
==== Front
Redox Biol
Redox Biol
Redox Biology
2213-2317
Elsevier

S2213-2317(24)00299-4
10.1016/j.redox.2024.103321
103321
Review Article
Epigenetic regulation of diverse regulated cell death modalities in cardiovascular disease: Insights into necroptosis, pyroptosis, ferroptosis, and cuproptosis
Chen Cong a1
Wang Jie wangjie0103@126.com
a⁎
Zhang Shan b1
Zhu Xueying c1
Hu Jun a
Liu Chao a
Liu Lanchun a
a Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing, 100053, China
b Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
c Department of Anatomy, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
⁎ Corresponding author. wangjie0103@126.com
1 Co-first author:These authors contributed equally to this work.

19 8 2024
10 2024
19 8 2024
76 10332113 7 2024
17 8 2024
18 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Cell death constitutes a critical component of the pathophysiology of cardiovascular diseases. A growing array of non-apoptotic forms of regulated cell death (RCD)—such as necroptosis, ferroptosis, pyroptosis, and cuproptosis—has been identified and is intimately linked to various cardiovascular conditions. These forms of RCD are governed by genetically programmed mechanisms within the cell, with epigenetic modifications being a common and crucial regulatory method. Such modifications include DNA methylation, RNA methylation, histone methylation, histone acetylation, and non-coding RNAs. This review recaps the roles of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs in cardiovascular diseases, as well as the mechanisms by which epigenetic modifications regulate key proteins involved in cell death. Furthermore, we systematically catalog the existing epigenetic pharmacological agents targeting novel forms of RCD and their mechanisms of action in cardiovascular diseases. This article aims to underscore the pivotal role of epigenetic modifications in precisely regulating specific pathways of novel RCD in cardiovascular diseases, thus offering potential new therapeutic avenues that may prove more effective and safer than traditional treatments.

Keywords

Epigenetic modification
Necroptosis
Pyroptosis
Ferroptosis
Cuproptosis
==== Body
pmc1 Introduction

The balance between cell death and proliferation plays a vital role in maintaining physiological or pathological homeostasis [1]. Cells may die from accidental cell death (ACD) or RCD, where ACD is a biologically uncontrolled process, and RCD involves structured signal cascades and molecularly defined effector mechanisms [2]. Increasingly, novel non-apoptotic forms of RCD have been discovered and are intimately linked to various human pathologies [2,3]. The mechanisms of cell death pertinent to specific human pathologies may be triggered by the activation of programmed cell death pathways and the loss of cellular survival mechanisms [4,5]. For example, necroptosis and pyroptosis are caused by the activation of programmed cell death pathways, while ferroptosis and cuproptosis result from the deactivation or disruption of essential cellular survival mechanisms required for maintaining normal cellular homeostasis [6].

China is one of the countries most burdened by cardiovascular diseases (CVD) worldwide [7]. Over the past three decades, it has been shown that RCD plays a pathological role in heart diseases. As terminally differentiated cells, the death of cardiomyocytes leads to a reduction in their numbers, thereby causing defects in cardiac structure and function and exacerbating heart failure (HF) [[8], [9], [10]]. RCD is a key pathogenic mechanism in heart diseases [9], for example, in HFwith reduced ejection fraction, the gradual decline in cardiomyocyte function through RCD is one of the multiple mechanisms leading to adverse cardiac remodeling and contractile dysfunction [11]. Most cell deaths in myocardial ischemia/reperfusion injury (MIR) are mediated through regulated programs of cell death [12]. Although the fundamental mechanisms of RCD have been extensively elucidated, what factors regulate RCD in cardiomyocytes and where the balance lies remain critical questions with significant research value and clinical translation potential [13].

Various epigenetic modifications, including DNA methylation, RNA methylation, histone methylation, histone acetylation, and non-coding RNAs, are key regulators of cell death mechanisms [[14], [15], [16]]. Dysregulation of epigenetic modifying enzymes or disruptions in non-coding RNA homeostasis can alter the expression of downstream genes, thereby mediating cardiomyocyte death. This review focuses on the regulatory mechanisms of novel programmed cell death and cell state changes induced by cell death in CVD, providing potential targets for treatment and insights for stimulating cardiac repair after injury. In addition to the novel forms of RCD discussed in this review, apoptosis remains a fundamental pathway in cardiovascular health and disease. Its well-established mechanisms contrast with the emerging pathways of necroptosis, pyroptosis, ferroptosis, and cuproptosis, which are just beginning to be understood in the context of cardiac pathology.

2 Epigenetic regulation in the heart

2.1 DNA methylation

DNA methylation is a normal and widespread modification in eukaryotic cells, typically occurring before cytosine nucleotides at CpG sites [17].

5-methylcytosine (m5C) serves as a central epigenetic marker in mammalian DNA, playing a fundamental role in chromatin regulation [18]. m5C involves the addition of a methyl group (-CH3) to the fifth carbon atom of cytosine, playing a crucial role in gene expression regulation, cell differentiation, the inheritance and stability of genetic information, and disease progression [19]. m5C is primarily catalyzed by DNA methyltransferases (DNMTs), with DNMT1 responsible for maintaining methylation and DNMT3A/DNMT3B for de novo methylation. m5C can further be oxidized to 5-hydroxymethylcytosine (5hmC), a step performed by TET enzymes (Ten-Eleven Translocation methylcytosine dioxygenases) [19,20]. The balance and regulation of m5C and 5hmC after myocardial infarction (MI) are crucial for cardiac repair [21]. NEIL3, a DNA glycosylase involved in the base excision repair pathway, regulates the dynamic balance of m5C and 5hmC. Changes in NEIL3 expression affect the distribution of m5C and 5hmC, which in turn influences the proliferation of cardiac fibroblasts and the remodeling of the extracellular matrix [22].

It has been reported that N6-methyladenine (6 mA) can appear in the mitochondrial genome of mammalian cells, suggesting that 6 mA is a new type of mtDNA methylation besides m5C [23]. In the case of heart failure, the level of 6 mA modification in mtDNA significantly increases [24]. Notably, these modifications are concentrated in the promoter regions of mtDNA, which are crucial for controlling gene expression. Methyltransferase-like protein 4 (METTL4), a methyltransferase primarily located in the mitochondria of adult cardiomyocytes, significantly increases m6A modification in HF, directly affecting the transcription of mtDNA. The modification impedes the assembly of the transcription initiation complex, particularly affecting the binding of mitochondrial transcription factor A (TFAM) and mitochondrial RNA polymerase (POLRMT) at mtDNA promoters [24]. This results in blocked mtDNA transcription, thereby reducing the gene expression of components of the electron transport chain (ETC), affecting mitochondrial respiratory function. Therefore, targeting METTL4 to correct the excess m6A modification in mtDNA might represent a novel therapeutic strategy.

