Methods of treating dilated cardiomyopathy

Abstract

Provided herein are compositions of one or more compounds for treating a heart failure (e.g., dilated cardiomyopathy such as a heart failure with reduced ejection fraction), and methods of using the same for treatment of the heart failure.

Description

METHODS OF TREATING DILATED CARDIOMYOPATHYRELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 515,030, filed on July 21, 2023, which is incorporated herein by reference in its entirety for all purpose.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under grant no. TRANI-12907 awarded by the California Institute for Regenerative Medicine (CIRM). The government has certain rights in the invention.BACKGROUND

[0003] Cardiomyopathies are disorders of the cardiac muscle that cause mechanical and / or electrical dysfunction that result in dilated, hypertrophic or restrictive pathophysiology. Dilated cardiomyopathy (DCM) is a non-ischemic heart muscle disease with structural and functional myocardial abnormality, characterized by left ventricular or biventricular dilation and impaired contraction. DCM-associated heart failure occurs in about 1:400 to 1 :2500 individuals and is characterized by deranged cardiac metabolism and deficient contractile function that lead to reduced ejection fraction and ventricular chamber dilation. Similar to other forms of heart failure with reduced ejection fraction (HFrEF), current therapy for DCM is based mainly on neurohumoral blockade. Even with optimal therapy, DCM remains one of the most common causes of heart failure and sudden cardiac death, as well as the major indication for heart transplantation. Despite detailed knowledge of about 50 mutations that cause a third of all DCM cases, no therapies have been developed that target the underlying causes of the disease. Therefore, there is a dire need for therapeutics that can target the underlying pathogenic mechanisms of DCM.SUMMARY

[0004] The present disclosure encompasses the recognition that inhibition of the transcription factor BACH1 in subjects with dilated cardiomyopathy (DCM) is beneficial for the subject. Accordingly, provided herein are methods for treating dilated cardiomyopathy (DCM) in a subject having or at risk of having the DCM. The method comprises the administration of a therapeutically effective amount of a BTB and CNC homology 1 (BACH1) inhibitor to the subject.

[0005] The present disclosure also encompasses the recognition that activation of the nuclear factor erythroid 2-related factor 2 (NRF2) is beneficial to the subject. Accordingly, provided herein are methods for treating dilated cardiomyopathy (DCM) in a subject having or at risk of having the DCM comprising administration of a therapeutically effective amount of a BTB and CNC homology 1 (BACH1) inhibitor to the subject.

[0006] The present disclosure also encompasses the recognition that inhibition of the transcription and simultaneous activation of the nuclear factor erythroid 2-related factor 2 (NRF2) is beneficial to the subject. Accordingly, provided herein are methods for treating dilated cardiomyopathy (DCM) in a subject having or at risk of having the DCM comprising administration of a therapeutically effective amount of a BTB and CNC homology 1 (BACH1) inhibitor and a NRF2 activator to the subject.

[0007] In some embodiments, the DCM is heart failure with reduced ejection fraction (HFrEF).

[0008] In some embodiments, the administering (a) improves peak contraction amplitude; (b) improves contraction force; (c) increases contraction velocity; (d) increases oxidative metabolism and efficiency of ATP production without increasing reactive oxygen species (ROS) or inducing mitochondrial stress; (e) increases contractility without altering intracellular Ca2+ levels or inducing signs of arrhythmia; or any combination of (a), (b), (c), (d) and (e) in the subject.

[0009] In some embodiments, the combination of the BACH1 inhibitor and the NRF2 activator has a synergistic effect, leading to a lower dosage and toxicity.

[0010] In some embodiments, the BACH1 inhibitor is a small molecule compound. In some embodiments, the BACH1 inhibitor is selected from the group consisting of ML-0207 / ASP8731, HPP-A, HPP-B, HPP-C, HPP-D, HPP-E, HPP971, HPP-1014, HPP-4382, cadmium, hemin(Panhematin®), and any derivative thereof. In some embodiments, the BACH1 inhibitor is HPP- E.

[0011] In some embodiments, the NRF2 activator is a small molecule compound. In some embodiments, the NRF2 activator is selected from the group consisting of dimethyl fumarate, Tecfidera®, oltipraz (OPZ), CBR-470-1, CDDO Im, bardoxolone-m ethyl (CDDO-Me), (±)- eriodictyol, INF 4E, ML334, NK 252, 4-Octyl itaconate, RA 839, resveratrol, sulforaphane, curcumin, agmatine, naringenin, RTA-408 (omavel oxoIone), ALKS-8700, ursodiol, sulforadex (SFX-01), ITH12674, CXA-10, SCIIU909, and any derivative thereof. In some embodiments, the NRF2 activator is dimethyl fumarate. In some embodiments, the NRF2 activator is Tecfidera®.

[0012] Each of the aspects and embodiments described herein are capable of being used together, unless excluded either explicitly or clearly from the context of the embodiment or aspect.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0014] FIGs. 1A and IB shows schematic diagrams illustrating gene expression signature histograms for genes up and down regulated in DCM hearts and non-failing hearts and the gene expression signatures of transcription factors that antagonize the DCM gene expression signature.

[0015] FIG. 2A shows a schematic diagram illustrating the identification of gene expression signatures for the murine homologue of BACH1, Bachl inhibition in mice and DCM in patients. FIG. 2B shows a graph of the gene expression changes in DCM versus non failing hearts as identified in FIG. 2A (blue line: genes upregulated by Bachl cKO in mice; red line: genes downregulated by Bachl cKO in mice; black solid line: all other significantly affected genes.

[0016] FIG. 3 shows a schematic diagram illustrating that BACHl inhibition de-represses a subset of NRF2 target genes that are beneficial for DCM.

[0017] FIG. 4 shows a schematic diagram illustrating the synergistic activity of HPP-E (BACH1 inhibitor) and Tecfidera (NRF2 activator) in dilated cardiomyopathy (DCM).

[0018] FIG. 5 shows a schematic diagram illustrating the identification and testing for candidate drugs on DCM hiPSC-cardiomyocytes.DETAILED DESCRIPTION

[0019] Provided herein are, inter alia, methods of treating a heart failure (e.g., dilated cardiomyopathy such as HFrEF) in a subject having or at risk of having the heart failure by administering therapeutically effective amount of one or more compounds that can restore myocardial contractility by normalizing one or more metabolic dysfunction in the subject.

[0020] The following descriptions and examples illustrate embodiments of the present disclosure in detail. Although the present disclosure has been described in some details by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims.

[0021] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0022] Although various features of the disclosure can be described in the context of a single embodiment, the features can also be provided separately or in any suitable combination. Conversely, although the present disclosure can be described herein in the context of separate embodiments for clarity, the present disclosure can also be implemented in a single embodiment. It is to be understood that the present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are variations and modifications of the present disclosure, which are encompassed within its scope.

[0023] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0024] All patent filings, websites, other publications, accession numbers and the like cited above or below are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be so incorporated by reference. If different versions of a sequence are associated with an accession number at different times, the version associated with the accession number at the effective filing date of this application is meant. The effective filing date means the earlier of the actual filing date or filing date of a priority application referring to the accession number if applicable. Likewise, if different versions of a publication, website or the like are published at different times, the version most recently published at the effective filing date of the application is meant unless otherwise indicated. Any feature, step, element, embodiment, or aspect of the disclosure can be used in combination with any other unless specifically indicated otherwise.Definitions

[0025] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0026] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated cases, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0027] In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0028] In this application, the use of “or” means “and / or” unless stated otherwise. The terms “and / or” and “any combination thereof’ and their grammatical equivalents as used herein, can be used interchangeably. These terms can convey that any combination is specifically contemplated. Solely for illustrative purposes, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof’ can mean “A individually; B individually; C individually; A andB; B and C; A and C; and A, B, and C”. The term “or” can be used conjunctively or disjunctively, unless the context specifically refers to a disjunctive use.

[0029] Furthermore, the use of the term “including” as well as other forms, such as “include”, “includes” and “included”, is not limiting.

[0030] Reference in the specification to “some embodiments”, “an embodiment”, “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures.

[0031] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0032] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, z.c., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. In another example, the amount “about 10” includes 10 and any amounts from 9 to 11. In yet another example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. Alternatively, particularly with respect to biological systems or processes, the term “about” can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0033] The term “treating”, “treatment”, or any grammatical variant thereof of a condition as used herein includes preventing or alleviating a condition, slowing the onset or rate ofdevelopment of a condition, reducing the risk of developing a condition, preventing or delaying the development of symptoms associated with a condition, reducing or ending symptoms associated with a condition, generating a complete or partial regression of a condition, curing a condition, or some combination thereof. With regard to a heart failure, “treating” or “treatment” can refer to, but not limited to, improving peak contraction, improving contraction force, increasing contraction velocity, increasing oxidative metabolism and efficiency of ATP production without increasing reactive oxygen species (ROS) or inducing mitochondrial stress, and increasing contractility without altering intracellular Ca2+levels or inducing signs of arrhythmia, or any combination thereof.

[0034] The term “therapeutically effective amount”, “effective dosage”, or any grammatical variant thereof refers to the dosage or concentration of a drug effective to treat a disease or a condition, such as a heart failure. For example, with regard to the use of one or more compounds, such as a BACHl inhibitor, aNRF2 activator, or a combination of a BACH1 inhibitor and a NRF2 activator, to treat heart failure, e.g., dilated cardiomyopathy (DCM), a therapeutically effective amount is the dosage or concentration of the one or more compounds capable of eradicating all or partly of any of the symptoms of the disease or the condition, ameliorating any symptom or marker associated with the disease or the condition, preventing or delaying the development of the disease or the condition, or some combination thereof. The “therapeutically effective amount” can vary depending, for example, but not limited to, on the compound, the disease or the condition and / or symptoms thereof, severity of the disease or the condition and / or symptoms thereof, the age, weight, and / or health of the subject to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance can be ascertained by those skilled in the art or capable of determination by routine experimentation.

[0035] A “subject” or “individual” can be a vertebrate, a mammal, or a human. Mammals include, but are not limited to, farm animals, sport animals, pets, primates, rodents, mice and rats. In one aspect, a subject is a human.

[0036] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the disclosure are specificallyembraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub combination was individually and explicitly disclosed herein.Dilated Cardiomyopathy

[0037] Heart failure is a heterogeneous disease with an age-related increase in prevalence. The increasing prevalence of heart failure in the elderly population may be attributed to the elevated number of long-term survivors after myocardial infarction who are particularly prone to develop left ventricular dysfunction, a main driver of heart failure. In addition to age, obesity and diabetes have been identified as important risk factors for heart failure. Diabetes is one of the most relevant risk factors for heart failure, the prevalence of which is increasing worldwide. Heart failure often manifests as the first cardiovascular event in people with diabetes. Even individuals with pre-diabetes are at a greater risk of developing heart failure. In addition, heart failure itself is emerging as an antecedent for diabetes development. Thus, diabetes and heart failure are interrelated: diabetes increases the risk of heart failure, heart failure is highly prevalent in patients with diabetes, and heart failure may increase the risk of developing diabetes.

[0038] Three main phenotypes describe heart failure according to the measurement of the left ventricle ejection fraction. Heart failure with reduced ejection fraction (HFrEF) has ejection fraction less than or equal to about 40%. Heart failure with preserved ejection fraction (HFpEF) has ejection fraction is greater than or equal to about 50%. Heart failure with mid-range ejection fraction (HFmrEF) (other names are: HFpEF-borderline and HFpEF-improved when ejection fraction in HFrEF improves to greater than 40%) has ejection fraction about 41% to about 49% per European guidelines and about 40% to about 49% per the US guidelines. All patients with HFrEF have concomitant diastolic dysfunction; in contrast, diastolic dysfunction can occur in the absence of systolic dysfunction. Risk factors specific for HFrEF include a history of cardiovascular diseases such as myocardial infarction. The mortality rate of HFrEF patients is slightly higher than for those with HFpEF and is mainly caused by cardiovascular death.

