Targeting ferroptosis as a promising therapeutic strategy to treat cardiomyopathy

Cardiomyopathies are a clinically heterogeneous group of cardiac diseases characterized by heart muscle damage, resulting in myocardium disorders, diminished cardiac function, heart failure, and even sudden cardiac death. The molecular mechanisms underlying the damage to cardiomyocytes remain unclear. Emerging studies have demonstrated that ferroptosis, an iron-dependent non-apoptotic regulated form of cell death characterized by iron dyshomeostasis and lipid peroxidation, contributes to the development of ischemic cardiomyopathy, diabetic cardiomyopathy, doxorubicin-induced cardiomyopathy, and septic cardiomyopathy. Numerous compounds have exerted potential therapeutic effects on cardiomyopathies by inhibiting ferroptosis. In this review, we summarize the core mechanism by which ferroptosis leads to the development of these cardiomyopathies. We emphasize the emerging types of therapeutic compounds that can inhibit ferroptosis and delineate their beneficial effects in treating cardiomyopathies. This review suggests that inhibiting ferroptosis pharmacologically may be a potential therapeutic strategy for cardiomyopathy treatment.


Introduction
Cardiomyopathies are a clinically heterogeneous group of cardiac diseases characterized by heart muscle damage, causing cardiac muscle or myocardium disorders, diminished cardiac function, heart failure, and even sudden cardiac death (Franz et al., 2001;Schultheiss et al., 2019;Li D. et al., 2022). Cardiomyopathies are often related to electrical or mechanical dysfunction, frequently with a genetic origin or etiology (Maron et al., 2006). The 2006 American Heart Association classification categorizes and groups cardiomyopathy into primary or secondary categories (Maron et al., 2006). In primary categories (genetic, mixed, or acquired), the disease process is solely or predominantly confined to the heart. Secondary cardiomyopathies (i.e., dilated, hypertrophic, and restrictive cardiomyopathy) result from systemic conditions, i.e., cardiac involvement occurs as a part of systemic conditions (Brieler et al., 2017;Li T. et al., 2022). Researchers have divided the secondary causes of cardiomyopathy into various categories, including infectious, toxic, ischemic, metabolic, autoimmunogenic, and neuromuscular categories. The burden of ischemic cardiomyopathy (ICM), diabetic cardiomyopathy (DCM), doxorubicin-induced cardiomyopathy (DICM), and septic cardiomyopathy (SCM) is increasing in nearly all countries. The basic pathological mechanism of these cardiomyopathies (ICM, DCM, DICM and SCM) is cell death in cardiomyocytes. The pathogenesis and molecular mechanisms underlying these cardiomyopathies are poorly understood, warranting further investigation (Gilgenkrantz et al., 2021). Therefore, it is important to acquire insights into their pathogenesis to achieve the appropriate management and treatment of these disorders, thus providing support for protecting cardiac function.
In the past decades, ferroptosis, a non-apoptotic iron-dependent and peroxidation-driven regulated cell death (RCD) mechanism, has been rapidly acquiring attention in cardiomyopathies. Novel studies have explored the role of ferroptosis in DICM and ICM in murine models of cardiomyopathy (Conrad and Proneth, 2019;Fang et al., 2019), which demonstrated an association between ferroptosis and cardiac cell death induced by iron overload in vivo. Thereafter, several studies have revealed that ferroptosis plays a vital role in the pathogenesis of cardiomyopathy (Li D. et al., 2022). Meanwhile, certain compounds exert their therapeutic effects on experimental cardiomyopathy models by inhibiting ferroptosis.
In this review, we summarize the core mechanism by which ferroptosis leads to the genesis of cardiomyopathies. We focus on the emerging variety of therapeutic compounds that can inhibit ferroptosis and delineate their beneficial effects for treating cardiomyopathies. This review indicates that inhibiting ferroptosis pharmacologically may be a promising therapeutic strategy for treating cardiomyopathies.