2.2 RNA methylation

N6-methyladenosine (m6A) refers to the methylation of the sixth N atom of adenine in RNA molecules, occurring near stop codons, in 5' and 3' UTR regions, long internal exons, and the conserved sequence RRACH (R = G/A and H = A/C/U) [25]. The m6A modification of RNA is performed by "writers," including methyltransferases (METTL3 and METTL14), Wilms tumor 1-associated protein (WTAP), KIAA1429, zinc finger CCCH domain-containing protein 13 (ZC3H13), and RNA-binding motif protein 15 (RBM15). The demethylation of m6A is catalyzed by human AlkB homolog H5 (ALKBH5) and the α-ketoglutarate-dependent dioxygenase family of fat mass and obesity (FTO), known as "erasers"; m6A "readers" are categorized into three types: Class I readers include those with YTH domains, such as YTHDC1/2 and YTHDF1/2/3, which recognize and bind transcripts containing m6A. Class II readers are heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP C and hnRNP A2B1, which regulate the selective splicing or processing of transcripts. The IGF2BP family proteins IGF2BP1/2/3 are Class III readers, sharing six RNA-binding domains, including two RNA recognition motifs and four KH domains (Table 1).Table 1 Classification, Function, and Impact of m5C, 6 mA, and m6A Modification-Related Proteins in Cardiovascular Diseases.

Table 1Classification	Members	Roles and Functions	Impact on CVD	Ref	
DNA Methylation	
m5C	
Writers	NSUN2	Methylates most expressed tRNAs, along with other abundant non-coding RNAs and a few of mRNAs	NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress	[26,27]	
	NSUN3	Catalyzes m5C in mitochondrial tRNA	NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complexes in mice	[28,29]	
	NSUN5	Modulates protein synthesis by targeting m5C on 28S rRNA	Mutations in RNA Methyltransferase Gene NSUN5 Confer High Risk of Outflow Tract Malformation	[30,31]	
	DNMT2 (TRDMT1)	Methylates C38 in particular tRNAs	DNMT2-mediated DNA methylation of the GPX1 promoter inhibits cardiac function	[32,33]	
Eraser	TET1/2/3	Catalyzes first step of m5C demethylation	TETs regulate proepicardial cell migration through extracellular matrix organization	[34,35]	
Readers	NEIL3	Recognize and process oxidized derivatives of methylated cytosine	NEIL3-dependent regulation of cardiac fibroblast proliferation prevents myocardial rupture	[22]	
	YTHDF2	Modulates the maturation of m5C-modified rRNAs	YTHDF2 alleviates cardiac hypertrophy via regulating Myh7 mRNA decoy.	[36,37]	
	YBX1	Recruit stability maintainer ELAVL1 to stabilize m5C-modified mRNAs	Translational control of Ybx1 expression regulates cardiac function in response to pressure overload in vivo	[38,39]	
6 mA	
Writers	METTL4	Involved in the modification of mitochondrial DNA with 6 mA.	Amplification of myocardial mitochondrial DNA 6 mA leads to spontaneous mitochondrial dysfunction and HF phenotype.	[24]	
RNA Methylation	
m6A	
Writers	METTL3	Catalyzes methylation of the 6th atom of adenine (A) in RNA	Alleviates myocardial fibrosis inflammation by disrupting DNA-PKcs/Fis1-dependent mitochondrial fission.	[40]	
Mettl3-mediated modification of Fgf16 restricts cardiomyocyte proliferation during cardiac regeneration.	[41]	
Accelerates the maturation of pri-miR-221/222 in an m6A-dependent manner, mediating angiotensin II-induced cardiac hypertrophy.	[42]	
METTL14	Serves as an RNA-binding scaffold, activating and enhancing the catalytic activity of METTL3.	METTL14-induced m6A modification improves microcirculatory disorders in septic cardiomyopathy.	[43]	
METTL14 inhibits cellular apoptosis by downregulating TINCR lncRNA.	[44]	
WTAP	Lacks catalytic activity; promotes m6A methylation by recruiting METTL3 and METTL14.	Suppresses proliferation and migration of vascular smooth muscle cells.	[45]	
RBM15	Binds METTL3 and WTAP, recruiting them to specific RNA sites to promote m6A modification.	Essential for embryonic development of cardiac and splenic vasculature branching and morphology.	[46]	
ZC3H13	Associates with WTAP to retain it within nuclear speckles (NSs), facilitating m6A modification.	Participates in the regulation of the coronary artery disease immune microenvironment.	[47]	
KIAA1429	Guides regional methylation by recruiting the m6A MTC to the 3' UTR and stop codons.	KIAA1429 enhances the stem cell characteristics of endothelial cells.	[48]	
Influences the progression of aortic dissection.	[49]	
METTL15	Not a part of MTC; independently catalyzes m6A methylation.	Maintains mitochondrial homeostasis, incorporates N4-methylcytidine into human mitochondrial 12S rRNA, and is essential for mitochondrial ribosome biogenesis.	[50,51]	
METTL16	Promotes m6A modification of U6-snRNA and participates in RNA pre-splicing.	METTL16-mediated m6A modification induces COPD-related pulmonary microvascular damage.	[52]	
Promotes erythropoiesis by protecting genomic integrity.	[53]	
Erasers	ALKBH5	Directly removes m6A modifications.	Induces the transformation of fibroblasts to myofibroblasts during hypoxia to prevent cardiac rupture post-myocardial infarction.	[54]	
ARID2 exacerbates DOX-induced cardiomyocyte apoptosis.	[55]	
FTO	Catalyzes demethylation by oxidizing m6A into N6-hydroxymethyladenosine and N6-acetyl-adenosine, followed by hydrolysis to adenine.	Regulates myocardial fibrosis.	[56]	
Inhibits cardiomyocyte apoptosis and dysfunction.	[57]	
Modulates inflammatory responses.	[58]	
Suppresses oxidative stress responses.	[59]	
Protects mitochondrial functions.	[60]	
Promotes vascular regeneration and functional recovery.	[61]	
Regulates glucose uptake and metabolism.	[62]	
Inhibits lipid uptake and cholesterol efflux.	[63]	
Modulates vascular tone.	[64]	
Affects autonomic regulation.	[65]	
Readers	YTHDF1/2/3	Recognizes and binds transcripts containing m6A through the YTH domain; YTHDF1/2/3 are involved in transcript stability and degradation	YTHDF1 promotes cardiomyocyte differentiation, while YTHDF3 has the opposite effect.	[66]	
YTHDF2 degrades Myh7 mRNA to alleviate cardiac hypertrophy during heart failure progression.	[36]	
YTHDF1/YTHDF2 synergistically stimulate an atherosclerotic inflammatory cascade in vascular endothelial cells by upregulating NLRP1 and downregulating KLF4.	[67]	
YTHDC1/2	Recognizes and binds transcripts containing m6A through the YTH domain; YTHDC1 is involved in nuclear export and gene amplification	Promotes ferroptosis mediated by ferritinophagy during sepsis.	[68]	
hnRNP C, hnRNP A2B1	Regulates selective splicing or processing of transcription; hnRNP A2B1 also involved in nuclear accumulation.	hnRNPC acts as a mechanosensitive switch affecting RNA metabolism in HF and mechanically regulates pathological cardiac ECM remodeling.	[69]	
IGF2BP1/2/3	Shares six RNA-binding domains, including two RNA recognition motifs and four KH domains; involved in transcript stability and translation.	Overexpression of IGF2BP2 in the heart downregulates sarcomere and mitochondrial proteins, with fragmented mitochondria and elongated sarcomeres.	[70]	
EIF3	Promotes ncRNA translation.	eIF3-f is a critical target of MAFbx during muscle wasting and plays a primary role in skeletal muscle hypertrophy.	[71]	
HuR	Affects transcript stability.	HuR enhances the expression of aging inducers p21 12, 13, and displacement is a cause of impaired cardiac function.	[72]	
Regulates DOX-induced ferroptosis.	[73]	
Modulates phosphoprotein expression during isoproterenol-induced cardiac remodeling.	[74]	
Regulates inflammatory responses and myocardial fibrosis.	[75]	
RSF3	Regulates the selective splicing of transcription.	–		
CYCLINL1	Participates in transcription.	–		
DGCR8	Involved in the maturation of miRNAs.	Essential miRNA processing proteins.	[76]	
Regulates cardiomyocyte proliferation.	[77]	
Abbreviations: ALKBH5, AlkB Homolog 5; ARID2, AT-rich Interaction Domain 2; COPD, Chronic Obstructive Pulmonary Disease; CVD, Cardiovascular Disease; CYCLINL1, Cyclin L1; DGCR8, DiGeorge Syndrome Critical Region Gene 8; DNA-PKcs, DNA-Dependent Protein Kinase, Catalytic Subunit; DOX, Doxorubicin; EIF3, Eukaryotic Translation Initiation Factor 3; Fgf16, Fibroblast Growth Factor 16; Fis1, Fission, Mitochondrial 1; FTO, Fat Mass and Obesity-associated Protein; HF, Heart Failure; HuR, Human antigen R; IGF2BP1/2/3, Insulin-like Growth Factor 2 mRNA Binding Protein 1/2/3; KIAA1429, A gene identifier, generally a placeholder name for a protein before it has been characterized; KLF4, Kruppel Like Factor 4; MAFbx, Muscle Atrophy F-box; METTL, Methyltransferase Like; m6A, N6-methyladenosine; 6 mA, N6-methyladenine; MTC, Methyltransferase Complex; Myh7, Myosin Heavy Chain 7; NLRP1, NLR Family Pyrin Domain Containing 1; ncRNA, Non-coding RNA; NSs, Nuclear Speckles; RBM15, RNA Binding Motif Protein 15; RSF3, Remodeling and Spacing Factor 3; rRNA, Ribosomal RNA; TINCR, TINCR Ubiquitin Domain Containing; U6-snRNA, U6 Small Nuclear RNA; UTR, Untranslated Region; WTAP, Wilms' Tumor 1-Associating Protein; YTHDC1/2, YTH Domain Containing 1/2; YTHDF1/2/3, YTH Domain Family 1/2/3; ZC3H13, Zinc Finger CCCH-Type Containing 13.