[0039] Left ventricular dysfunction, a main driver of heart failure, can be classified into abnormalities of systolic function or abnormalities of myocardial relaxation, previously knownas diastolic dysfunction. The initial step of the clinical manifestation of systolic dysfunction is an injury to myocytes, e.g., due to myocardial infarction or ischemia. Injury-induced myocyte damage and thus progressive myocyte loss provokes an inflammatory response and thereby causes ventricular remodeling. Remodeling generates an imbalanced heart wall structure with eccentric hypertrophy characterized by an increased length of myocytes. The inflammatory process triggers an excessive production of fibrotic tissues, further disturbing cardiac function by an impaired transduction of myocyte contraction into cardiac force, culminating in an uncoordinated contraction of the myocyte bundles. In many cases, HFrEF manifests as systolic dysfunction.

[0040] Cardiomyopathy is characterized by heart morphology and contractile function changes that cause high morbidity and mortality. Classifications of cardiomyopathy can include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM). DCM can be defined by the presence of left ventricular dilatation and left ventricular systolic dysfunction in the absence of abnormal loading conditions (e.g., hypertension, valve disease) or coronary artery disease sufficient to cause global systolic impairment. In some embodiments, a predominant phenotype of DCM is HFrEF. In some embodiments, right ventricular dilation and dysfunction can be present in DCM. In some embodiments, DCM can also occur in patients with mitochondrial cytopathies and inherited metabolic disorders (e.g. hemochromatosis). HCM is defined by the presence of myocardial hypertrophy in the absence of hemodynamic stresses sufficient to account for the degree of hypertrophy and systemic diseases (e.g., amyloidosis and glycogen storage disease). RCM is characterized by a pattern of ventricular filling in which increased stiffness of the myocardium causes ventricular pressure to rise precipitously with only small increases in volume. RCM is defined as restrictive ventricular physiology in the presence of normal or reduced diastolic volumes (of one or both ventricles), normal or reduced systolic volumes, and normal ventricular wall thickness.

[0041] DCM, characterized by reduced ejection fraction and ventricular chamber dilation, is a major unmet medical need. DCM occurs in about 1 :400 to 1 :2500 individuals. Given the lack of therapeutics, DCM is one of the most common causes of heart failure (HF) and sudden cardiac death as well as the major indication for heart transplantation. Current therapy for DCM is similar to that for other forms of heart failure (HF) with reduced ejection fraction and is basedmainly on neurohumoral blockade. Even with optimal therapy, morbidity and mortality remain high.

[0042] Seminal research has identified variants in over 50 genes associated with non- syndromic DCM. These variants account for about a third of all cases of DCM, and it is estimated that about half of DCM has a genetic contribution. Despite this knowledge, there is no approved therapeutics that can target the underlying pathogenic mechanisms of DCM, such as those that have revolutionized cancer therapy by counteracting oncogene activity. For DCM, the challenge is that most of the disease-causing gene variants encode critical components of the contractile machinery (e.g., Titin, Myosin, Actin, and Troponin) or key regulators of contraction (e. ., the splicing factor RBM20, the Ca2+cycling regulator phospholamban (PLN), and the nuclear envelope protein Lamin A / C (LMNA)). In addition, the mutations typically induce subtle (often decreased) alterations in activity. For these reasons, it has been difficult to develop small molecules that precisely counteract the effects of the variants without further compromising heart function. For example, Omecamtiv mecarbil by Cytokineticsis the first drug developed, although not developed to revert the action of a DCM-causing variant, to improve myocardial contractility by directly binding to myosin to increase force generation. Subgroup analysis of data from the GALACTIC -HF phase 3 randomized clinical trial indicated that Omecamtiv mecarbil prolonged the time to a heart failure event or death among patients with the most severe heart failure (HF). Unfortunately, the effect on patients with less severe HF, such as those at earlier stages of disease, was deemed unlikely to be clinically significant. Omecamtiv mecarbil has an elegant mechanism of action that involves recruiting additional myosin heads to thin filaments and its partial success illustrates the challenge of engineering drugs to alter the delicate function of sarcomeric proteins.

[0043] There is a lack of mechanism-based therapeutics for treating DCM despite the major effort to define common pathogenic mechanisms downstream of the mutated proteins that lead to DCM in hopes of finding actionable points of intervention for the broadest patient population.

[0044] The present disclosure describes the first large-scale, unbiased exploration of protein targets using DCM human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as screenable models. The present disclosure provides, inter alia, the first therapeutic small molecule candidates that can target the underlying pathogenic mechanism of DCM.BACH1

[0045] BTB and CNC homology 1 (BACH1) is a basic leucine zipper protein that can physically bind and suppress the function of the transcriptional activators NRF1 and NRF2. NRFs can activate the gene encoding ATF4 (and ATF4 similarly activates NRF genes), which can lead to an increase in ATF4 protein production. BACH1 through its interactions with NRFs and indirectly with ATF4 can regulate several processes, including the anti-oxidant response, protein homeostasis and endoplasmic reticulum stress processes including the unfolded protein response (UPR), metabolic processes such as serine metabolism, glycolysis and oxidative metabolism important for cellular bioenergetics.

[0046] BACH1 inhibition is not the same as activation of NRFs. BACH1 inhibition can derepress only a subset of NRF target genes. BACH1 can also bind at other sites in chromatin indicating that it can regulate non-NRF target genes possibly through interactions with other transcription factors.

[0047] The BACH1 KO mice have a normal lifespan with no adverse health concerns. These mice have been used to establish the beneficial effect of BACH1 loss of function on several diseases including atherosclerosis and Parkinson’s disease. KOs of NRF1, NRF2, and ATF4, in contrast, can cause either early lethality or compromised health.

[0048] The role of BACH1 in the pathogenesis of DCM has never been examined. It has been shown that the KO of BACH1 can partially protect against loss of contractile motion and fibrotic remodeling in a pressure overload (TAC)-induced model of heart failure. The KO of BACH1 can also protect against cardiac ischemia / reperfusion injury in mice.

[0049] Provided herein are, inter alia, the first one or more therapeutic compounds that can treat one or more symptoms of a heart failure e.g., dilated cardiomyopathy such as HFrEF). In some embodiments, the composition of the present disclosure includes a BTB and CNC homology 1 (BACH1) inhibitor, such as, but not limited to, HPP-E. In some embodiments, the composition of the present disclosure includes a nuclear factor erythroid 2-related factor 2 (NRF2) activator, such as, but not limited to, dimethyl fumarate or Tecfidera®. In some embodiments, the composition of the present disclosure includes a combination of the BACH1 inhibitor (e.g, HPP-E or M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5-yloxy)methyl]-4-(2- methoxyphenyl)]) and the NRF2 activator (e.g., dimethyl fumarate or Tecfidera®).BACH 1 Inhibitor

[0050] A BACH1 inhibitor refers to a compound that can inhibit BACHl’s repression of genes that are positively regulated by NRF2 and can activate the NRF2 pathway. Non-limiting exemplary BACH1 inhibitors can include ML-0207 / ASP8731, HPP-A, HPP-B, HPP-C, HPP-D, HPP-E, HPP971, HPP-1014, HPP-4382, M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5- yloxy)methyl]-4-(2-methoxyphenyl)] and analogues, cadmium, hemin (Panhematin®), or any derivative thereof, and a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the BACH1 inhibitor can be HPP-A. In some embodiments, the BACH1 inhibitor can be HPP-B. In some embodiments, the BACH1 inhibitor can be HPP-C. In some embodiments, the BACH1 inhibitor can be HPP-D. In some embodiments, the BACH1 inhibitor can be HPP-E. In some embodiments, the BACH1 inhibitor can be HPP971. In some embodiments, the BACH1 inhibitor can be cadmium. In some embodiments, the BACH1 inhibitor can be hemin. In some embodiments, the BACH1 inhibitor can be HPP-1014. In some embodiments, the BACH1 inhibitor is HPP-4382. In some embodiments, the BACH1 inhibitor can be M2.

[0052] HPP-E is a highly potent, selective small molecule inhibitor of BACH1 capable of activating the NRF2 pathway in human and murine models. Nataraja et al., Blood 138(1 ):854. HPP-E can induce mRNA expression of NRF2 target genes, such as, but not limited to, HGB1, HBG2, HM0X1, SLC7A11, GCLM, and / or NQO1.

[0053] HPP971 can bind to human BACH1 protein and activate HM0X1 expression in an NRF2-dependent manner.

[0054] M2 [1 -Piperazineethanol, a-[(l,3-benzodioxol-5-yloxy)methyl]-4-(2 -methoxyphenyl)] was identified in a structure-based virtual screen for inhibitors of BACH1, and has been shown to have a safe toxicity profile and efficacy for protection from Aflatoxin Bl -induced liver damage in rats. Zhang, J. et al., (2022) Antioxidants (Basel) 11. 10.3390 / antioxl 1091787.

[0055] Cadmium is known to induce nuclear export of BACH1, enhancing expression of target genes including HM0X1 in response to oxidative stress. The cytoplasmic localization signal (CLS) domain conserved at the C-terminal of BACH1 and BACH2 is responsible for cadmium response. Since cadmium activates p38 and ERK1 / 2 pathways for NRF2 activity, BACH1 is also regulated by p38 and ERK1 / 2 signaling. However, BACH1 remains in the nucleus in the presence of cadmium when cells are treated with a MEK1 / 2 inhibitor. Thus, cadmium mayinactivate BACH1 through another mechanism in addition to nuclear export. Suzuki et al., J Biol Chem 278(49):49246-53 (2003).

[0056] Hemin (Panhematin®) is protoporphyrin IX containing a ferric iron (Fe3+) ion with a coordinating chloride ligand. Hemin induces ubiquitination and degradation of BACH1. Sun et al., EMBO J. 21(19):5216-5224 (2002); Zenke-Kawasaki et al., Mol Cell Biol. 27(19):6962-6971 (2007).