Core molecular mechanisms underlying ferroptosis
Ferroptosis is an iron-dependent, oxidative form of nonapoptotic RCD, characterized by the iron-dependent oxidative modification of phospholipid membranes (Dixon et al., 2012). A delicate imbalance between ferroptosis inducers and inhibitors dictates its execution and induction. The inhibition of the solute carrier family 7 member 11/glutathione peroxidase 4 (SLC7A11/ GPX4) antioxidant system and free iron accumulation are two key signals for inducing ferroptosis (Chen H. Y. et al., 2021). When the levels of iron-dependent ROS and lethal lipid peroxide (LPO), the two promoting factors of ferroptosis, substantially surpass the antiferroptotic capacity of ferroptosis defense systems, peroxidated phospholipid polyunsaturated fatty acids (PUFA-PL-OOH) accumulate on cellular membranes and induce its rupture, eventually resulting in ferroptosis (Lei et al., 2022). Phospholipid polyunsaturated fatty acids (PUFA-PLs) have an intrinsic susceptibility to peroxidation chemistry, which makes them the primary substrates for LPO (Hadian and Stockwell, 2020). Acyl-coenzyme A synthetase long chain family member 4 (ACSL4) catalyzes the addition of coenzyme A (CoA) to the longchain polyunsaturated bonds of arachidonic acid (AA), causing PUFA esterification to form phospholipids. Following the activation of ACSL4, lysophosphatidylcholine acyltransferase 3 (LPCAT3) inserts acyl groups into lysophospholipids and incorporates free PUFAs into phospholipids (PL), participating in ferroptotic lipid signaling. Under the catalysis of oxidase and bioactive iron, PUFA-PLs in the membrane can be converted to phospholipid peroxides by both non-enzymatic Fenton reactions and enzymatic LPO reactions Liang et al., 2022). Iron serves as an essential cofactor for arachidonate lipoxygenases (ALOXs) and cytochrome P450 oxidoreductase (POR) to initiate the non-enzymatic Fenton reaction. ALOXs and POR promote lipid peroxidation. In enzymatic LPO, ACSL4 catalyzes the ligation of free PUFAs [such as AA and adrenic acid (AdA)] with CoA to generate PUFA-CoAs, which include AA-CoA or AdA-CoA (Dixon et al., 2015;Doll et al., 2017). Subsequently, LPCAT3 incorporates PUFA-CoAs into pLs to generate PUFA-PLs, which includes AA-phosphatidylethanolamine or AdA-phosphatidylethanolamine (Dixon et al., 2015;Kagan et al., 2017). Once the PUFA-PLs incorporated lipid bilayers, the iron-dependent enzymes (such as POR and ALOXs) and labile iron use O 2 to perform a peroxidation reaction, generating peroxidated PUFA-PL or polyunsaturated-fatty-acid-containing -phospholipid hydroperoxides (PUFA-PL-OOH) (Hadian and Stockwell, 2020;Zou et al., 2020). Other membrane electron transfer proteins, particularly the NADPH oxidases, are also involved in ferroptosis by contributing to ROS production for LPO (Xie et al., 2017). LPO and its secondary products, namely, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), cause pore formation in the lipid bilayers, eventually resulting in cell death and ferroptosis (Tang and Kroemer, 2020). Ferroptosis has acquired substantial attention in cardiomyopathy research. Further, it plays a vital role in the pathogenesis of cardiomyopathies, such as ICM, DCM, DICM, and SCM. Therapeutic strategies targeting ferroptosis may facilitate the treatment of these cardiomyopathies. 2015). MIRI leads to oxidative stress and energy metabolism disturbances, among other issues (Li D. et al., 2021). Therefore, understanding the mechanisms of MIRI is essential for attenuating the triggers of cardiomyocyte cell death and preventing left ventricular remodeling and HF.
A novel study reported on the role of ferroptosis in ischemia/ reperfusion (I/R)-induced cardiomyopathy in murine models (Fang et al., 2019), which established an in vivo correlation between ferroptosis and cardiac cell death (Conrad and Proneth, 2019). Thereafter, emerging studies delved into the pathophysiological role of ferroptosis in the development of MIRI and ICM ( Figure 1). Numerous molecular mechanisms and pathways are related to the genesis of MIRI, including iron homeostasis imbalance, lipid peroxidation, and redox homeostasis imbalance. Since the introduction of ferroptosis in 2012, researchers have revisited the role of iron homeostasis imbalance, lipid peroxidation, or glutathione metabolism disorder in MIRI, thus proposing that ferroptosis participates in MIRI pathogenesis. Among all types of organ ischemia/reperfusion injury (IRI), the role of ferroptosis in the pathogenesis of MIRI has been the most extensively studied.