2.3 Histone modifications

Histones are small, highly conserved alkaline proteins. There are five main types: H1, H2A, H2B, H3, and H4. Two copies each of H2A, H2B, H3, and H4, known as the core histones, form a histone octamer that is wrapped by 145–147 base pairs of DNA [78]. Additionally, histone H1 stabilizes the nucleosome's position on DNA by binding to two adjacent nucleosomes [79]. Histone modifications, which refer to post-translational modifications (PTMs) of histone N-terminal amino acids, have been extensively studied and include well-known modifications such as acetylation, methylation, and ubiquitination [80]. However, emerging research has identified additional PTMs that play significant roles in gene regulation and cellular function, including phosphorylation, GlcNAcylation, and sumoylation [81]. These modifications illustrate that our understanding of epigenetic mechanisms is continually evolving, revealing more complex layers of regulation. These modifications are controlled and mediated by proteins classified as writers, erasers, or readers based on their functions. Writers, including histone acetyltransferases (HATs) and histone methyltransferases (HMTs), catalyze histone acetylation and methylation. Erasers remove acetyl and methyl groups, including deacetylases and demethylases. Readers are proteins that bind to these histone marks and mediate their biological effects by regulating chromatin organization or the activity of other proteins [82,83]. Among these, histone acetylation is most closely linked with cardiovascular diseases (Table 2).Table 2 HDACs and HATs involved in cardiovascular diseases.