[0057] In some embodiments, the BACH1 inhibitor can be selected from the group consisting of: l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid (2-methoxy-ethyl)-amide; l-Methyl-2-(6-trifluorom ethoxy - benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide; 1- Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)- lH-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide; l-Methyl-2-(6-trifluoromethyl- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide; 2-(6- Chloro-benzothiazol-2-ylamino)-l -methyl- lH-benzoimidazole-5-carboxylic acid (2 -methoxy - ethyl)-amide; 6-Fluoro-l-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid ethylamide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2- ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide; 1-Methyl- 2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(2- fluoro-ethoxy)-ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid ((S)-2-hydroxy-propyl)-amide; 1 -Methyl -2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid ((R)-2- hydroxy-propyl)-amide; 6-Methoxy- 1 -methyl-2-(6-trifluorom ethoxy -benzothiazol -2-ylamino)- lH-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; l-Methyl-2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l-methyl-lH- benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide; l-Methyl-2-(6-trifluorom ethoxy - benzothiazol-2-ylamino)-lH-benzimidazole-5-carboxylic acid (2-ethanesulfonyl-ethyl)-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzimidazole-5-carboxylic acid (3-methanesulfonyl-propyl)-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l -methyl- 1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide; 1 -Methyl -2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzimidazole-5 -carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzimidazole-5-carboxylic acid [2-(4-methyl- piperazin-l-yl)-2-oxo-ethyl]-amide; 1 -Methyl -2-(6-trifluoromethoxy-benzothiazol-2-ylamino)- lH-benzoimidazole-5-carboxylic acid ((S)-l-dimethylcarbamoyl-ethyl)-amide; 1 -Ethyl -2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-ethoxy- ethyl)-amide; l-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid (2-ethoxy-ethyl)-amide; 2-(6-Chloro-benzothiazol-2- ylamino)-! -ethyl- lH-benzoimidazole-5-carboxylic acid (2-fluoro-ethyl)-amide; 2-(6-Chloro- benzothiazol-2-ylamino)-l -ethyl- lH-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)- amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH- benzoimidazole-5-carboxylic acid ((S)-2-hydroxy-propyl)-amide; 2-(6-Chloro-benzothiazol-2- ylamino)-l -methyl- lH-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)- lH-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(2 -methoxy - ethoxy)-ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid [2-(2-dimethylamino-ethoxy)-ethyl]-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-morpholin-4- yl-ethyl)-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l-methyl-lH-benzoimidazole-5- carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6-trifluoromethyl- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-dimethylcarbamoyl-ethyl)- amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (3-morpholin-4-yl-3-oxo-propyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2- ylamino)-lH-benzoimidazole-5-carboxylic acid methylcarbamoylmethyl-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((R)-3- hydroxy-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; 2-(6-Chl oro-benzothiazol -2 -ylamino)-! -methyl-lH-benzoimidazole-5-carboxylic acid [2-((R)-3-methoxy-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l -methyl- lH-benzoimidazole-5-carboxylic acid [2-((S)-3- methoxy-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2- ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((S)-3 -methoxy -pyrrolidin-1 -yl)-2-oxo- ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((S)-3- dimethylamino-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)- amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(4-methyl-piperazin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((R)-3-hydroxy-piperidin-l- yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid [2-((S)-3-hydroxy-piperidin-l-yl)-2-oxo-ethyl]-amide; 1- Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-l-yl)-2-oxo-ethyl]-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l- methyl-lH-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-l-yl)-2-oxo-ethyl]-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l -methyl- lH-benzoimidazole-5-carboxylic acid ((S)-l - dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH- benzoimidazole-5-carboxylic acid ((S)-l-dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid ((S)-l-methyl-2- morpholin-4-yl-2-oxo-ethyl)-amide; l-Methyl-2-(6-trifluorom ethyl -benzothiazol-2-ylamino)- lH-benzoimidazole-5-carboxylic acid ((R)-l-dimethylcarbamoyl-ethyl)-amide; 1 -Methyl -2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [(R)-l-methyl-2- (4-methyl-piperazin-l-yl)-2-oxo-ethyl]-amide; and any derivative thereof.

[0058] In some embodiments, the BACH1 inhibitor for use in combination with a NRF2 activator can be HPP-E (ML-0207 / ASP8731). In some embodiments, the BACH1 inhibitor for use in combination with a NRF2 activator can be M2 [l-Piperazineethanol,a-[( 1,3-benzodioxoi- 5-yloxy)methyl]-4-(2-methoxyphenyl)]. Additional compounds that inhibit BACH1 function include, but are not limited to BACH1 siRNAs that inhibit BACH1 expression or BACH1 short hairpin RNA to deplete BACH1. In some embodiments, the BACH1 siRNA targets the BACH1gene or a BACH1 regulatory region. In some embodiments, the BACH1 short hairpin RNA can be delivered to the heart by a virus (e.g., adeno-associated virus (AAV)).NRF2

[0059] Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) transcription factor with a Cap“n”Collar (CNC) structure. NRF2 possesses seven highly conserved domains called NRF2-ECH homology (Neh) domains. The Nehl domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins (MAFF, MAFG, MAFK). The Neh2 domain allows for binding of NRF2 to its cytosolic repressor Keapl . The Neh3 domain may play a role in NRF2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus. The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CREB), which possesses intrinsic histone acetyltransferase activity. The Neh6 domain may contain a degron that is involved in a redoxinsensitive process of degradation of NRF2. This can occur even in stressed cells, which normally extend the half-life of NRF2 protein relative to unstressed conditions by suppressing other degradation pathways. The Neh7 domain is involved in the repression of Nrf2 transcriptional activity by the retinoid X receptor a through a physical association between the two proteins.

[0060] Under normal or unstressed conditions, NRF2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, NRF2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins. NRF2 is kept in the cytoplasm by Kelch like-ECH- associated protein 1 (KEAP1) and Cullin 3, which degrade NRF2 by ubiquitination. Cullin 3 ubiquitinates NRF2, while KEAP1 is a substrate adaptor protein that facilitates the reaction. Once NRF2 is ubiquitinated, it is transported to the proteasome, where it is degraded and its components recycled. Under normal conditions, NRF2 can have a half-life of about 20 minutes. Oxidative stress or electrophilic stress disrupts critical cysteine residues in KEAP1, disrupting the Keapl -Cul3 ubiquitination system. When NRF2 is not ubiquitinated, it can build up in the cytoplasm, and translocate into the nucleus. In the nucleus, it can combine (forms a heterodimer)with one of small Maf proteins (MAFF, MAFG, MAFK) and bind to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription.NRF2 Activator

[0061] A NRF2 activator refers to a compound that can dissociate NRF2 from a NRF2-KEAP1 complex. This dissociation frees NRF2 from NRF2-KEAP1 complex and allows it to translocate into the nucleus. Once in the nucleus, NRF2 can bind to one or more AREs in association with other transcription factors and regulates the expression of a series of antioxidant enzymes. Most pharmacological NRF2 activators are electrophilic molecules that can covalently modify cysteine residues present in the thiol-rich KEAP1 protein by oxidation or alkylation. Many cysteines of KEAP1 are modified by different electrophiles. Exemplary cysteine residues of KEAP1 most susceptible to electrophile reaction can include, but not limited to, Cysisi, Cys273, and Cys288 of KEAP1. Other sensitive cysteines of KEAP1 are CyS226, CyS434, and CyS6i3. This “cysteine- code” controls KEAP1 activity when the protective response mediated by NRF2 is needed.

[0062] Non-limiting exemplary activators of the NRF2 pathway can include dimethyl fumarate (e.g., Tecfidera®), Oltipraz (OPZ), CBR-470-1, CDDO Im, bardoxolone-methyl (CDDO-Me), (±)-eriodictyol, INF 4E, ML334, NK 252, 4-Octyl itaconate, RA 839, resveratrol, sulforaphane, curcumin, agmatine, naringenin, RTA-408 (omaveloxolone), ALKS-8700, ursodiol, sulforadex (SFX-01), ITH12674, CXA-10, SCIIU909, or any derivative thereof, and a pharmaceutically acceptable salt thereof. In an embodiment, the NRF2 activator can be dimethyl fumarate. In another embodiment, the NRF2 activator can be Tecfidera®. In other embodiments, the NRF2 activator can be selected from the group consisting of dimethyl fumarate (e.g., Tecfidera®), Oltipraz (OPZ), CBR-470-1, CDDO Im, bardoxolone-methyl (CDDO-Me), (±)-eriodictyol, INF 4E, ML334, NK 252, 4-Octyl itaconate, RA 839, resveratrol, sulforaphane, curcumin, agmatine, naringenin, RTA-408 (omaveloxolone), ALKS-8700, ursodiol, sulforadex (SFX-01), ITH12674, CXA-10, SCIIU909, and any derivative thereof.

[0063] Dimethyl fumarate (f.g, Tecfidera®), also known as dimethyl (2£)-but-2-enedioate, / ra / AS- l ,2-ethylenedicarboxylic acid, and dimethyl ester and (7'.’)-2-butenedioic acid dimethyl ester, and its metabolite (e.g., monomethyl fumarate) can activate the NRF2 pathway. Oltipraz (OPZ), 4-methyl-5-(2-pyrazinyl)-l,2-dithiol-3-thione), can increase expression of a number ofmetabolic enzymes. Induction of these metabolic enzymes has been linked to the transcription factor NRF2 and its activation of the antioxidant response element / electrophile response element (ARE / EpRE). CBR-470-1, (3 / ?,41S')- / 'e / -4-[(4-Chlorophenyl)sulfonyl]tetrahydro- / V-(2- methylpropyl)-3-thiophenamine-l,l-dioxide, is a phosphoglycerate kinase 1 (PGK1) inhibitor. CBR-470-1 can promote accumulation of the reactive metabolites methylglyoxal (MGO) resulting in KEAP1 modification and dimerization, which in turn leads to activation of the NRF2 transcriptional program. CBR-470-1 protects SH-SY5Y neuroblastoma cells from MPP+- induced cytotoxicity via the KEAP1-NRF2 cascade. CDDO Im, l-(2-Cyano-3, 12,28- trioxooleana-l,9(l l)-dien-28-yl)-17 / -imidazoleis, an NRF2 signaling activator that can increase NRF2 protein expression and enhance NRF2-dependent cytoprotective gene expression. Bardoxolone-methyl (CDDO-Me), 2-cyano-3, 12-dioxooleana- 1,9(1 l)-dien-28-oic acid methyl ester, is a Nrf2 pathway activator, which can induce expression of NRF-2 regulated, cytoprotective genes in vivo. It can also block the NF-KB pathway by direct inhibition of IKKp and inhibits production of a wide range of inflammatory mediators in vitro. (±)-eriodictyol, 2- (3,4-dihydroxyphenyl)-2,3-dihydro-5,7-dihydroxy-4H-l-benzopyran-4-one, is a potent antioxidant that can protect against FECh-induced neurotoxicity in vitro by activation of Nrf2 / ARE signaling. INF 4E, ethyl 2[(2-chlorophenyl)(hydroxy)methyl]acrylate, a NLRP3 inflammasome and caspase-1 inhibitor, that can activate the Keapl-NRF2 pathway. ML 334, (15,27?)-2-[[(l,SY)-l-[(l,3-dihydro-l,3-dioxo-277-isoindol-2-yl)methyl]-3,4-dihydro-2(l / / )- isoquinolinyl]carbonyl]cyclohexanecarboxylic acid, is an NRF2 activator and can inhibit Nrf2 / Keapl interaction, promoting Nrf2 nuclear translocation and inducing antioxidant response element (ARE) activity in vitro. NK 252, A-[5-(2-Furanyl)-l,3,4-oxadiazol-2-yl]-A’-(2- pyridinylmethyl)urea, is an Nrf2 activator that can interact with the Nrf2 -binding site of Keapl . 4-Octyl itaconate, 2-methylenebutanedioic acid 4-octyl ester, can activate Nrf2. RA 839, (3S)-1- [4-[[(2,3,5,6-tetramethylphenyl)sulfonyl]amino]-l-naphthalenyl]-3-pyrrolidinecarboxylic acid, is an Nrf2 activator, inhibiting Nrf2 / Keap 1 interaction.

[0064] In some embodiments, a NRF2 activator can be selected from the group consisting of: chaicone derivatives such as 2-trifluoromethyl-2 '-methoxy chaicone, auranofin, ebselen, 1,2- naphthoquinone, cynnamic aldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, and -quinone, (tBHQ, tBQ), vitamins KI, K2 and K3, menadione, fumaric acid esters, i.e.. fumaric acid mono- and / or di ester which can be selectedfrom the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate (DMF), monoethyl hydrogen fumarate, and diethyl fumarate, 2-cyclopentenones, ethacrynic acid and its alkyl esters, bardoxolone methyl (methyl 2- cyano-3,12-dioxooleana-l,9(l l)dien-28-oate) (CDDO-Me, RTA 402), ethyl 2-cyano-3,12- dioxooleana-l,9(l l)dien-28-oate, 2-cyano-3,12-dioxooleana-l,9(l l)dien-28-oic acid (CDDO), l[2-Cyano-3,12-dioxooleana- 1,9(1 l)-dien-28-oyl]imidazole (CDDO-Im), (2-cyano-N-methyl- 3,12-dioxooleana-l,9(l l)-dien-28 amide (CDDO-methyl amide, CDDO-MA), isothiocyanate such as sulforaphane, 1,2-dithi ole-3 -thi one such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3 -hydroxy coumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctyl isothiocyanate, corticosteroids, such as dexamethasone, 8-iso prostaglandin A2, alkyl pyruvate, such as methyl and ethyl pyruvate, diethyl or dimethyl oxaloproprionate, 2-acetamidoacrylate, methyl or ethyl-2-acetamidoacrylate, hypoestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[0010] -Shogaol, eugenol, l'-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(methylthio)-3- butenyl isothiocyanate and 6-methylsulfinylhexyl isothiocyanate, ferulic acid and its esters, such as ferulic acid ethyl ester, and ferulic acid methyl ester, sofalcone, 4-methyl daphnetin, imperatorin, auraptene, poncimarin, bis[2-hydroxybenzylidene]acetones, alicylcurcuminoid, 4- bromo flavone, -naphthoflavone, sappanone A, aurones and its corresponding indole derivatives such as benzylidene-indolin-2-ones, perillaldehyde, quercetin, fisetin, koparin, genistein, tanshinone HA, BHA, BHT, PMX-290, AL-1, avicin D, gedunin, fisetin, andrographolide, tricyclic bis(cyano enone) TBE-31 [(+ / -)-(4bS,8aR,10aS)-10a-ethynyl-4-b,8,8-trimethyl-3,7- dioxo-3,4-b,7,8,-8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile], and any derivative thereof.

