-deficient mice by reducing lipid peroxidation. Furthermore, oxidized-low density lipoprotein (ox-LDL)-induced cell death was also examined in mouse aortic endothelial cells (in vitro). More importantly, Fer-1 reduced cell death in ox-LDL-treated cells, suggesting the involvement of ferroptosis during the initiation and development of atherosclerosis. In addition, ferroptosis has also been linked to atherosclerosis in human coronary artery specimens by analyzing the correlation to ferroptosis markers such as PTGS2 (upregulated), ACSL4 (upregulated), and GPX4 (downregulated) ^[46][140].

Both excessive ROS generation and iron overload have a close association with arrhythmogenesis ^{[1][13][47][48]}[12,73,112,141]. However, the implication of ferroptosis in arrhythmogenesis has not been investigated. It has been suggested that cardiac arrhythmias are one of the clinical features of coronavirus disease 2019 (COVID-19). An earlier study by Jacobs et al. observed lipid peroxidation in the myocardium and suggested that ferroptosis may be a detrimental factor in cardiac damage resulting from COVID-19 ^[49][142]. A recent study ^[50][143] investigated the potential role of ferroptosis-induced sinus node damage in causing cardiac arrhythmias. The study used human embryonic stem cell (hESC)-derived sinoatrial node (SAN)-like pacemaker cells and showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induced ferroptosis and caused the dysfunction of human SAN-like pacemaker cells. This result suggests that ferroptosis is a potential mechanism for inducing arrhythmias in patients with COVID-19. Iron chelators and/or ferroptosis inhibitors might be able to block SARS-CoV-2 infection and be used to treat cardiac arrhythmias as well as other CoV-2–associated organ failures.