Role of dysregulation of iron metabolism in MIRI
The accumulation of iron, a core characteristic of ferroptosis, plays a pathogenic role in AMI and MIRI. Excessive iron is transported into the cardiomyocytes, thus predisposing them to undergo ferroptosis by the Fenton reaction and ROS generation after I/R (Li J. Y. et al., 2021). Ferroptosis predominantly occurs in the reperfusion phase of cardiac tissues, characterized by a gradual increase in the ACSL4, Fe 2+ , and MDA levels, along with decreased levels of GPX4 (Tang et al., 2021a). Cardiomyocytes are vulnerable to the dysregulation of iron homeostasis, which is central to MIRI through different pathways to increase the iron content. The heart utilizes several iron uptake transport systems, including L-type (LTCC) or T-type (TTCC) voltage-dependent Ca 2+ channels, transferrin (TF) receptor (TfR1), and divalent metal transporter (DMT1) (Lillo-Moya et al., 2021).
Iron enters the cardiomyocytes principally through TfR1 as TF or through LTCC as non-TF-bound iron, TTCC, and DMT1. During MIRI, the intracellular iron-storing protein, the degraded ferritin to release iron and perform iron-mediated Fenton reaction, resulting in oxidative damage to cardiomyocytes and loss of cardiac function. Studies have demonstrated excessive iron accumulation in
Frontiers in Pharmacology frontiersin.org 03 the myocardial scar in mice MIRI models (Baba et al., 2018;Fang et al., 2019), thereby suggesting iron overload as a primary characteristic of ferroptosis. The ferroptosis inhibitor ferostatin-1 (Fer-1) or iron chelator dexrazoxane (DXZ) inhibits cardiac remodeling and fibrosis induced by IRI (Fang et al., 2019). Increased cellular iron content exists in IRI mice, apart from decreased activities of GPX4 and ferritin heavy chain-1 (FTH1) as well as decreased glutathione (GSH) levels in the cardiac issue after MIRI (Chen et al., 2021c). Moreover, the ubiquitin-specific protease 7 (USP7)/p53 pathway activates TfR1 to exacerbate cardiomyocyte ferroptosis in subsequent I/R (Tang et al., 2021a). The pharmacological inhibition of USP7 results in increased p53 activity and decreased TfR1, thus leading to decreased ferroptosis and MIRI . Therefore, the pharmacological inhibition of TfR1 activity may inhibit ferroptosis in MIRI.

Role of LPO in MIRI
Deferoxamine therapy decreases myocardial injury by inhibiting ferroptosis in I/R-induced rat hearts. The specific redox reactions of PUFA-PLs in ischemia-induced cardiomyocytes initiate oxidative damage in the reperfusion phase. ALOX15 induction by ischemia/ hypoxia initiates the oxidation of PUFA-PLs (particularly PUFA-PE) and results in cardiomyocyte ferroptosis. Further, ALOX15 ablation in mice confers resistance to PUFA-dependent ischemia-induced cardiac injury (Ma X. et al., 2022). The overexpression of activating transcription factor 3 (ATF3) inhibits the classical ferroptosis activators ras-selective lethal small molecule 3 and erastin-induced ferroptosis in cardiomyocytes. ATF3 expression increases in the early phase of reperfusion, whereas its ablation significantly aggravates IRI. The binding of ATF3 to the transcriptional start site of the FA complementation group D2 can enhance its promoter activity, thereby exerting cardioprotective effects against H/R injury through an antiferroptosis mechanism (Liu M. Z. et al., 2022). Bai and colleagues have demonstrated that SENP1 expression is upregulated by hypoxia, which protects cardiomyocytes against ferroptosis through deSUMOylating hypoxia-inducible factor-1α and ACSL4 .