Table 2Category	Localization and Function in Cells	Histone Deacetylases/Acetyltransferases	Expression in Cardiac Tissue	Impact on Cardiovascular Diseases	Ref	
Class I HDACs	Primarily located in the nucleus, involved in gene expression regulation. Often binds to transcriptional repression complexes to inhibit gene expression.	HDAC1	Right ventricle, lungs	Regulating vascular calcification by promoting autophagy.	[84]	
Promoting pathological CH.	[85]	
Promoting apoptosis of cardiomyocytes.	[86]	
Activating CF.	[87]	
HDAC2	Heart	Promoting CF.	[88]	
Regulating early-stage ventricular APD remodeling and ion channel expression in heart failure.	[89]	
Promoting pathological CH.	[90]	
Promoting ultrastructural disorder in cardiomyocytes.	[91]	
Promoting endothelial-mesenchymal transition.	[92]	
HDAC3	Heart, blood vessels	Maintaining endothelial integrity and function, and regulating proliferation and migration of VSMCs.	[93]	
Promoting CF.	[94]	
Antagonizing NO production in endothelial cells.	[95]	
Regulating the function of Nkx2.5 in adult cardiac conduction.	[96]	
Regulating oxidative stress and apoptosis.	[97]	
Maintaining cardiac energy metabolism.	[98]	
Promoting proliferation of cardiomyocytes.	[99]	
HDAC8	Heart	Promoting pathological CH.	[100]	
Promoting myocardial inflammation and fibrosis.	[101]	
Class IIa HDACs	Can shuttle between the nucleus and cytoplasm, involved in signal transduction and gene regulation.	HDAC4	Blood vessel smooth muscle cells, Heart	Regulating metabolic reprogramming of macrophages.	[102]	
Regulating pathological CH.	[103]	
HDAC5	Blood vessel smooth muscle cells, Heart	Controlling redox homeostasis in cardiomyocytes.	[104]	
Promoting pathological CH.	[105]	
HDAC7	Blood vessel smooth muscle cells, Heart	Regulating necroptosis in cardiomyocytes.	[106]	
Promoting pathological CH.	[107]	
Participating in VEGF-stimulated endothelial cell migration, tube formation, and microvascular sprouting.	[108]	
HDAC9	Heart, blood vessel smooth muscle cells	HDAC9 deficiency promoting resolution of inflammation and reverse cholesterol transport.	[109]	
Inhibiting pathological CH.	[110]	
Class IIb HDACs	Primarily located in the cytoplasm, involved in deacetylation of non-histones.	HDAC6	Heart, blood vessel smooth muscle cells	Promoting apoptosis of cardiomyocytes.	[111]	
Promoting destabilization of alpha-tubulin and disruption of microtubule structure in cardiomyocytes.	[112]	
Regulating endothelial cell migration and angiogenesis.	[113]	
HDAC10	Heart, blood vessel smooth muscle cells	Promoting cell proliferation in VSMCs.	[114]	
Promoting angiogenesis.	[115]	
Class III HDACs	Dependent on NAD+, with deacetylase and ADP-ribosyltransferase activities, involved in various cellular processes including metabolic regulation, aging, and stress response.	SIRT1	Heart, blood vessels	Promoting angiogenesis.	[116]	
Inhibiting oxidative stress.	[117]	
Inhibiting pathological CH, metabolic dysfunction, and inflammation.	[118]	
Improving endothelial function.	[119]	
Inhibiting ferroptosis in cardiomyocytes.	[120]	
Inhibiting apoptosis of cardiomyocytes.	[121]	
Promoting autophagy.	[122]	
Regulating mitochondrial ROS.	[123]	
SIRT2	Heart	Delaying aging of cardiomyocytes.	[124]	
Inhibiting CH.	[125]	
Regulating microtubule stability in cardiomyocytes.	[126]	
Regulating apoptosis in cardiomyocytes.	[127]	
SIRT3	Heart, blood vessels	Inhibiting CH.	[128]	
Inhibiting myocardial inflammation.	[129]	
Maintaining mitochondrial homeostasis.	[130]	
Inhibiting ferroptosis in cardiomyocytes.	[131]	
Inhibiting cellular oxidative stress.	[132]	
Regulating apoptosis in cardiomyocytes.	[133]	
Regulating mitochondrial dynamics.	[134]	
Protecting mitochondrial DNA from damage.	[135]	
Promoting autophagy.	[136]	
SIRT4	Heart	Inhibiting autophagy.	[137]	
Inhibiting apoptosis in cardiomyocytes.	[138]	
Promoting inflammatory response in macrophages.	[139]	
SIRT5	Heart	Enhancing mitochondrial quality control and inhibiting necroptotic cell death in cardiomyocytes.	[140]	
Inhibiting ferroptosis in cardiomyocytes.	[141]	
Improving fatty acid metabolism in cardiomyocytes.	[142]	
SIRT6	Heart	Enhancing mitochondrial biogenesis and mitophagy, improving metabolism in cardiomyocytes.	[143]	
Inhibiting CH.	[144]	
Inhibiting apoptosis in cardiomyocytes.	[145]	
Inhibiting inflammatory responses and oxidative stress.	[146]	
SIRT7	Heart, blood vessels	Regulating autophagy to promote repair of cardiac tissue.	[147]	
Inhibiting oxidative stress and apoptosis in cardiomyocytes.	[148]	
Regulating proliferation and migration of VSMCs.	[149]	
Promoting CF.	[150]	
Dynamically regulating mitochondrial function.	[151]	
Class IV HDACs	Mainly located in the nucleus, regulates gene expression	HDAC11	Heart, blood vessels	Alleviating oxidative stress.	[152]	
Promoting endothelial cell ferroptosis.	[153]	
Histone Acetyltransferases	Mainly located in the nucleus, or at specific chromatin regions, regulating chromatin structure and gene expression through acetylation of histones.	p300/CBP	Heart, blood vessels	Dynamically controlling maturation of cardiomyocytes.	[154]	
Regulating mitochondrial function.	[155]	
Promoting CH.	[156]	
Promoting apoptosis of cardiomyocytes.	[157]	
Regulating autophagy.	[158]	
Enhancing glycolysis, promoting aging of the heart.	[159]	
Promoting CF.	[160]	
Regulating myocardial pyruvate metabolism.	[161]	
Regulating CFR and arterial stiffness.		
Regulating CD36 expression and foam cell formation.	[162]	
Abbreviations: APD, Action Potential Duration; AS, Atherosclerosis; AMPK, Adenosine Monophosphate-Activated Protein Kinase; CBP, CREB Binding Protein; CF, Cardiac Fibrosis; CFR, Coronary Flow Reserve; CH, Cardiomyocyte Hypertrophy; eNOS, Endothelial Nitric Oxide Synthase; HDAC, Histone Deacetylase; HDACs, Histone Deacetylases; HF, Heart Failure; NAD+, Nicotinamide Adenine Dinucleotide; NO, Nitric Oxide; p300, Protein 300 (Histone Acetyltransferase); VEGF, Vascular Endothelial Growth Factor; VSMC, Vascular Smooth Muscle Cells; VSMCs, Vascular Smooth Muscle Cells.

2.4 Noncoding RNAs

Noncoding RNAs, which do not encode proteins, include microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), and small interfering RNAs (siRNAs). These RNA mechanisms, including miRNAs, lncRNAs, and circRNAs, are key epigenetic regulators in cardiovascular diseases. Most miRNA genes are transcribed by RNA polymerase II (Pol II) into large primary miRNAs (pri-miRNAs) that contain one or more stem-loop structures, each about 70 nucleotides long [163]. miRNAs function in post-transcriptional gene expression regulation. Their transcription levels are controlled by tissue-specific epigenetic modifications, involving DNA methylation and various histone modifications [164]. LncRNAs influence a variety of biological processes, including regulating mRNA stability, RNA splicing, miRNA-mediated gene regulation, and chromatin structure [165]. Additionally, lncRNAs coordinate many epigenetic regulatory processes, including chromatin dynamics, DNA methylation, mRNA, and other noncoding RNA stability, as well as the availability of epigenetic substrates [165]. circRNAs are a class of long-chain noncoding endogenous RNA molecules with a single-stranded covalent loop, lacking a 5'-Cap and a 3'-poly(A) tail. The functional mechanism of circRNAs is thought to involve interactions with miRNAs, altering the levels of free miRNAs in the 'sponge', thereby regulating the expression of disease-related proteins (Table 3) [166].Table 3 Noncoding RNAs: Regulators, dysregulation mechanisms, targets, and roles in CVD.