[0065] In some embodiments, a NRF2 activator can be selected from the group consisting of: camosic acid, 2-naphthoquinone, cynnamic aldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, vitamins KI, K2 and K3, fumaric acid esters, i.e., fumaric acid mono- and / or diester which can be selected from the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, isothiocyanate such as sulforaphane, 1,2-dithiole-3-thione such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3 -hydroxy coumarin, 4- hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctyl isothiocyanate, 8-iso prostaglandin A2, alkyl pyruvate, such as methyl and ethyl pyruvate, diethyl or dimethyl oxaloproprionate, 2-acetamidoacrylate, methyl or ethyl-2-acetamidoacrylate, hypoestoxide, parthenolide, eriodictyol, 4-Hydroxy-2-nonenal, 4-oxo- 2nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[0010] -Shogaol, eugenol, 1 '-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(Methylthio)-3-butenyl isothiocyanate and 6-methylsulfinylhexyl isothiocyanate and the respective quinone or hydroquinone form of the aforementioned quinone and hydroquinone derivative.

[0066] In some embodiments, a NRF2 activator can be a Michael reaction acceptor, such as dimethylfumarate, monomethyl hydrogen fumarate isothiocyanates and 1,2-dithi ole-3 -thi ones. In some embodiments, NRF2 activators can be selected from monomethyl hydrogen fumarate, dimethyl fumarate, oltipraz, 1 ,2-naphthoquinone, tert-butylhydroquinone, methyl or ethyl pyruvate, 3,5-di-tert-butyl-4-hydroxytoluene, diethyl and dimethyl oxaloproprionate, hypoestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[0010] -Shogaol, eugenol, l'-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(Methylthio)-3- butenyl isothiocyanate and 6-Methyl sulfinylhexyl isothiocyanate.

[0067] In some embodiments, the NRF2 activator for use in combination with a BACH1 inhibitor is dimethyl fumarate (e.g., Tecfidera®).Methods of the Disclosure

[0068] Provided herein are, inter alia, methods of treating a heart failure (e.g., dilated cardiomyopathy such as HFrEF) in a subject having or at risk of having the heart failure by administering therapeutically effective amount of one or more compounds that can restore myocardial contractility by normalizing one or more metabolic dysfunction in the subject. In some embodiments, the one or more compounds can target the underlying pathogenic mechanisms of the heart failure (e.g., dilated cardiomyopathy such as HFrEF).

[0069] In some embodiments, the heart failure is dilated cardiomyopathy (DCM) In some embodiments, the dilated cardiomyopathy can be alcoholic cardiomyopathy, congestive cardiomyopathy, diabetic cardiomyopathy, familial dilated cardiomyopathy, idiopathic cardiomyopathy, ischemic cardiomyopathy, peripartum cardiomyopathy, or primary cardiomyopathy. In some embodiments, the DCM is HFrEF.

[0070] In an embodiment, the one or more compounds comprises a BTB and CNC homology 1 (BACH1) inhibitor. In another embodiment, the one or more compounds comprises a nuclear factor erythroid 2-related factor 2 (NRF2) activator. In yet another embodiment, the one or more compounds comprises a combination of a BACH1 inhibitor and a NRF2 activator. In some embodiments, the one or more compounds is one or more small molecule compounds. In some embodiments, the one or more small molecule compounds comprises a BACH1 inhibitor. In some embodiments, the one or more small molecule compounds comprises a NRF2 activator. In some embodiments, the one or more small molecule compounds comprises a combination of a BACH1 inhibitor and a NRF2 activator.

[0071] In an embodiment, provided herein is a method of treating a DCM in the subject having or at risk of having the DCM by administering to the subject a therapeutically effective amount of a BACH1 inhibitor. In another embodiment, provided herein is a method of treating the DCM in the subject by administering to the subject a therapeutically effective amount of aNRF2 activator. In yet another embodiments, provided herein is a method of treating the DCM in the subject by administering to the subject a therapeutically effective amount of a combination of a BACH1 inhibitor and a NRF2 activator.

[0072] Provided herein are methods of treating a heart failure (e.g., dilated cardiomyopathy such as HFrEF) with reduced ejection fraction (HFrEF) in a subject having or at risk of having the HFrEF by administering to the subject a therapeutically effective amount of one or more compounds. In an embodiment, the one or more compounds comprises a BACH1 inhibitor. In another embodiment, the one or more compounds comprises a NRF2 activator. In yet another embodiment, the one or more compounds comprises a combination of a BACH1 inhibitor and a NRF2 activator.

[0073] In an embodiment, provided herein is a method of treating the HFrEF in the subject having or at risk of having the HFrEF by administering to the subject a therapeutically effective amount of a BACH1 inhibitor. In another embodiment, provided herein is a method of treatingthe HFrEF in the subject by administering to the subject a therapeutically effective amount of a NRF2 activator. In yet another embodiments, provided herein is a method of treating the HFrEF in the subject by administering to the subject a therapeutically effective amount of a combination of a BACH1 inhibitor and a NRF2 activator.Methods of Treating PCM with BACH1 Inhibitor

[0074] Provided herein is a method of treating a heart failure (e.g., dilated cardiomyopathy) in a subject having or at risk of having the heart failure by administering therapeutically effective amount of a BACH1 inhibitor. In an embodiment, the heart failure is a DCM. In another embodiment, the heart failure is HFrEF. In yet another embodiment, the DCM is HFrEF. In some embodiments, the method as provided herein improves peak contraction amplitude; improves contraction force; increases contraction velocity; increases oxidative metabolism and efficiency of ATP production without increasing reactive oxygen species (ROS) or inducing mitochondrial stress; increases contractility without altering intracellular Ca2+levels or inducing signs of arrhythmia; or any combination thereof in the subject having or at risk of having the heart failure (e.g, dilated cardiomyopathy). In some embodiments, the method as provided herein improves cardiac output or stroke volume; decreases end diastolic volumes; in general decreases symptoms of heart failure; enhances survival, or decrease in cardiac events / hospitalization; or any combination thereof in the subject having or at risk of having the heart failure (e.g., dilated cardiomyopathy).

[0075] In some embodiments, the BACH1 inhibitor is a small molecule drug or a small molecule compound. In some embodiments, the BACH1 inhibitor is selected from the group consisting of ML-0207 / ASP8731, HPP-A, HPP-B, HPP-C, HPP-D, HPP-E, HPP971, HPP-1014, HPP-4382, M2 [I -Piperazineethanol, a-[(l, 3-benzodioxol-5-yloxy )methyl]-4-(2- methoxyphenyl)], cadmium, hemin (Panhematin®), and any derivative thereof. In some embodiments, the BACH1 inhibitor is ML-0207 / ASP8731 or any derivative thereof. In some embodiments, the BACH1 inhibitor is M2 [1 -Piperazineethanol, a-[(l,3-benzodioxol-5- yloxy)methyl]-4-(2-methoxyphenyl)] or an analogue thereof In some embodiments, the BACH1 inhibitor is selected from the group consisting of: l -Methyl-2-(6-trifluoromethoxy-benzothiazol- 2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide; l-Methyl-2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2 -methoxy-ethyl)-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid (2-hydroxy-ethyl)-amide; 1 -Methyl-2-(6-trifluorom ethoxy -benzothiazol -2- ylamino)-lH-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide; 1-Methyl- 2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2- methoxy-ethyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH- benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide; 2-(6-Chloro-benzothiazol-2- ylamino)-l-methyl-lH-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide; 6-Fluoro-l- methyl-2-(6-trifluoromethoxy -benzothiazol -2-ylamino)-lH-benzoimidazole-5-carboxylic acid ethylamide; l-Methyl-2-(6-trifluoromethoxy -benzothiazol -2-ylamino)-lH-benzoimidazole-5- carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(2-fluoro-ethoxy)-ethyl]- amide; 1 -Methyl -2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid ((S)-2-hydroxy-propyl)-amide; 1 -Methyl-2-(6-trifluorom ethoxy -benzothiazol-2- ylamino)-lH-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide; 6-Methoxy-l- methyl-2-(6-trifluoromethoxy -benzothiazol -2 -ylamino)-lH-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide; 2-(6-Chloro-benzothiazol- 2-ylamino)-l-methyl-lH-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide; l-Methyl-2- (6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzimidazole-5-carboxylic acid (2- ethanesulfonyl-ethyl)-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzimidazole-5 -carboxylic acid (3-methanesulfonyl-propyl)-amide; 2-(6-Chloro-benzothiazol- 2-ylamino)-l-methyl-lH-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide; 1- Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide; 1 -Methyl-2-(6-trifluoromethoxy -benzothiazol -2-ylamino)-lH- benzimidazole-5 -carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzimidazole-5-carboxylic acid [2-(4-methyl- piperazin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)- lH-benzoimidazole-5-carboxylic acid ((S)-l-dimethylcarbamoyl-ethyl)-amide; l-Ethyl-2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-ethoxy- ethyl)-amide; l-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l -ethyl-lH-benzoimidazole-5-carboxylic acid (2-fluoro-ethyl)-amide; 2-(6-Chloro- benzothiazol-2-ylamino)- 1 -ethyl- lH-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)- amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid ((S)-2-hydroxy-propyl)-amide; 2-(6-Chloro-benzothiazol-2- ylamino)-! -methyl- lH-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)- lH-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide; 1 -Methyl -2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(2 -methoxy - ethoxy)-ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH- benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-ethoxy)-ethyl]-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-morpholin-4- yl-ethyl)-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l-methyl-lH-benzoimidazole-5- carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6-trifluoromethyl- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-dimethylcarbamoyl-ethyl)- amide; 1 -Methyl -2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (3-morpholin-4-yl-3-oxo-propyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2- ylamino)-lH-benzoimidazole-5-carboxylic acid methylcarbamoylmethyl-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((R)-3- hydroxy-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l-methyl- lH-benzoimidazole-5-carboxylic acid [2-((R)-3-methoxy-pyrrolidin-l-yl)-2-oxo-ethyl]-amide;2-(6-Chloro-benzothiazol-2-ylamino)-l -methyl- lH-benzoimidazole-5-carboxylic acid [2-((S)-3- methoxy-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2- ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((S)-3-m ethoxy -pyrrolidin-l-yl )-2-oxo- ethyl]-amide; l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6- trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((S)-3- dimethylamino-pyrrolidin-l-yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)- amide; 1 -Methyl -2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylicacid [2-(4-methyl-piperazin-l -yl)-2-oxo-ethyl]-amide; 1 -Methyl-2-(6-trifluoromethyl- benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-((R)-3-hydroxy-piperidin-l- yl)-2-oxo-ethyl]-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH- benzoimidazole-5-carboxylic acid [2-((S)-3-hydroxy-piperidin-l-yl)-2-oxo-ethyl]-amide; 1- Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-l-yl)-2-oxo-ethyl]-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l- methyl-lH-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-l-yl)-2-oxo-ethyl]-amide; 2-(6-Chloro-benzothiazol-2-ylamino)-l -methyl- lH-benzoimidazole-5-carboxylic acid ((S)-l- dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH- benzoimidazole-5 -carboxylic acid ((S)-l-dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid ((S)-l-methyl-2- morpholin-4-yl-2-oxo-ethyl)-amide; l-Methyl-2-(6-trifluorom ethyl -benzothiazol-2-ylamino)- lH-benzoimidazole-5-carboxylic acid ((R)-l-dimethylcarbamoyl-ethyl)-amide; l-Methyl-2-(6- trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5-carboxylic acid [(R)-l-methyl-2- (4-methyl-piperazin-l-yl)-2-oxo-ethyl]-amide; and any derivative thereof.