Role of SLC7A11/GPX4 axis inhibition in MIRI
Increased levels of ACSL4, Fe 2+ , and MDA, along with decreased GPX4 levels, are observed in the myocardium after MIRI (Tang et al., 2021a). The inhibition of the GSH-generation pathway, either iron chelation or glutaminolysis, could alleviate IRI by blocking ferroptosis (Gao et al., 2015). A specific ferroptosis inhibitor suitable for animal models, i.e., liproxstatin 1, can protect the mouse myocardium against IRI by decreasing voltage-dependent anionselective channel protein 1 levels and upregulating GPX4 levels (Feng et al., 2019). The expression of USP22, SIRT1, and SLC7A11 is inhibited after IRI injury, whereas p53 is highly expressed in the myocardial tissues. Conversely, the overexpression of USP22, SIRT1, or SLC7A11 reduces the degree of IRI injury by inhibiting ferroptosis and improves the viability of cardiomyocytes (Ma et al., 2020).

Ferroptosis in diabetic cardiomyopathy
DCM, a specific form of cardiomyopathy independent of hypertension and coronary artery disease (Tan et al., 2020), is caused by diabetes mellitus (DM)-associated dysregulated glucose and lipid metabolism (Tan et al., 2020). DM increases oxidative stress and activates multiple inflammatory pathways, leading to cellular injury, cardiac remodeling, and systolic and diastolic dysfunction (Tan et al., 2020;Khan et al., 2021). The eventual outcome is cardiomyocyte cell death. The clinical features and pathogenesis of DCM have been wellcharacterized in the past 4 decades; however, its effective therapeutic regimen is still limited, thus suggesting the need to explore novel mechanisms underlying DCM development. Ferroptosis may be associated with the pathological progression of DCM Wei LY. et al., 2022;Wei Z. et al., 2022). Ferroptosis plays a role in DM (Behring et al., 2014;Bruni et al., 2018;Lutchmansingh et al., 2018;Shu et al., 2019;Krümmel et al., 2021) (Figure 1). A novel study reported on the role of ferroptosis in the heart of diabetic mice in 2022, thus demonstrating that Nrf2 activation attenuates ferroptosis by upregulating SLC7A11 and ferritin levels (Wang D. et al., 2022). GPX4 can inhibit DCM in GPX4 transgenic mouse models (Baseler et al., 2013).
The ablation of cluster of differentiation 74 (CD74; a receptor for the regulatory cytokine macrophage migration inhibitory factor) prevents DM-evoked and oxidative stress. Ferroptosis inhibitors preserve the cardiomyocyte function and inhibit LPO induced by the high glucose/high fat (HGHF) challenge in vitro. Recombinant MIF mimics HGHF-induced LPO and depletes GSH and ferroptosis. Conversely, MIF inhibitors reverse these effects mediated by recombinant MIF. Taken together, CD74 ablation rescues DCM by inhibiting ferroptosis, thus indicating CD74 as a promoter of ferroptosis (Chen H. et al., 2022). FUN14 domain-containing 1 (FUNDC1) insufficiency sensitizes DCM through ACSL4-mediated Frontiers in Pharmacology frontiersin.org ferroptosis, thus indicating FUNDC1 as an inhibitor of ferroptosis (Pei et al., 2021). Further, long non-coding RNAs (LncRNAs) regulate ferroptosis in DCM. The lncRNA-zinc finger antisense 1 works as a competing endogenous RNA that sponges miR-150-5p and downregulates cyclin D2 (CCND2), promoting ferroptosis and DCM development (Ni J. et al., 2021). In summary, ferroptosis plays a significant role in the development of DCM. However, the molecular mechanism warrants further investigation.