Table 3Types of noncoding RNAs	Description and Size	Major regulator	Targets & mechanism	Role in CVD	Refs	
miRNA	Regulates gene expression by complementary pairing with target mRNA, usually through translation repression or mRNA degradation. (∼22 nucleotides)	miR-27b	Inhibition of FBW7	Increasing the stability of Snail protein promotes the proliferation of cardiac fibroblasts, collagen deposition, and myocardial fibrosis.	[167]	
miR-1954	Inhibition of THBS1	Reducing the expression of collagen I, III, and IV, and decreasing the expression of fibrosis marker genes such as CTGF and TGFβ1.	[168]	
miR-1468-3p	Modulation of the DUSPs/MAPK pathway	Promoting collagen deposition and aging in cardiac fibroblasts by regulating the TGF-β1/p38 signaling pathway.	[169]	
miR-425	Modulation of TGFβ1	Negative regulation of CF.	[170]	
miR-744	Modulation of TGFβ1	Negative regulation of CF.	[170]	
miR-22	Inhibition of PTEN	Promoting the activation of the PI3K/Akt signaling pathway, thereby enhancing cardiomyocyte hypertrophy.	[171]	
miR-212/miR-132	Downregulation of FOXO3, SERCA2A, NOS3, STIL, TEK	Pathological growth of cardiomyocytes leading to cardiac hypertrophy and adverse cardiac remodeling; affecting calcium uptake and release, resulting in abnormal contraction and relaxation functions of cardiomyocytes; impacting cardiovascular function, leading to further deterioration of cardiac function.	[172,173]	
miR-92a	Targeting various mRNAs involved in angiogenesis, including integrins and matrix metalloproteinases	Anti-angiogenic effect, downregulating genes necessary for angiogenesis, resulting in reduced neovascularization and impaired repair of infarcted myocardium.	[174]	
miR-21	Targeting multiple genes related to cell proliferation, fibrosis, and inflammation, particularly affecting the extracellular signal-regulated MAP kinase pathway	Promoting fibroblast proliferation and collagen production, leading to increased fibrosis; enhancing inflammatory response; activating the ERK-MAP kinase signaling pathway, resulting in adverse cardiac remodeling.	[175]	
miR-29	Negative regulation of mRNAs encoding various fibrosis proteins, such as multiple types of collagen, fibrinogen, and elastin	Preventing excessive extracellular matrix deposition after myocardial infarction, thereby inhibiting fibrosis.	[176]	
miR-327	Inhibition of ITGB3	Promoting the differentiation of cardiac fibroblasts into myofibroblasts, increasing CF and hypertrophy.	[177]	
miR-125b	Inhibition of apelin	Enhancing the proliferation and FMT of cardiac fibroblasts.	[178]	
miR-99b-3p	Inhibition of GSK-3β	Inhibition of GSK-3β leads to increased Smad3 phosphorylation, which activates the expression of fibrosis-related genes, promoting the proliferation and migration of CF and enhancing ECM synthesis.	[179]	
miR-130a	Inhibition of PPARγ	Promoting the differentiation of fibroblasts into myofibroblasts, increasing α-SMA expression, and enhancing the expression of fibrosis-related genes such as Col I, Col III, CTGF, and Fn.	[180]	
miR-143-3p	Inhibition of SPRY3	Activating the P38, ERK, and JNK pathways, which promote the proliferation, migration, transformation of CF, and excessive ECM accumulation.	[181]	
miR-150-5p	Inhibition of Smad7	Activating the TGF-β/Smad pathway, promoting the proliferation, migration, transformation of CF, and excessive accumulation of ECM.	[182]	
miR-133/miR-1	RhoA/Cdc42/Nelf-A/WHSC2	Controlling cardiac hypertrophy.	[183]	
miR-233	Modulation of ARC	Promoting myocardial hypertrophy, cardiomyocyte apoptosis, and myocardial fibrosis.	[184]	
LncRNA	Regulates gene expression, involved in chromatin remodeling, and controls other RNA molecules among various biological processes. (>200 nucleotides)	Lnc-CARDINAL	Inhibition of DRG1/DFRP1	Regulating the protein translation rate in the heart during stress response, inhibiting myocardial hypertrophy.	[185]	
Lnc-CFIRL	Promotion of ENO1/IL-6	Promoting fibroblast proliferation and cardiomyocyte hypertrophy.	[186]	
Lnc-ZNF593-AS	Promotion of Mfn2 and improvement of mitochondrial function	Inhibiting cardiomyocyte hypertrophy.	[187]	
Lnc-CHKB-DT	Promotion of ALDH2	Regulating mitochondrial function, improving ATP production and cardiac energy metabolism.	[188]	
Lnc-MIR217HG	Promotion of THBS1	Promoting cardiomyocyte hypertrophy and fibrosis.	[189]	
Lnc-CFRL	Promotion of CTGF/FN1	Promoting fibrosis.	[190]	
Lnc-HOTAIR	Promotion of RORA	Inhibiting pyroptosis, reducing myocardial injury.	[191]	
Lnc-DANCR	Modulation of miR-758-3p/PRG4/Smad	Regulating cardiac hypertrophy and fibrosis.	[192]	
Lnc-THBS1-AS1	Modulation of TGFBR1	Promoting myocardial fibrosis.	[193]	
Lnc-CFAR	miR-449a-5p/LOXL3/mTOR	Promoting CF.	[194]	
Lnc-HFRL	Blocking miR-149-5p/22A collagen	Regulating cardiac inflammation, proliferation, and fibrosis.	[195]	
Lnc-cytb	Mitigation of miR-103-3p inhibition on PTEN	Inhibiting oxidative stress and myocardial hypertrophy.	[196]	