[0076] In some embodiments, the BACH1 inhibitor (e.g., HPP-E) is administered to a subject having or at risk of having the heart failure (e.g., dilated cardiomyopathy such as HFrEF) about 10 mg / day to 1,000 mg / day, about 20 mg / day to 800 mg / day, about 30 mg / day to about 600 mg / day, about 40 mg / day to about 400 mg / day, or about 50 mg / day to about 200 mg / day. In some embodiments, the BACH1 inhibitor is administered to a subject having or at risk of having the HFrEF about 0.1 mg / day, about 0.2 mg / day, about 0.3 mg / day, about 0.4 mg / day, about 0.5 mg / day, about 0.6 mg / day, about 0.7 mg / day, about 0.8 mg / day, about 0.9 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 550 mg / day, about 600 mg / day, about 700 mg / day, about 750 mg / day, about 800 mg / day, about 850 mg / day, about 900 mg / day, about 950 mg / day, or about 1000 mg / day. In some embodiments, the BACH1 inhibitor is administered to a subject having or at risk of having the HFrEF less than about 10 mg / day, less than about 20 mg / day, less than about 30 mg / day, less than about 40 mg / day, less than about 50 mg / day, less than about 60 mg / day, less than about 70 mg / day, less than about 80 mg / day, less than about 90mg / day, less than about 100 mg / day, less than about 150 mg / day, less than about 200 mg / day, less than about 250 mg / day, less than about 300 mg / day, less than about 350 mg / day, less than about 400 mg / day, less than about 450 mg / day, less than about 500 mg / day, less than about 550 mg / day, less than about 600 mg / day, less than about 700 mg / day, less than about 750 mg / day, less than about 800 mg / day, less than about 850 mg / day, less than about 900 mg / day, less than about 950 mg / day, or less than about 1000 mg / day.Methods of Treating PCM with NRF2 Activator

[0077] Provided herein is a method of treating a heart failure (e.g., dilated cardiomyopathy) in a subject having or at risk of having the heart failure by administering therapeutically effective amount of a NRF2 activator. In an embodiment, the heart failure is a DCM. In another embodiment, the heart failure is HFrEF. In yet another embodiment, the DCM is HFrEF. In some embodiments, the method as provided herein improves peak contraction amplitude; improves contraction force; increases contraction velocity; increases oxidative metabolism and efficiency of ATP production without increasing reactive oxygen species (ROS) or inducing mitochondrial stress; increases contractility without altering intracellular Ca2+levels or inducing signs of arrhythmia; or any combination thereof in a subject having or at risk of having the heart failure (e.g, dilated cardiomyopathy). In some embodiments, the method as provided herein improves cardiac output or stroke volume; decreases end diastolic volumes; in general decreases symptoms of heart failure; enhances survival, or decrease in cardiac events / hospitalization; or any combination thereof in the subject having or at risk of having the heart failure (e.g, dilated cardiomyopathy).

[0078] In some embodiments, the NRF2 activator is a small molecule compound. In some embodiments, the NRF2 activator can be selected from the group consisting of dimethyl fumarate, Tecfidera®, oltipraz (OPZ), CBR-470-1, CDDO Im, bardoxolone-methyl (CDDO- Me), (±)-eriodictyol, INF 4E, ML334, NK 252, 4-Octyl itaconate, RA 839, resveratrol, sulforaphane, curcumin, agmatine, naringenin, RTA-408 (omaveloxolone), ALKS-8700, ursodiol, sulforadex (SFX-01), ITH12674, CXA-10, SCIIU909, and any derivative thereof. In some embodiments, the NRF2 activator is dimethyl fumarate. In some embodiments, the NRF2 activator is Tecfidera®.

[0079] In some embodiments, a NRF2 activator can be selected from the group consisting of: chaicone derivatives such as 2-trifluoromethyl-2 '-methoxy chaicone, auranofin, ebselen, 1,2- naphthoquinone, cynnamic aldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, and -quinone, (tBHQ, tBQ), vitamins KI, K2 and K3, menadione, fumaric acid esters, i.e., fumaric acid mono- and / or di ester which can be selected from the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate (DMF), monoethyl hydrogen fumarate, and diethyl fumarate, 2-cyclopentenones, ethacrynic acid and its alkyl esters, bardoxolone methyl (methyl 2- cyano-3,12-dioxooleana-l,9(l l)dien-28-oate) (CDDO-Me, RTA 402), ethyl 2-cyano-3,12- dioxooleana-l,9(l l)dien-28-oate, 2-cyano-3,12-dioxooleana-l,9(l l)dien-28-oic acid (CDDO), 1 [2-Cyano-3,12-dioxooleana- 1,9(1 l)-dien-28-oyl]imidazole (CDDO-Im), (2-cyano-N-methyl- 3, 12-di oxool eana- 1,9(1 l)-dien-28 amide (CDDO-methyl amide, CDDO-MA), isothiocyanate such as sulforaphane, 1 ,2-dithi ole-3 -thi one such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3 -hydroxy coumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctyl isothiocyanate, corticosteroids, such as dexamethasone, 8-iso prostaglandin A2, alkyl pyruvate, such as methyl and ethyl pyruvate, diethyl or dimethyl oxalopropri onate, 2-acetamidoacrylate, methyl or ethyl-2-acetamidoacrylate, hypoestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[0010] -Shogaol, eugenol, l'-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(methylthio)-3- butenyl isothiocyanate and 6-m ethyl sulfinylhexyl isothiocyanate, ferulic acid and its esters, such as ferulic acid ethyl ester, and ferulic acid methyl ester, sofalcone, 4-methyl daphnetin, imperatorin, auraptene, poncimarin, bis[2-hydroxybenzylidene]acetones, alicylcurcuminoid, 4- bromo flavone, -naphthoflavone, sappanone A, aurones and its corresponding indole derivatives such as benzylidene-indolin-2-ones, perillaldehyde, quercetin, fisetin, koparin, genistein, tanshinone HA, BHA, BHT, PMX-290, AL-1, avicin D, gedunin, fisetin, andrographolide, tricyclic bis(cyano enone) TBE-31 [(+ / -)-(4bS,8aR,10aS)-10a-ethynyl-4-b,8,8-trimethyl-3,7- dioxo-3,4-b,7,8,-8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile], and any derivative thereof.

[0080] In some embodiments, a NRF2 activator can be selected from the group consisting of: camosic acid, 2-naphthoquinone, cynnamic aldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, vitamins KI, K2 and K3, fumaric acid esters, z.c., fumaric acid mono- and / or diester which can be selected from the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, isothiocyanate such as sulforaphane, 1,2- dithiole-3-thione such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3 -hydroxy coumarin, 4- hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctyl isothiocyanate, 8-iso prostaglandin A2, alkyl pyruvate, such as methyl and ethyl pyruvate, diethyl or dimethyl oxalopropri onate, 2-acetamidoacrylate, methyl or ethyl-2-acetamidoacrylate, hypoestoxide, parthenolide, eriodictyol, 4-Hydroxy-2-nonenal, 4-oxo- 2nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[0010] -Shogaol, eugenol, 1 '-acetoxy chavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(Methylthio)-3-butenyl isothiocyanate and 6-methylsulfmylhexyl isothiocyanate, the respective quinone or hydroquinone form of the aforementioned quinone and hydroquinone derivative, and any derivative thereof.

[0081] In some embodiments, a NRF2 activator can be Michael reaction acceptors, such as dimethylfumarate, monomethyl hydrogen fumarate isothiocyanates and 1,2-dithi ole-3 -thi ones. In some embodiments, NRF2 activators can be selected from monomethyl hydrogen fumarate, dimethyl fumarate, oltipraz, 1, 2-naphthoquinone, tert-butylhydroquinone, methyl or ethyl pyruvate, 3,5-di-tert-butyl-4-hydroxytoluene, diethyl and dimethyl oxalopropri onate, hypoestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,

[0010] -Shogaol, eugenol, l'-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(Methylthio)-3- butenyl isothiocyanate, 6-Methylsulfinylhexyl isothiocyanate, and any derivative thereof.

[0082] In some embodiments, a NRF2 activator (e.g., dimethyl fumarate) is administered to a subject having or at risk of having the heart failure (e.g., dilated cardiomyopathy such as HFrEF) about 10 mg / day to 1,000 mg / day, about 20 mg / day to 800 mg / day, about 30 mg / day to about 600 mg / day, about 40 mg / day to about 400 mg / day, or about 50 mg / day to about 200 mg / day. In some embodiments, the NRF2 activator is administered to a subject having or at risk of havingthe HFrEF about 0.1 mg / day, about 0.2 mg / day, about 0.3 mg / day, about 0.4 mg / day, about 0.5 mg / day, about 0.6 mg / day, about 0.7 mg / day, about 0.8 mg / day, about 0.9 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 550 mg / day, about 600 mg / day, about 700 mg / day, about 750 mg / day, about 800 mg / day, about 850 mg / day, about 900 mg / day, about 950 mg / day, or about 1000 mg / day. In some embodiments, the NRF2 activator is administered to a subject having or at risk of having the HFrEF less than about 10 mg / day, less than about 20 mg / day, less than about 30 mg / day, less than about 40 mg / day, less than about 50 mg / day, less than about 60 mg / day, less than about 70 mg / day, less than about 80 mg / day, less than about 90 mg / day, less than about 100 mg / day, less than about 150 mg / day, less than about 200 mg / day, less than about 250 mg / day, less than about 300 mg / day, less than about 350 mg / day, less than about 400 mg / day, less than about 450 mg / day, less than about 500 mg / day, less than about 550 mg / day, less than about 600 mg / day, less than about 700 mg / day, less than about 750 mg / day, less than about 800 mg / day, less than about 850 mg / day, less than about 900 mg / day, less than about 950 mg / day, or less than about 1000 mg / day.Combination Therapy

[0083] Provided herein is a method of treating a heart failure (e.g., dilated cardiomyopathy such as HFrEF) in a subject having or at risk of having the heart failure ( .g., dilated cardiomyopathy such as HFrEF) by administering therapeutically effective amount of one or more compounds. In some embodiments, the one or more compounds comprises a combination of a BACH1 inhibitor and a NRF2 activator. In some embodiments, the method as provided herein improves peak contraction amplitude; improves contraction force; increases contraction velocity; increases oxidative metabolism and efficiency of ATP production without increasing reactive oxygen species (ROS) or inducing mitochondrial stress; increases contractility without altering intracellular Ca2+levels or inducing signs of arrhythmia; or any combination thereof in a subject having or at risk of having the heart failure (e.g., dilated cardiomyopathy such as HFrEF). In some embodiments, the method as provided herein improves cardiac output or stroke volume; decreases end diastolic volumes; in general decreases symptoms of heart failure;enhances survival, or decrease in cardiac events / hospitalization; or any combination thereof in the subject having or at risk of having the heart failure (e.g., dilated cardiomyopathy).