Ferroptosis in DOX-induced cardiomyopathy
Anthracyclines are the most widely used anticancer chemotherapeutic agents. However, doxorubicin (DOX) causes cardiotoxicity, resulting in DICM, thereby limiting its clinical efficacy (Herrmann, 2020;Fang et al., 2023). Ferroptosis plays an essential role in the pathogenesis of DICM (Fang et al., 2023) ( Figure 1). Wang et al. have demonstrated that DOX induces heart injury and increases cardiac iron levels, lipid-derived ROS, and the biomarkers of ferroptosis (Fang et al., 2019). They presented novel evidence that the contributions of ferroptosis to DICM in DOX-treated mice and its subsequent inhibition exert cardioprotection (Fang et al., 2019). Their findings were corroborated by other studies which revealed that ferroptosis is a crucial mechanism in DICM and that acyl-CoA thioesterase 1 (ACOT1) plays a critical role during the process. Thus, they demonstrated ACOT1 as a ferroptosis inhibitor and that targeting the inhibition of ferroptosis is a strategy for DICM treatment . Tadokoro and colleagues have revealed that DOX inhibits GPX4 and induces LPO, thus leading to mitochondria-dependent ferroptosis in a DICM mouse model (Tadokoro et al., 2020). Further, the ferroptosis inhibitor ferrostatin-1 (Fer-1) can protect cardiomyocytes against DOX-induced cell injury (Tadokoro et al., 2020).  have indicated that DOX upregulates high mobility group box 1 expression, which promotes ferroptosisassociated cardiotoxicity in DOX-treated rats. Fer-1 or DXZ reverse DOX-induced ferroptosis and DICM. In summary, ferroptosis inhibition is a therapeutic target for DICM.

Ferroptosis in septic cardiomyopathy
Sepsis is a life-threatening organ dysfunction resulting from dysregulated immune response to an infection. Seventy percent of patients with sepsis develop septic cardiomyopathy (SCM), which is the leading cause of sepsis-related morbidity and mortality (Nabzdyk et al., 2019;Hollenberg and Singer, 2021). Ferroptosis is involved in SCM ( Figure 1). GSH depletion and the downregulation of GPX4 expression, as well as increased iron content and LPO levels, exist in cecal ligation and punctureinduced sepsis animal model, implying the involvement of ferroptosis in the pathogenesis of SCM . Dexmedetomidine exerts cardioprotective effects through ferroptosis inhibition by decreasing iron accumulation, downregulating the protein levels of HO-1, and inducing GPX4 . The ferroptosis inhibitors deferoxamine and Fer-1 can improve cardiac function and decrease mortality in septic mice by decreasing the levels of ferroptosis in cardiomyocytes . These results support the hypothesis that ferroptosis is involved in the pathogenesis of sepsis-induced myocardial injury. Ferritinophagy-mediated ferroptosis plays a pathogenic role in sepsis-induced myocardial injury . Li et al. (2020) have demonstrated that ferroptosis plays a crucial role in sepsisinduced cardiomyopathy in sepsis-related models, including a lipopolysaccharide (LPS)-induced model of septic cardiomyopathy .
Specific regulators play a role in modulating ferroptosis and SCM. The transmembrane protein 43 (TMEM43), a transmembrane protein related to cardiomyopathy, protects against SCM by inhibiting ferroptosis in LPS-induced mice (Chen L. et al., 2022). The knockdown of TMEM43 in the heart aggravates LPS-induced cardiomyopathy, accompanied by an increased cardiac ferroptosis. TMEM43 overexpression decreases LPS-induced ferroptosis and cardiac injury by inhibiting LPO. TMEM43 silencing promotes ferroptosis and cell injury in LPS-induced rat H9c2 cardiomyocytes. TMEM43 downregulates the expression of P53 and ferritin but upregulates the levels of GPX4 and SLC7A11, thereby inhibiting LPS-induced ferroptosis. Fer-1 can ameliorate TMEM43 knockdown-induced deteriorating effects in LPS-induced cardiac injury. Taken together, TMEM43 protects against SCM by inhibiting ferroptosis (Chen Z. et al., 2022). The islet cell autoantigen 69, which can regulate inflammation and immune response, induces ferroptosis to cause septic cardiac dysfunction through the stimulator of interferon gene trafficking (Kong et al., 2022). The neutrophil-derived lipocalin-2 induces ferroptosis by increasing the labile iron pool in the cardiomyocytes of LPS-induced mouse SCM model (Huang Q. et al., 2022).