Lnc-ExACT1	Regulation of miRNA-222, calcineurin signaling, and Hippo/Yap1 signaling	Inducing pathological hypertrophy, impairing cardiac regeneration, and promoting post-injury scar formation.	[197]	
Lnc-HOX	Regulation of miR-30a-5p/KDM3A	Improving cardiac function, reducing oxidative stress, and mitigating myocardial cell damage.	[198]	
Lnc-NEAT1	Modulation of EZH2/Smad7	Promoting CF.	[199]	
Lnc-AABR07017145.1	Regulation of MMP9/TIMP1/TFR-1	Promoting ferroptosis in CMEC.	[200]	
Lnc-NRON	miR-133a	Regulating myocardial hypertrophy.	[201,202]	
Lnc-TINCR	miR-211-3p/VEGFB/SDF-1α-CXCR4	Inhibiting myocardial hypertrophy.	[203]	
Lnc-Snhg1	Inhibition of PTEN and activation of the PI3K/AKT pathway	Promoting cardiomyocyte proliferation, angiogenesis, and inhibiting cardiomyocyte apoptosis.	[204]	
Lnc-Miat	Downregulation of Serca2a and RyR2 exacerbates stress-induced Ca2+ handling dysfunction	Impairing myocardial cell calcium handling and contraction function.	[205]	
Lnc-SNHG20	miR-335/Galectin-3	Regulating CF and hypertrophy.	[206]	
Lnc-Caren	Activation of Hint1/ATM-DDR	Activating mitochondrial bioenergetics to maintain cardiac function under pathological stress.	[207]	
Lnc-ZNF593-AS	Promotion of RYR2 mRNA stability	Improving cardiac Ca2+ handling and contraction function.	[208]	
Lnc-H19	Inhibition of histone H3K27 trimethylation at the anti-hypertrophic Tescalcin locus and expression of NFAT	Counteracting pathological cardiac remodeling.	[209]	
circRNA	Formed by back-splicing of exons or introns, involved in gene expression regulation and acts as a sponge for miRNAs. (Variable)	Circ-NSD1	miR-429-3p/SULF1/Wnt/β-catenin	Promoting CF.	[210]	
Circ-RBCK1	miR-133a	Improving cardiac diastolic function.	[211]	
Circ-Slc8a1	miR-133a	Regulating cardiomyocyte hypertrophy.	[212]	
Circ-CHRC	miR-431-5p/KLF15	Modulating myocardial hypertrophy.	[213]	
Circ-Cacna1c	miR-29b-2-5p/NFATc1	Inducing cardiomyocyte proliferation and preventing cardiomyocyte apoptosis.	[214]	
Circ-Samd4	Promotion of Vcp mitochondrial translocation and reduction in Vdac1 expression to decrease CM mitochondrial oxidative stress and induce cell cycle progression	Regulating energy metabolism in cardiomyocytes.	[215]	
Circ-SNRK	Improvement of ATP synthesis via miR-33	Regulating ferroptosis.	[216]	
Circ-Nfix	miR-145-5p/ATF3	Promoting cardiomyocyte growth, angiogenesis, and enhancing the effects of adrenaline.	[217]	
Circ-Snx12	miR-224-5p	Reducing cardiomyocyte apoptosis, enhancing neovascularization, and improving left ventricular function.	[218]	
Circ-Hipk3	Regulation of the Notch1 pathway and miR-133a, regulation of MiR-17-3p - ADCY6	Counteracting hypoxia-induced ATP depletion and improving cardiomyocyte apoptosis.	[219,220]	
Circ-HRCR	Inhibition of miR-223	Inhibiting fibrosis of cardiac fibroblasts.	[184]	
Circ-Fndc3b	FUS/VEGF-A	Promoting cardiomyocyte proliferation.	[221]	
Circ-Ttc3	miR-15b/Arl2	Promoting CF.	[222]	
Mmu_circ_0005019	miR-499-5p/Kcnn3	Improving cardiac diastolic function.	[223]	
Circ-CDYL	miR-4793-5p/APP	Regulating cardiomyocyte hypertrophy.	[224]	
Abbreviations: ALDH2, Aldehyde Dehydrogenase 2; APP, Amyloid Precursor Protein; ARC, Apoptosis Repressor with CARD; ATF3, Activating Transcription Factor 3; ATM-DDR, Ataxia Telangiectasia Mutated, DNA Damage Response; CF, Cardiac Fibroblast; CMECs, Cardiac Microvascular Endothelial Cells; CMs, Cardiomyocytes; CTGF, Connective Tissue Growth Factor; DRG1, Developmentally Regulated GTP Binding Protein 1; DUSPs, Dual Specificity Phosphatases; ECM, Extracellular Matrix; ENO1, Enolase 1; FBW7, F-box and WD Repeat Domain Containing 7; FMT, Fibrotic Myofibroblast Transformation; FOXO3, Forkhead Box O3; FUS, Fused in Sarcoma; GSK-3β, Glycogen Synthase Kinase 3 Beta; HCFs, Human Cardiac Fibroblasts; IL-6, Interleukin 6; ITGB3, Integrin Subunit Beta 3; JNK, c-Jun N-terminal Kinase; KLF15, Kruppel Like Factor 15; MAPK, Mitogen-Activated Protein Kinase; Mfn2, Mitofusin 2; miRNA, MicroRNA; MMP9, Matrix Metallopeptidase 9; mTOR, Mammalian Target Of Rapamycin; NOS3, Nitric Oxide Synthase 3; NFAT, Nuclear Factor of Activated T-cells; NFATc1, Nuclear Factor of Activated T-cells, cytoplasmic 1; PDGF, Platelet-Derived Growth Factor; PI3K, Phosphoinositide 3-Kinase; PPARγ, Peroxisome Proliferator-Activated Receptor Gamma; PTEN, Phosphatase and Tensin Homolog; RhoA, Ras Homolog Family Member A; RYR2, Ryanodine Receptor 2; SERCA2A, Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2A; Smad3, SMAD Family Member 3; Smad7, SMAD Family Member 7; STIL, SCL/TAL1 Interrupting Locus; Tescalcin, EF-Hand Calcium Binding Domain 6; TFR-1, Transferrin Receptor 1; THBS1, Thrombospondin 1; THBS1-AS1, Thrombospondin 1 Antisense RNA 1; TGF-β, Transforming Growth Factor Beta; TGFBR1, Transforming Growth Factor Beta Receptor 1; TIMP1, Tissue Inhibitor Of Metalloproteinases 1; VEGF-A, Vascular Endothelial Growth Factor A; VEGFB, Vascular Endothelial Growth Factor B; WHSC2, Wolf-Hirschhorn Syndrome Candidate 2.