[0084] In some embodiments, combining the BACH1 inhibitor and the NRF2 activator has a synergistic effect, leading to a lower dosage and toxicity. Administration of one compound can act such that the therapeutically effective dose of either compound or both compounds can be reduced relative to administering only a single compound. For example, the therapeutic effect of the combination of the BACH1 inhibitor and the NRF2 activator can be greater than the sum of the effects that result from using each compound alone. Put another way, administering a BACH1 inhibitor can reduce the amount of BACH1 available to repress expression of ARE- regulated genes in a system, and thereby increase the sensitivity of the system to NRF2. This increase in sensitivity can reduce the amount of an NRF2 activator necessary to achieve a therapeutic effect.

[0085] In some embodiments, the combination therapy as described herein can be administered simultaneously or sequentially. When administered sequentially, the combination therapy can be administered in two or more administrations. In some embodiments, the BACH1 inhibitor and the NRF2 activator are combined in a unitary dosage form for simultaneous administration to a subject having or at risk of having a heart failure (e.g., dilated cardiomyopathy such as HFrEF). The combination therapy as used herein refers to a BACH1 inhibitor with a NRF2 activator being simultaneously or sequentially administered to a subject having or at risk of having a heart failure (e.g., dilated cardiomyopathy such as HFrEF), such that both of the therapeutically effective amount of each compound are present at the same time in the body of the subject. The combination therapy can include a simultaneous administration of both a BACH1 inhibitor and a NRF2 activator. The combination therapy can include an administration of one compound before or after administration of the other compound e.g., within seconds, minutes, or hours of each other. In some embodiments, the first agent is administered, and the second agent is administered after about 0.1 hours, about 0.2 hours, about 0.3 hours, about 0.4 hours, about 0.5 hours, about 0.6 hours, about 0.7 hours, about 0.8 hours, about 0.9 hours, about 1.0 hours, about1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours,about 13.5 hours, about 14 hours, about 14.5 hours, about 15 hours, about 15.5 hours, about 16 hours, about 16.5 hours, about 17 hours, about 17.5 hours, about 18 hours, about 18.5 hours, about 19 hours, about 19.5 hours, about 20 hours, about 20.5 hours, about 21 hours, about 21.5 hours, about 22 hours, about 22.5 hours, about 23 hours, about 23.5 hours, or about 24 hours. In some embodiments, the first agent is administered, and the second agent is administered after about 1 days, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In some embodiments, the first agent is administered, and the second agent is administered after more than 7 days.

[0086] In some embodiment, the combination of the BACH1 inhibitor and the NRF2 activator can eliminate or reduce severity of one or more adverse effects associated with the use of a BACH1 inhibitor alone or a NRF2 activator alone. In some embodiments, the combination of the BACH1 inhibitor and the NRF2 activator can reduce the therapeutically effective dosage for treating a heart failure (e.g., dilated cardiomyopathy such as HFrEF) of one or both of the compounds employed in the combination treatment, and one or more side effects associated with the use of the BACH1 inhibitor alone or the NRF2 activator alone can be eliminated or reduced.

[0087] In some embodiments, the combination of the BACH1 inhibitor and the NRF2 activator can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 % reduction of the therapeutically effective BACH1 inhibitor dosage.

[0088] In some embodiments, the combination of the BACH1 inhibitor and the NRF2 activator can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least10 %, at least 1 1 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 % reduction of the therapeutically effective NRF2 activator dosage.

[0089] In some embodiments, a combination of the BACH1 inhibitor and the NRF2 activator can result in any of about at least 1 %, at least 2 %, at least 3 %, at least 4 %, at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5%, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5%, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3%, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9%, or 100% reduction of toxicity of and / or one or more adverse effect(s) associated with the BACH1 inhibitor.

[0090] In some embodiments, a combination of the BACH1 inhibitor and the NRF2 activator can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 1 1 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %,at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 % or 100% reduction of toxicity of and / or one or more adverse effect(s) associated with the NRF2 activator.

[0091] In some embodiments, any one of the methods provided herein upregulation of antioxidant response genes. In some embodiments, any one of the methods provided herein increases utilization of fatty acid as an energy source without increasing cardiotoxicity. In some embodiments, an increased cardiotoxicity is evident by cell death, increased reactive oxygen species (ROS), mitochondrial stress, or intracellular Ca2+.

[0092] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 1 1 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78%, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater improvement of peak contraction amplitude.

[0093] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater improvement of contraction force.

[0094] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 1 1 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater increase of contraction velocity.

[0095] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 1 1 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, atleast 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99. 1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater increase of oxidative metabolism and efficiency of ATP production without increasing reactive oxygen species (ROS) or inducing mitochondrial stress.

[0096] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99. 1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater increase of contractility without altering intracellular Ca2+levels or inducing signs of arrhythmia.

[0097] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, atleast 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater increase of cardiac output or stroke volume.

[0098] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater decrease of end diastolic volumes.

[0099] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 1 1 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least 18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater decrease of symptoms of heart failure.

[0100] In some embodiments, any one of the methods provided herein can result in any of about at least 5 %, at least 6 %, at least 7 %, at least 8 %, at least 9 %, at least 10 %, at least 11 %, at least 12 %, at least 13 %, at least 14 %, at least 15 %, at least 16 %, at least 17 %, at least18 %, at least 19 %, at least 20 %, at least 25 %, at least 30 %, at least 35 %, at least 40 %, at least 45 %, at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 71 %, at least 72 %, at least 73 %, at least 74 %, at least 75 %, at least 76 %, at least 77 %, at least 78 %, at least 79 %, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90.0 %, at least 90.5 %, at least 91.0 %, at least 91.5 %, at least 92.0 %, at least 92.5 %, at least 93.0 %, at least 93.5 %, at least 94.0 %, at least 94.5 %, at least 95.0 %, at least 95.5 %, at least 96.0 %, at least 96.5 %, at least 97.0 %, at least 97.5 %, at least 98.0 %, at least 98.5 %, at least 99.0 %, at least 99.1 %, at least 99.2 %, at least 99.3 %, at least 99.4 %, at least 99.5 %, at least 99.6 %, at least 99.7 %, at least 99.8 %, at least 99.9 %, or greater increase in survival, or decrease in cardiac events / hospitalization.Pharmaceutical Compositions and Kits

[0101] The presently described disclosure contemplates a BACH1 inhibitor (e.g., HPP-E or M2 [ 1 -Piperazineethanol, a-[( l,3-benzodioxol-5-yloxy)methyl]-4-(2-methoxyphenyl)]), a NRF activator e.g., dimethyl fumarate or Tecfidera®), or a combination thereof incorporated into a pharmaceutical composition (e.g., a sterile pharmaceutical composition) containing one or more pharmaceutically acceptable carriers. As used herein, a “pharmaceutically acceptable carrier” or a “pharmaceutically acceptable excipient” or a “pharmaceutically acceptable salt” according to the present disclosure is a component such as a carrier, diluent, or excipient of a composition that is compatible with the other ingredients of the composition in that it can be combined with the agents and / or compositions of the present disclosure without eliminating the biological activity of the agents or the compositions (for example, but not limited to, a BACH1 inhibitor (e.g., HPP- E or M2 [I -Piperazineethanol, a-[(l, 3-benzodioxol-5-yloxy)methyl]-4-(2-methoxyphenyl)]), a NRF activator (e.g., dimethyl fumarate or Tecfidera®), or a combination thereof) and is suitable for use in subjects as provided herein without undue adverse side effects (such as toxicity, irritation, allergic response, and death). Side effects are “undue” when their risk outweighs the benefit provided by the pharmaceutical composition. Non-limiting examples of pharmaceutically acceptable components include, without limitation, any of the standard pharmaceutical carriers such as phosphate buffered saline solutions, water, sterile water, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, sesame oil, emulsions such asoil / water emulsions or water / oil emulsions, microemulsions, nanocarriers and various types of wetting agents. Additives such as water, alcohols, oils, glycols, preservatives, flavoring agents, coloring agents, suspending agents, and the like may also be included in the composition along with the carrier, diluent, or excipient. In one embodiment, a pharmaceutically acceptable carrier appropriate for use in the compositions disclosed herein is sterile, pathogen free, and / or otherwise safe for administration to a subject without risk of associated infection and other undue adverse side effects.

[0102] Any of the pharmaceutical compositions disclosed herein can be formulated for administration using any number of administrative methods available in the art. Administration can be by a variety of routes including pump, patch, catheter, stent, oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intranasal, and the like. In some embodiments, the above methods of administration can be used for delivery of suspensions comprising a BACH1 inhibitor (e.g., HPP-E or M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5-yioxy)methyl]-4-(2- methoxyphenyl)]), a NRF activator (c. ., dimethyl fumarate or Tecfidera®), or a combination thereof. These compositions can be effective as both injectable and oral compositions. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. When employed as oral compositions, the polypeptide compositions can be protected from acid digestion in the stomach by a pharmaceutically acceptable protectant.

[0103] In some embodiments, any of the pharmaceutical compositions disclosed herein can be incorporated into an engineered patch for administration directly to the epicardium or damaged tissue of the myocardium. In some embodiments, highly hydrated collagen gels can be compressed in order to remove excess water and produce a dense biomaterial with improved biological and mechanical properties.

[0104] In some embodiments, any of the pharmaceutical compositions disclosed herein can be delivered via an osmotic pump. In some embodiments, any of the pharmaceutical compositions disclosed herein can be delivered as a single or several subcutaneous bolus.

[0105] Also provided herein are kits comprising (i) a BACH1 inhibitor (e.g., HPP-E or M2 [1- Piperazineethanol, a-[( 1 ,3 -benzodi ox ol-5-yloxy)methyl]-4-(2 -methoxy phenyl )]), a NRF activator (e.g., dimethyl fumarate or Tecfidera®), or a combination thereof; and (ii) one or more pharmaceutically acceptable excipients. One or both of these kit components can be made to besterile so that it can be administered to a subject with a heart failure (e.g, dilated cardiomyopathy such as HFrEF).EXAMPLES

[0106] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.EXAMPLE 1. Identification of BACH1 in heart disease

[0107] This example describes the identification of genes relevant in heart disease by analysis of gene expression profiles in DCM hearts and non-failing hearts in human subjects and matching them to gene expression signatures of transcription factors that are conditionally deleted in mouse hearts of transgenic mice.

[0108] Briefly, gene expression signatures of genes dysregulated in DCM were analyzed in a dataset of 165 DCM versus 162 cohort matched non-failing human hearts using the curated and processed data from the Myocardial Applied Genomics Network MAGNet consortium (www at shiny.dieterichlab.org / app / magnetique).

[0109] Differentially expressing genes (DCM vs non-failing) were filtered by p-values (adjusted for multiple testing) (<0.05) to yield a gene signature for DCM vs non-failing human hearts. The gene signature consisted of 16,167 genes that were differentially expressed in DCM versus non-failing hearts (p-value adjusted for multiple testing <0.05). A schematic of the gene expression signature results for exemplary genes upregulated or downregulated in DCM hearts compared to non-failing hearts is shown in FIG. 1A. Transcription factors that antagonize the DCM gene expression signature can be identified by their reverse gene signatures (shown in FIG. IB), for example genes that are upregulated in DCM hearts are downregulated by a candidate transcription factor and genes that are downregulated in DCM hearts are upregulated.