Pharmacological inhibition of ferroptosis for treating cardiomyopathy
Ferroptosis was first described in 2012; the studies on its role in cardiomyopathy are still in their infancy. However, existing evidence suggests a strong correlation between ferroptosis and cardiomyopathy. Thus, the inhibition of ferroptosis may be a promising target for treating cardiomyopathy. Ferroptosis reportedly plays a pathogenic role in cardiomyopathy; thus, scientists have begun identifying a targeted antiferroptosis approach for cardiomyopathy treatment. Numerous drugs have been recognized to exert a therapeutic impact on cardiomyopathy treatment by inhibiting ferroptosis. Several experimental compounds and clinical drugs inhibit ferroptosis to achieve therapeutic purposes in cardiomyopathies. The pharmacological inhibition of ferroptosis is becoming a cardioprotective strategy for cardiomyopathy prevention in vitro or in vivo. We try to sort these ferroptosis-inhibiting small molecules by mode of action. These categories maybe include activator of system Xc − , ferroptosis-inhibiting Nrf2 activators, GPX4 activator (direct or indirect), ferroptosis inhibitors through combined mechanisms, or ferroptosis inhibitors through unknown mechanisms. However, it is hard to clearly classify the ferroptosis-inhibiting small molecules into a specific categories.

Icariin
(1), a natural flavonoid compound, is the main component of the Chinese herb Epimedium (also called YinYangHuo in Traditional Chinese Medicine) that has the functions of anti-aging, anti-inflammation, antioxidation, antiosteoporosis, and ameliorating fibrosis (Su et al., 2023).1 is a potent inducer of Nrf2 (Moratilla-Rivera et al., 2023). 1 inhibit hypoxia/reoxygenation (H/R)-induced ferroptosis by increasing GPX4 and decreasing ACSL4 and content of Fe 2+ in cardiomyocytes through activating the Nrf2/HO-1 signaling pathway . Owing to outstanding medicinal properties in preventing and curing many common health issues, 1 and its derivates, icariside II (ICS) and icaritin (ICT) have garnered great interest in drug development. 1 possesses a variety of beneficial effects in regulating cardiovascular inflammation and other biological activities. In China, YinYangHuo and its compound have been used in the treatment of numerous diseases, like AD, stroke, and depression. ICA and its metabolites, which contain flavonoids, polysaccharides, vitamin C, and other active compounds, have been proven to have cardio-cerebrovascular protective benefits . 1 can works as a prodrug was subjected to preclinical studies. We must realize that the oral bioavailability rate is only 12.02% for 1. Studies have shown the addition of cyclodextrins (CDs) to ICA can result in a vast increase in its water solubility, consequently achieving considerably better bioavailability (Cui et al., 2013;Jin et al., 2013). The degradation of ICA into ICS in vivo promotes ICA absorption (Cheng et al., 2015).
Frontiers in Pharmacology frontiersin.org anesthetic agent. 4 mitigated IR-induced ICM through inhibiting ferroptosis by upregulating GPX4 expression, and decreasing the levels of MDA and iron and ACSL4. Nrf2 inhibitors ML385 eliminated the inhibition of 4 on ferroptosis induced by IR, suggesting that 4 attenuated the myocardial injury by inhibiting IR-induced ferroptosis via Nrf2 . Gossypol Acetic Acid (GAA, 5), a natural product taken from the seeds of cotton plants, attenuates ICM through inhibiting ferroptosis by chelating iron content, and downregulating mRNA levels of Ptgs2 in RSL3, and Fe-SP-induced H9c2, inhibiting LPO in oxygen-glucose deprivation/reperfusion (OGD/R)-induced H9c2.5 attenuates IR-induced ICM through inhibiting ferroptosis by decreasing the production of LPO, increasing the Nrf2 and GPX4 protein, while decreasing the mRNA levels of Ptgs2 and Acsl4, and the protein levels of ACSL4 . Dexmedetomidine (6), a highly selective alpha2adrenoceptor agonist with sedative, analgesic, sympatholytic, and hemodynamic-stabilizing properties, posess the protective effect against I/R (Xiao Z. et al., 2021;Deng et al., 2022;Yang et al., 2022;Hu et al., 2023) and H/R (Wu W. et al., 2022; induced cardiomyocyte injury. 6 attenuates ICM through inhibiting ferroptosis by activating AMPK/GSK-3β-dependant Nrf2/SLC7A11/GPX4 (Wang et al., 2022d). Sulforaphane (7) is a naturally occurring dietary phytochemical extracted from cruciferous vegetables .7 is a potent Nrf2 activators and inhibit cardiomyopathy Su et al., 2021;Wang et al., 2022e). 7 is an important member of the isothiocyanates, and is abundant in cruciferous plants with excellent anti-cancer effects (Wei LY. et al., 2022).7 attenuates ICM in diabetic rats through inhibiting ferroptosis by activation of Nrf2/FPN1 pathway (Tian H. et al., 2021). As a well known activator of Nrf2, 7 can upregulate multiple antioxidants and protect against various oxidative damages. 7 prevents rat cardiomyocytes from H/R injury in vitro via activating SIRT1 and subsequently inhibiting ER stress . 7 protects from myocardial ischemia-reperfusion damage through activating Nrf2 (Silva-Palacios et al., 2019).7 inhibit intermittent hypoxia-induced cardiomyopathy in mice through activating Nrf2 . Several clinical studies with 7 for the (supportive) treatment of non-alcoholic fatty liver disease (NCT04364360), chronic kidney disease (NCT05153174, NCT04608903) and anthracycline related cardiotoxicity in breast cancer (NCT03934905) are ongoing. A multi-center, randomized, placebo-controlled clinical trial is needed to be conducted to investigate 7 in adult patients with ICM.