3 The role and mechanisms of epigenetic modifications in cardiac cell death pathways

Cardiomyocyte death due to MIR is a crucial cause of heart failure. As the disease progresses, chronic factors such as hypertension, chronic ischemia, diabetes, or chronic valvular diseases continuously stress and damage cardiomyocytes, gradually inducing RCD. This programmed death of cardiomyocytes leads to cardiac remodeling, causing a progressive decline in cardiac function, ultimately manifesting as heart failure. In this process, epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNA regulation play key roles. For instance, changes in the methylation status of specific genes can influence cardiomyocyte survival and apoptosis [225], and alterations in the balance of histone acetylation and deacetylation may affect the heart's ability to respond to stress [226]. Additionally, the expression patterns of miRNAs and lncRNAs that regulate cardiomyocyte remodeling in the progression of cardiovascular diseases show significant changes. These molecules fine-tune gene expression, further impacting the heart's structure and function.

3.1 Necroptosis

Traditionally viewed as a passive, unregulated type of cell death, recent studies clearly demonstrate that necrosis is also a strictly regulated and intricately designed process involving complex molecular circuits [9,227] (Fig. 1). The necroptotic process is initiated by the activation of cell surface death receptors (such as FasR, TNFR1, IFN receptors, and TLRs) and intracellular RNA and DNA sensing molecules. Typically, TNF activates pro-inflammatory genes through the NF-κB signaling pathway, inducing an inflammatory response. After TNF binds to its receptor, TNFR1, a complex I consisting of TRADD, TRAF2, RIPK1, cellular inhibitors of apoptosis (cIAP1 or cIAP2), and the linear ubiquitin chain assembly complex (LUBAC) is recruited [228]. In complex I, cIAP and LUBAC promote RIPK1 ubiquitination through K63-linked and linear ubiquitin chains, providing a platform for recruiting downstream proteins such as TGF-activated kinase 1 (TAK1), TAK1-binding proteins 2/3 (TAB2/3), and the IκB kinase (IKK) complex composed of IKKα, IKKβ, and NEMO. The recruited downstream complexes activate the NF-κB and mitogen-activated protein kinase (MAPK) pathways, leading to increased expression of pro-inflammatory genes [228]. However, under certain conditions, such as instability of complex I or inhibition of RIPK1 ubiquitination, TNF can trigger the formation of a cytoplasmic apoptotic complex (complex IIa or IIb), comprising Fas-associated protein with a death domain (FADD) and caspase-8, which executes apoptosis (Table 4) [229].Fig. 1 Mechanisms of Cellular Necroptosis and Epigenetic Regulation. (a) Binding of TNF to TNFR1 on the cell surface promotes the assembly of the TNFR1-associated complex I, thereby generating NF-κB and MAPK signaling pathways that induce the expression of pro-inflammatory and pro-survival genes; (b) The secondary cytoplasmic complex II is nucleated by TRADD or RIPK1. Complex II only initiates apoptosis when cFLIP levels are reduced or mechanisms inhibiting RIPK1 activation are compromised; (c) In the event of caspase-8 elimination or inhibition, complex II becomes more stable as RIPK1 is not cleaved. Active RIPK1 can then trigger necroptotic cell death by promoting RIPK3 oligomerization and activation, which in turn phosphorylates MLKL. The oligomerization and translocation of phosphorylated MLKL to the plasma membrane facilitate cellular lysis; (d) The RIP1-RIP3 necrosome induces necroptotic cardiomyocyte death through MLKL, CaMKII, PGAM5, and JNK. CaMKII and PGAM5/CypD induce the opening of the mitochondrial permeability transition pore, also known as MPT necrosis. PGAM5/Drp1 mediates mitochondrial fission. Iron pool instability, leading to oxidative stress, is exacerbated by JNK-mediated ferritin degradation. MLKL serves as a principal effector of membrane rupture in necroptotic cell death. Necroptotic factors are stringently regulated by SIRT3 and a range of noncoding RNAs in epigenetics. AS, Antisense; CaMKII, Calcium/Calmodulin-Dependent Protein Kinase II; CASP, Caspase; CFLIP, Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; CypD, Cyclophilin D; DAMPs, Damage-associated molecular patterns; DCM, Diabetic Cardiomyopathy; DR4/5, Death Receptor 4/5; Drp1, Dynamin-related protein 1; FADD, Fas-Associated protein with Death Domain; FAS, Fas Cell Surface Death Receptor; IFNR, Interferon Receptor; IKK, IκB kinase; IκBα, Inhibitor of kappa B alpha; JAK, Janus Kinase; JNK, c-Jun N-terminal kinases; K48, Lysine 48; K63, Lysine 63; LncNR, Long Noncoding RNA; LUBAC, Linear Ubiquitin Chain Assembly Complex; MAPK, Mitogen-Activated Protein Kinase; MI, Myocardial Infarction; MLKL, Mixed Lineage Kinase Domain-Like Protein; mPTP, Mitochondrial Permeability Transition Pore; NEMO, NF-kappa-B essential modulator; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; PGAM5, Phosphoglycerate Mutase Family Member 5; RIPK1, Receptor-interacting serine/threonine-protein kinase 1; ROS, Reactive Oxygen Species; SIRT3, Sirtuin 3; STAT, Signal Transducer and Activator of Transcription; TAB2/3, TAK1-binding protein 2/3; TAK1, TGF-beta activated kinase 1; TLR4, Toll-Like Receptor 4; TNF, Tumor Necrosis Factor; TNFR1, TNF Receptor 1; TRADD, TNFR1-associated death domain protein; TRAF2, TNF Receptor Associated Factor 2; TRAIL, TNF-related apoptosis-inducing ligand; TRIF, TIR-domain-containing adapter-inducing interferon-β; ZBP1, Z-DNA binding protein 1.

Fig. 1

Table 4 Epigenetic regulation of necroptosis in cardiovascular diseases.

Table 4Types of epigenetic	Diseases	Major regulator	Targets	Role in CVD	Ref	
Histone modification	DCM	SIRT3	RIPK1/RIPK3/cleaved caspase 3	The deficiency of SIRT3 upregulates the expression of necroptotic apoptosis-associated proteins, such as RIPK1, RIPK3, and cleaved caspase-3.	[230]	
Noncoding RNAs	MIR	miR-223-5p/3p	TNFR1/IκBα	TNFR1 is a direct target of miR-223-5p, whereas miR-223-3p directly inhibits the expression of NLRP3 and IκB kinase α, both of which are known mediators involved in I/R-induced inflammation and necroptotic apoptosis.	[231]	
	MIR	miR-105	RIP3	miR-105, as a miRNA, directly inhibits the expression of RIP3 and BNIP3, both critical mediators in cellular necroptosis and apoptosis.	[232]	
	MI	miR-325-3p	RIPK1/RIPK3/p-MLKL	The necroptotic apoptosis induced by the RIPK1/RIPK3/p-MLKL axis during MI is mediated by the miRNA module miR-325-3p, which effectively improves MI symptoms by inhibiting the expression of RIPK3.	[233]	
	MI	miR-103	FADD/RIPK	miR-103's potential role in MI treatment involves targeting the FADD/RIPK pathway.	[234]	
	AS	miR-223-3p	RIPK3	miR-223-3p improves advanced atherosclerosis by targeting Ripk3 within a negative feedback loop to prevent necroptotic macrophage death.	[235]	
	AS	miR-210	Decr1	miR-210 induces a cellular energy crisis by inhibiting Decr1, leading to reduced mitochondrial ATP production, thus favoring activation of the necroptotic pathway over survival pathways.	[236]	
	AS	miR-383	Parg	miR-383 stabilizes cellular energy status and reduces necroptotic death by inhibiting Parg to prevent excessive energy consumption during DNA repair.	[236]	
	MIR	Lnc-NRF	miR-873/RIPK1/RIPK3	Lnc-NRF acts as an endogenous sponge RNA, inhibiting the expression of miR-873, directly binding to it and regulating the expression of RIPK1/RIPK3, and necroptosis.	[237]	
	AS	Circ-HIPK3	DRP1	CircHIPK3 targets the protein DRP1, leading to increased mitochondrial fission rates, which in turn causes increased reactive oxygen species and impaired mitochondrial function, ultimately resulting in necroptotic apoptosis of VSMCs and vulnerable plaque formation.	[238]	
	MIR	Circ-CNEACR	HDAC7/FOXA2/RIPK3	CNEACR directly interacts with cytoplasmic histone deacetylase (HDAC7), interfering with its nuclear entry. This leads to diminished transcriptional repression by FOXA2, which is HDAC7-dependent, and inhibits RIPK3-dependent necroptotic/necrotic death in cardiomyocytes.	[106]	
Abbreviations: DCM, Diabetic Cardiomyopathy; CVD, Cardiovascular Disease; MI, Myocardial Infarction; AS, Atherosclerosis; Decr1, 2,4-dienoyl CoA reductase; Parg, Poly (ADP-ribose) glycohydrolase; DRP1, Dynamin-Related Protein 1; HDAC7, Histone Deacetylase 7; FOXA2, Forkhead Box A2.