[0110] To identify transcription factors that can antagonize the DCM gene expression signature in humans, gene expression signatures in mice with conditional knockouts (cKO) for transcription factors were analyzed. The data from the RNAseq study of a homozygous mouse cardiac conditional knockout of the murine homologue (A / y / ?6mERCremERBachl^) in Wei et al., was further analyzed. (Wei et al., Cardiovascular Research, published as doi.org / 10.1093 / cvr / cvad086). In the mouse, cardiac conditional knockout (cKO) of the murinehomologue of BACH1, Bachl, alters gene expression. BACH1 is a transcription factor that regulates the activity of another, structurally related transcription factor NRF2 among others. The gene expression signatures of mouse Bachl in strain-matched normal mice and Bachl cardiac conditional KO mice were analyzed to obtain a Bachl gene expression signature. The identified mouse genes were then mapped to the human genome to obtain a human BACH1 gene expression signature. The human BACH1 gene expression signature was then compared with the DCM gene expression signature obtained from the human hearts and overlapping subsets of genes were identified. A schematic of the approach is shown in FIG. 2A.Briefly, mouse genes that were significantly affected (p-value adjusted for multiple testing <0.05) by the Bachl cKO were mapped to their human homologues using the MGI database (www.informatics.jax.org / downloads / reports / HOM_MouseHumanSequence.rpt).

[0111] Differentially expressed genes in DCM versus non-failing hearts were divided into 3 groups: 1. Human homologs of genes that are upregulated by Bachl cKO (Group 1, 181 genes); 2. Human homologs of genes that are downregulated by Bachl cKO (Group 2, 190 genes); 3. All other differentially expressed genes (Group 3, 16,167 genes). For each group of genes the distribution of Iog2-Fold Changes (DCM vs non-failing) was calculated. Distribution were compared using the Kolmogorov- Smirnov Tests as follows: Group 1 vs Group 3, one-sided, alternative = less, p-value = 0.0291; Group 2 vs Group 3, one-sided, alternative = greater, p- value = 0.0097. A graph of the results is shown in FIG. 2B. Analysis of genes that are up and down regulated by the Bachl cKO showed a biased distribution when mapped onto the DCM hearts vs non-failing hearts dataset. The results show that genes that are activated by the Bachl knockout in mice tend to be repressed by human DCM hearts relative to non-failing hearts, and genes that are suppressed by Bachl knockout tend to be activated by human DCM relative to non-failing hearts. These data indicate that BACH1 inhibition opposes gene expression changes caused by DCM relative to non-failing hearts, and suggested that BACH1 is a candidate target to treat DCM.

[0112] Mito et al., evaluated the role of the murine homologue of the BACH1 gene (Bachl)' in a mouse surgical model of compensatory hypertrophy and decompensated heart failure. Mito et al., Hypertension (2008) 51(6): 1570-1577. In this model, the aorta was constricted (transverse aortic constriction, TAC) to increase left ventricular (LV) pressures, leading to the development of pathological hypertrophy and heart failure. Genetic ablation of Bachl protected against TAC-induced hypertrophy, fibrosis, and loss of contractile function. Data presented in Mito et al., and the present disclosure together support the idea that pharmacological inhibition of BACH1 can be therapeutic for heart failure.EXAMPLE 2. NRF2 activation enhanced anti-oxidant and protective responses.

[0113] The BACH1 protein is a member of the cap’n’collar basic leucine zipper (CNC-bZIP) family of transcription factors known to regulate many processes including the oxidative stress response and cellular bioenergetics. Zhang et al., OxidMed Cell Longev 2018:1347969 (2018). In multiple contexts, including Parkinson’s disease and cancer, BACH1 represses genes that are positively regulated by another basic leucine zipper transcription factor, NRF2 (FIG. 3). Zhang et al., OxidMed Cell Longev 2018:1347969 (2018); Na and Surh, Free Radio Biol Med. 67:353- 365 (2014); Hushpulian et al., Front Aging Neurosci. 13:673205 (2021). Recently, chemical modification of a cannabinoid BACH1 inhibitor to also activate NRF2 was reported to enhance potency and efficacy against NRF2 target genes, in support of the idea that targeting both BACH1 and NRF2 may be beneficial. Casares et al., (2020) Redox Biol 37: 101689.

[0114] It is speculated, that in the presence of BACH1, a subset of NRF2-target genes are transcriptionally repressed. In the presence of Compound 1 (HPP-E) or Compound 2 (ASP- 8731), both inhibitors of BACH1, the repression by BACH1 can be relieved, allowing NRF2 to occupy the gene promoter region and activate transcription of the subset of genes (FIG. 3).

[0115] Most NRF2 activators are inhibitors of KEAP1 / Cul3 E3 ubiquitin ligase complex, which constantly targets NRF2 for ubiquitination and protein degradation. Hushpulian et al., Front Aging Neurosci. 13:673205 (2021); Robledinos-Anton et al., OxidMed Cell Longev 2019:9372182 (2019). Compound 3 (Tecfidera® (dimethyl fumarate)), a NRF2 activator, is thought to inhibit KEAP1 by electrophilic modification of cysteineisi. Robledinos-Anton et al., OxidMed Cell Longev 2019:9372182 (2019). BACH1 is induced by NRF2 as well as represses NRF2’s transcriptional activity. Thus, inhibition of BACH1 can overcome feedback inhibition of NRF2. It is speculated, that a combination of a BACH1 inhibitor and a NRF2 activator can lead to synergistic activity for heart contractility, ATP production, and cardioprotection (FIG. 4).

[0116] In the presence of BACH1, a subset of NRF2-target genes are transcriptionally repressed. In the presence of a BACH1 inhibitor such as Compound 1, the repression by BACH1 can be relieved, allowing NRF2 to occupy the gene promoter region and activate transcription.

[0117] NRF2 activators such as Compound 3 can augment this response since they can further increase the abundance of NRF2 in the cell.EXAMPLE 3. In vitro therapeutic efficacies of BACH1 inhibitor, NRF2 activator, or a combination thereof

[0118] As described in Example 2 above, BACH1 inhibitors and NRF2 activators converge on a subset of NRF2 target genes. Therefore, a BACH1 inhibitor (e.g., HPP-E) in combination with a NRF2 activator (e.g., dimethyl fumarate or Tecfidera®) can allow for lower therapeutic doses of either compound alone. This can be potentially advantageous in terms of potency and reduction of off-target effects caused by the NRF2 activator’s inhibition of the KEAP / Cul3 ubiquitin ligase complex and by its non-specific electrophilic effects on other proteins.

[0119] This Example describes experiments for determining relative therapeutic efficacies of a BACH1 inhibitor (e.g., HPP-E or M2 [1 -Piperazineethanol, a-[(l, 3-benzodioxol-5- yloxy)methyl]-4-(2-methoxyphenyl)]), a NRF2 activator (e.g., dimethyl fumarate or Tecfidera®), and a combination thereof using hiPSC-CM models of DCM. And exemplary scheme for testing candidate molecules is shown in FIG. 5.

[0120] Human iPSC such as DCM hiPSCs lines are obtained and isogenic controls are generated by CRISPR gene editing of the DCM gene variants to the normal variant.

[0121] Quality control of the cardiomyocyte preparation includes > 95% purity, Na channel dependent action potentials, inotropic response to isoproterenol. McKeithan et al., Front Physiol. 8:766 (2017). To control for biological variation, at least three differentiation batches (biological replicates) are tested in each of the assays described below and at least six technical replicates per differentiation batch are analyzed to account for technical variation.

[0122] Human cardiomyocytes produced from iPSCs (hiPSC-CMs) reproduce myopathic and metabolic defects characteristic of DCM. Thus, hiPSC-CMs have been used in gene and drug screening. Sun et al., Science Translation Medicine 4(130): 130ra47 (2012); Briganti et al., Cell Rep. 32(10): 108117 (2020); Feyen et al., Circulation 144(5):382-392 (2021). hiPSC-CMs are produced from human iPSCs using a conventional Wnt inhibitor procedure followed by 4-5 weeks of metabolic maturation. Feyen et al., Cell Rep. 32(3): 107925 (2020). For protocols for differentiation and maturation, see Sharma et al., Sci Transl Med. 9(377) (2017); Briganti et al., Cell Rep. 32(10): 108117 (2020); Feyen et al., Circulation 144(5):382-392 (2021); Cashman etal., J Med Chem. 64(9): 5384-5403 (2021); and McKeithan et al., Cell Stem Cell 27(5):813-821 (2020). hiPSC-CMs are cryo-preserved and stored in liquid N2 at two weeks of differentiation. Quality control ensures viability to exceed 75% upon thawing and plating.

[0123] Vials are thawed, and hiPSC-CMs are plated in 6-well plates and cultured for 4-5 weeks in a metabolic maturation media that enhances their fidelity of DCM modeling. Feyen et al., Cell Rep. 32(3): 107925 (2020). Each plate also includes two small molecule positive inotropes as positive controls (e.g., istaroxime and omecamtiv mecarbil). Each are evaluated in four DCM hiPSC-CM models and isogenic controls. Following compositions are tested in an 8- point dose series, > 6 replicates / datapoint: (1) a BACH1 inhibitor (e.g., HPP-E or M2 [1- Piperazineethanol,a-[(1 ,3 -benzodi oxol-5-yloxy)methyl]-4-(2-m ethoxyphenyl )]); (2) a NRF2 activator e.g., dimethyl fumarate or Tecfidera®); (3) a combination thereof. The experiments are repeated in differentiation batches.

[0124] To track contractile motion, cells are labeled with tetramethylrhodamine, ethyl ester (TMRE), a fluorescent dye that primarily stains mitochondria. High speed video recordings (10 second video clips) are acquired on the IC200 high content kinetic imaging cytometer at > 30 frames per second with 1 Hz electrical pacing to avoid complications caused by variable beat rates. Motions of the TMRE fluorescence are tracked by particle image velocity algorithms and used to calculate contractility parameters of contraction amplitude, contraction and relaxation rates and times. See Briganti et al., Cell Rep. 32(10): 108117 (2020); Feyen et al., Circulation 144(5):382-392 (2021); Feyen et al., Cell Rep. 32(3): 107925 (2020); Serrano et al., Phiophys.J. 2018(114):312A (2018).

[0125] Peak contraction amplitude and contraction Vmax are assessed for the BACH1 inhibitor (e.g., HPP-E or M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5-yloxy)methyl]-4-(2- methoxyphenyl)]), the NRF2 activator (e.g., dimethyl fumarate or Tecfidera®), a combination thereof. The force generated during contraction are determined for three doses bracketing the doses that gives the optimal concentration amplitudes and rates. Treatment with the BACH1 inhibitor (e.g., HPP-E or M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5-yloxy)methyl]-4-(2- methoxyphenyl)]), the NRF2 activator (e.g., dimethyl fumarate or Tecfidera®), a combination thereof improves peak concentration amplitude and contraction Vmax in DCM hiPSC-CMs.

[0126] EC50 and Emax are determined for the BACH1 inhibitor (e.g., HPP-E or M2 [1- Piperazineethanol,a-[( 1, 3 -benzodioxol-5-yloxy)methyl]-4-(2-m ethoxyphenyl)]) and the NRF2activator (e.g., dimethyl fumarate or Tecfidera®). Combinations of the BACH1 inhibitor (e.g, HPP-E or M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5-yloxy)methyl]-4-(2-methoxyphenyl)]) and the NRF2 activator (e.g, dimethyl fumarate or Tecfidera®) are formulated with both compounds at comparable potencies (i.e., matched according to the empirically determined EC50 values) and evaluated in an 8-point dose study to determine the EC50 and Emax values for each combination. Given that redox imbalance and metabolic derangement is a general property of failing cardiomyocytes, the effect is expected to be similar across DCM hiPSC-CMs regardless of the underlying genetic mutations (e.g, TNNT2 p.R173W, PLN p.R14del, RBM20 p.R634Q, and LMNA p.Kl 17fs). The outcome will resolve whether any of the combinations achieves a comparable or better Emax at a lower dose than the individual compounds.EXAMPLE 4. In vivo therapeutic efficacies of BACH1 inhibitor, NRF2 activator, or a combination thereof

[0127] This Example describes experiments for determining relative therapeutic efficacies of a BACH1 inhibitor e.g., HPP-E or M2 [l-Piperazineethanoi,a-[(l,3-benzodioxol-5- yloxy)methyl]-4-(2 -methoxyphenyl)]), a NRF2 activator (e.g., dimethyl fumarate or Tecfidera®), and a combination thereof in animals models of DCM in vivo. Common animal models for DCM are mouse models of inherited DCM. These mice develop DCM spontaneously as they age.