Conclusions and perspectives
The pathophysiology of cardiomyopathies is complex and still undergoing extensive investigation. In this review, we appraised articles that emphasized research progress in the pathological roles of ferroptosis in ICM, DCM, DICM, and SCM and ferroptosis inhibitors to mitigate cardiomyopathies. Meanwhile, researchers have identified novel targeted treatments for these cardiomyopathies through the pharmacological inhibition of ferroptosis. The pharmacological inhibition of ferroptosis is a potential therapeutic target for these cardiomyopathies, with potential novel drug targets and strategies for these diseases. However, the current research on the role of ferroptosis in cardiomyopathies is still in the infancy, and is still poorly understood. And more studies are required to clarify its role and functional mechanisms. Furthermore, most data reported in the literature are derived from experimental studies that do not directly report clinical applications and implications. Although a phase III clinical trial is underway to determine if resveratrol exert the potential heart benefits of resveratrol in patients with non-ischemic cardiomyopathy (phase III, n = 40, NCT01914081). In addition, a multi-center, randomized, placebo-controlled phase II clinical trial is also being conducted to investigate the LCZ696 in adult patients with non-obstructive hypertrophic cardiomyopathy (nHCM) (phase II, n = 45, NCT04164732). However, there is still lacking the study directly targeting ferroptosis to treat ICM, DCM, DICM, and SCM using bioactive compounds. Therefore, more clinical studies need to be conducted to inform practical treatment and management strategies. Despite these considerations, the current evidence strongly indicates that inhibiting ferroptosis marks a significant new direction for treating cardiomyopathies.

Author contributions
Conception and design: HS and XH; administrative support: All authors; collection and assembly of data: All authors; data analysis and interpretation: All authors; manuscript writing: HS; final approval of manuscript: All authors.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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