[0128] At time point zero, each animal is administered one of the following compositions (1) a BACH1 inhibitor (e.g., HPP-E or M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5- yloxy)methyl]-4-(2-methoxyphenyl)]); (2) a NRF2 activator (e.g., dimethyl fumarate or Tecfidera®); (3) a combination thereof or a control, for example PBS. Administration to the animals can be either by intravenous (IV) injection, intraperitoneal (IP) injection, or by oral gavage as appropriate depending on pharmacokinetics.

[0129] After drug administration, cardiac function is monitored periodically (e.g., monthly) in the animals by echocardiography or cardiac MRI.

[0130] Animals are monitored at monthly intervals (over 3-9 months) to follow the progression of DCM. Mice are minimally anesthetized with 1 -2% isoflurane and studied using an echocardiography instrument (e.g., Vevo 3100®, High-Resolution Imaging System (VisualSonics)). B- and M-mode images are obtained for mice at various time-points aftertreatment. Posterior wall and anterior wall diastolic and systolic thicknesses and left ventricular cavity end-diastolic (LVED,d) and end-systolic diameters (LVED,s) are measured, permitting estimation of LV volumes, fractional shortening and ejection fraction. Regional and global cardiac dynamics, including contractility and synchrony, are deconvoluted by speckle-tracking echocardiography. Cardiac cycles from the parasternal long-axis and mid-ventricular short-axis views will be used for assessment of radial, circumferential and longitudinal systolic strain / velocity, and time-to-peak systolic strain / velocity. Invasive hemodynamics is an additional measurement of cardiac function. Invasive hemodynamics is performed just prior to termination. Measurements of pressure-volume loops are made in anesthetized mice using a pressure-volume catheter (SPR-839, Millar Instruments Inc.) at baseline and after infusion of dobutamine. To measure preload-independent parameters, preload is acutely decreased by inferior vena cava compression following a limited right thoracotomy.

[0131] Molecular analyses: levels of cardiac protein indicators for HF by qRT-PCR such as BNP, TNFa, P-adrenergic receptors, and MYH isoforms (3 mice / sex at 4 and 9-month timepoints) are analyzed.

[0132] Histological analysis: Hematoxylin and eosin staining (assessment for pathogenesis) and picrosirius red (cardiac fibrosis); wheat germ agglutinin to determine myocyte dimensions (length vs width ratio) and cross-sectional area (samples from same mice as used for molecular analyses).

[0133] The results will resolve improvements in cardiac output or stroke volume; decrease in end diastolic volumes; general decreases of symptoms of heart failure; or enhancement in survival, or decrease in cardiac events / hospitalization; or a combination thereof.EXAMPLE 5. Analyses of gene expressions in response to treatment with BACH1 inhibitor, NRF2 activator, or a combination thereof

[0134] To examine induction of genes related to metabolism and redox homeostasis, an optimal timing after treatment with a BACH1 inhibitor (e.g., HPP-E or M2 [1 - Piperazineethanol, «-[( 1 ,3 -benzodi oxol-5-yloxy)methyl]-4-(2 -methoxyphenyl)]), a NRF2 activator (e.g., dimethyl fumarate or Tecfidera®), or a combination thereof is determined using a small number of bonafide early response target genes, known biomarkers BACH1 inhibition and NRF2 activation, such as, but not limited to, heme oxygenase-1 (HO-1). Mito et al.,Hypertension 51 (6)4570-1577 (2008); Hayes et al., Trends Biochem Sci. 39(4) 99-218 (2014). Once the optimal timing has been determined, samples are processed for RNAseq.Transcriptomic changes at the optimal early time point and at 1 week after continuous treatment are evaluated to visualize changes related to metabolic and redox reprogramming. RNAseq will provide an unbiased view of the effects of the compounds (e.g., HPP-E, M2 [1- Piperazineethanoi,a-[( 1 ,3 -benzodi ox ol-5-yloxyjmethyl]-4-(2 -methoxyphenyl )], dimethyl fumarate (or Tecfidera®), or a combination thereof). Specifically, (1) clustering of the differentially expressed genes (DEGs) by known functions provides information on the action of the compounds (e.g., HPP-E, M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5-yloxy)methyl]-4- (2 -methoxyphenyl )], dimethyl fumarate (or Tecfidera®), or a combination thereof) and whether the compounds reprogram cellular metabolism and redox homeostasis. Furthermore, comparison to untreated DCM and isogenic control hiPSC-CMs will reveal the extent to which the compounds (e.g., HPP-E, M2 [1 -Piperazineethanol, a-[(l, 3 -benzodi oxol-5-yloxy)methyl]-4-(2- methoxyphenyl)], dimethyl fumarate (or Tecfidera®), or a combination thereof) can normalize the aberrant transcriptional signatures of the DCM cells.EXAMPLE 6. Analysis of metabolic and mitochondrial functions in response to treatment with BACH1 inhibitor, NRF2 activator, or a combination thereof

[0135] Metabolic and mitochondrial functions play important roles in heart failure. Bertero et al., Nat Rev Cardiol. 15(8):457-470 (2018). Although much less explored, familial DCM has been associated with impaired mitochondrial function (e.g, TTN and LMNA mutant DCM). The effects of the compounds (e.g., HPP-E, M2 [1 -Piperazineethanol, a-[(l, 3-benzodioxol-5- yloxy)methyl]-4-(2-methoxyphenyl)], dimethyl fumarate (or Tecfidera®), or a combination thereof) are evaluated one week after continuous treatment with the compound to determine the effects on cellular glycolysis and respiration using the Seahorse XFe96 analyzer (Agilent). Glycolytic and mitochondrial ATP productions are evaluated based on the production of lactate acidification (ECAR) and oxygen consumption (OCR) rates determined by Seahorse Analyzer analysis. Positive responses to administration(s) of the compounds e.g., HPP-E, M2 [1- Piperazineethanol,a-[(1 ,3 -benzodi oxol-5-yloxy)methyl]-4-(2-methoxyphenyl)], dimethyl fumarate (or Tecfidera®), or a combination thereof) is confirmed by histochemical analyses, such as, but not limited to, MitoTracker™ and / or MitoSOX™ for mitochondrial DNA (mtDNA)assessment, and / or CellRox™, and / or Amplex™ Red for oxidative stress assessment (e.g., ROS generation and / or 4-HNE lipid peroxidation).EXAMPLE 7. Assessment of arrhythmia and intracellular Ca2+in response to treatment with BACH1 inhibitor, NRF2 activator, or a combination thereof

[0136] Inotropic therapies that increase intracellular Ca2carry the risk of increased arrhythmia. The mechanism of action of BACH1 inhibition and NRF2 activation is not expected to affect intracellular Ca2+or proarrhythmic ion channel activity directly. Therefore, a proarrhythmic or cardiotoxic effect is not expected in the treatment with a BACH1 inhibitor (e.g., HPP-E or M2 [1 -Piperazineethanol, a-[(l, 3-benzodioxol-5-yloxy)methyl]-4-(2- m ethoxyphenyl)]), a NRF2 activator (e.g., dimethyl fumarate or Tecfidera®), or a combination thereof. However, NRF2 activation has been suggested to be cardiotoxic under conditions of deficient autophagy, such as the one that occurs in a late stage of decompensated ischemic heart failure. Zang et al., Front Physiol. 11 :722 (2020). Thus, possible relationships to autophagy are evaluated. Furthermore, unintended inhibition of cardiac ion channels (e.g, hERG) can cause arrhythmia. Thus, Ca2+transient and action potential (AP) voltage traces hiPSC-CMs are analyzed for evidence of arrhythmia.

[0137] Arrhythmia and intracellular Ca2+data are acquired in parallel with acquiring contractility data for Example 3. Cardiac action potentials are recorded optically using a small molecule fluorescent voltage sensor at 30-100 Hz. Arrhythmia is quantified as aberrations in the action potential duration, induction of early and late after depolarizations, and ectopic beats. Vala Sciences arrhythmia assay is a sensitive assay for arrhythmogenic compounds, including but not limited to hERG blockers. Intracellular Ca2+is measured using a small molecule nonratiometric emission dye Cal520, or a ratiometric emission dye Cal Red™ 525 / 650 (AAT Bioquest), which emits at 525 nm in the absence of Ca2+and 650 nm with Ca2+. Pacing is obtained at 1 Hz, with 475 nm light excitement. A 6-beat movie with a FITC emission filter is acquired. Pacing is continued and a second 6-beat movie is acquired with a TRITC filter (12 seconds total acquisition).* * *

[0138] While the disclosure has been particularly shown and described with reference to specific embodiments (some of which are preferred embodiments), it should be understood by those having skill in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the present disclosure as disclosed herein.

Claims

CLAIMSWe claim:

1. A method of treating dilated cardiomyopathy (DCM) in a subject having or at risk of having the DCM, the method comprising administering to the subject a therapeutically effective amount of a BTB and CNC homology 1 (BACH1) inhibitor.

2. A method of treating DCM in a subject having or at risk of having the DCM, the method comprising administering to the subject a therapeutically effective amount of a nuclear factor erythroid 2-related factor 2 (NRF2) activator.

3. A method of treating DCM in a subj ect having or at risk of having the DCM, the method comprising administering to the subject a therapeutically effective amount of a BACH1 inhibitor and a NRF2 activator.

4. The method of any one of claims 1-3, wherein the DCM is heart failure with reduced ejection fraction (HFrEF).

5. The method of any one of claims 1-4, wherein the administering(a) improves peak contraction amplitude;(b) improves contraction force;(c) increases contraction velocity;(d) increases oxidative metabolism and efficiency of ATP production without increasing reactive oxygen species (ROS) or inducing mitochondrial stress;(e) increases contractility without altering intracellular Ca2+levels or inducing signs of arrhythmia; or(f) any combination of (a), (b), (c), (d) and (e) in the subject.

6. The method of claim 3, wherein the combination of the BACH1 inhibitor and the NRF2 activator has a synergistic effect, leading to a lower dosage and toxicity.

7. The method of claim 1 or 3, wherein the BACH1 inhibitor is a small molecule compound.

8. The method of claim 7, wherein the BACH1 inhibitor is selected from the group consisting of ML-0207 / ASP8731, HPP-A, HPP-B, HPP-C, HPP-D, HPP-E, HPP971, HPP-1014, HPP-4382, M2 [l-Piperazineethanol,a-[(l,3-benzodioxol-5-yloxy)methyl]-4-(2-methoxyphenyl)] and analogues, cadmium, hemin (Panhematin®), and any derivative thereof.

9. The method of claim 8, wherein the BACH1 inhibitor is HPP-E.

10. The method of any one of claims 2-3, wherein the NRF2 activator is a small molecule compound.

11. The method of claim 10, wherein the NRF2 activator is selected from the group consisting of dimethyl fumarate, Tecfidera®, oltipraz (OPZ), CBR-470-1, CDDO Im, bardoxolone-methyl (CDDO-Me), (±)-eriodictyol, INF 4E, ML334, NK 252, 4-Octyl itaconate, RA 839, resveratrol, sulforaphane, curcumin, agmatine, naringenin, RTA-408 (omaveloxolone), ALKS-8700, ursodiol, sulforadex (SFX-01), ITH12674, CXA-10, SCIIU909, and any derivative thereof.

12. The method of claim 11, wherein the NRF2 activator is dimethyl fumarate.

13. The method of claim 11, wherein the NRF2 activator is Tecfidera®.