3.2 Pyroptosis

Pyroptosis is an inflammatory RCD pathway utilized by various cell types, triggered by human caspases such as caspase-1, -3, -4, -5 (caspase-11 in mice), −6, −8, and −9, and activated by multiple inflammasomes including NLRP3, AIM2, NLRP1, PYRIN, and NLRC4 [[239], [240], [241]]. Inflammasomes activate caspase-1, which cleaves GSDMD, typically at its N-terminal domain, thus inducing pyroptosis [242]. Additionally, caspase-8 and caspase-3 can directly cleave GSDMD to induce pyroptosis [240] (Fig. 2). Common epigenetic modifications such as m6A methylation, histone modifications, and non-coding RNAs regulate cell death, impacting the development and prognosis of cardiovascular diseases (Table 5)。Fig. 2 Mechanisms of Cellular Pyroptosis and Epigenetic Regulation. (a). Activation of the NLRP3 Inflammasome: The initiation process is driven by the activation of NF-κB, triggered by membrane TLR4/IL-1R and Myd88 cascade. Lysosomal instability caused by crystals and indigestible substances is another mechanism leading to NLRP3 activation, mediated through the leakage of lysosomal enzyme cathepsin B and K+ induction. Mitochondrial damage and dysfunction generate ROS, resulting in the dissociation of TXNIP from TRX, allowing TXNIP to bind with NLRP3. Ineffective clearance of dysfunctional mitochondria through mitophagy results in lysosomal instability. Conversely, efficient mitophagy and autophagy limit NLRP3 activation; (b). Canonical Pathway: Classical inflammasomes, including NLRP1, NLRP3, NLRC4, AIM2, and PYRIN, typically comprise PRRs, ASC, and pro-caspase-1. PRR activation facilitates inflammasome formation, activating caspase-1, which cleaves GSDMD into GSDMD-N and processes pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18, respectively. These cytokines are then released through non-selective pores formed by GSDMD-N; (c). Non-Canonical Pathway: Extracellular Gram-negative bacterial LPS directly activate caspase-4/5/11, triggering pyroptosis via GSDMD cleavage. Additionally, GSDMD cleavage induces K+ efflux, subsequently activating the NLRP3/caspase-1 pathway, culminating in the release of mature IL-1β and IL-18 through the formed pores; (d). Caspase-Mediated Pathway: Chemotherapeutic agents trigger GSDME-dependent pyroptosis following caspase-3 activation. Cyt c binds Apaf-1, promoting the formation of the Apaf-1 apoptosome and caspase-9 activation, which subsequently activates caspase-3, leading to GSDME cleavage and pyroptosis. Under TNF-α activation, caspase-8 specifically cleaves GSDMC into GSDMC-N, forming pores in the cell membrane, resulting in cellular swelling, lysis, and death; (e). Gasdermin-Mediated Pathway: In CTL and NK cells, GZMA is delivered to target cells using perforin, subsequently cleaving GSDMB at the Lys244 inter-domain linker, inducing target cell pyroptosis. GZMB can cleave GSDME at the caspase-3 site, leading to pyroptosis. Additionally, Streptococcus pyogenes secreted SpeB directly and selectively cleaves GSDMA at Gln246, releasing the N-terminal domain which binds to lipid species in the inner leaflet of the plasma membrane, forming pores and inducing keratinocyte pyroptosis. AIM2, Absent in Melanoma 2; Apaf-1, Apoptotic Protease Activating Factor 1; ASC, Apoptosis-Associated Speck-Like Protein; CatG, Cathepsin G; CTL, Cytotoxic T Lymphocytes; Cyt c, Cytochrome c; ELANE, Neutrophil Elastase; GAS, Group A Streptococcus; GSDMA, Gasdermin A; GSDMB, Gasdermin B; GSDMC, Gasdermin C; GSDMD, Gasdermin D; GSDMD-N, N-terminal fragment of Gasdermin D; GSDME, Gasdermin E; GZMA, Granzyme A; GZMB, Granzyme B; IL-1R, Interleukin-1 Receptor; IL-1β, Interleukin-1 Beta; IL-18, Interleukin-18; LPS, Lipopolysaccharides; NF-κB, Nuclear Factor-kB; NK, Natural Killer (cells); NLRC4, NLR Family CARD Domain Containing 4; NLRP1, NLR Family Pyrin Domain Containing 1; NLRP3, NLR Family Pyrin Domain Containing 3; PRR, Pattern-Recognition Receptor; PRRs, Pattern Recognition Receptors; ROS, Reactive Oxygen Species; SpeB, Streptococcal Pyrogenic Exotoxin B; TLR, Toll-Like Receptor; TNF-α, Tumor Necrosis Factor Alpha; TRX, Thioredoxin; TXNIP, Thioredoxin-Interacting Protein.

Fig. 2

Table 5 Epigenetic regulation of pyroptosis in cardiovascular diseases.

Table 5Types of epigenetic	Diseases	Major r egulator	Targets	Role in CVD	Ref	
Methylation	MIR	METTL3	DGCR8/miR-143-3p	METTL3 enhances miR-143-3p expression through m6A modification of DGCR8 and pri-miR-143-3p binding, thereby inhibiting PRKCE transcription, which exacerbates cardiomyocyte apoptosis and MIR injury.	[243]	
	MIR	ALKBH5	miR-199a-5p/TRAF3	Silencing of ALKBH5 inhibits the expression of pri-miR-199a-5p, increases its m6A modification, and promotes the maturation and enhanced expression of miR-199a-5p, thus reducing TRAF3 expression to mitigate cellular apoptosis and alleviate MIR.	[244]	
	DCM	METTL14	Lnc-TINCR l	METTL14 increases the m6A methylation levels of the TINCR gene, leading to its downregulation, which inhibits apoptosis and DCM.	[44]	
	AS	METTL14	Lnc-NEAT1	METTL14 binds to m6A sites on Lnc-NEAT1 and promotes its expression through subsequent recognition by YTHDC1, thereby enhancing endothelial cell apoptosis.	[245]	
	ACS	METTL3	–	In ACS patients, METTL3 expression is significantly elevated in macrophages, and inhibition of METTL3 attenuates macrophage apoptosis.	[246]	
	CF	DNMT3A	Lnc-NEAT1	DNMT3A methylation decreases the expression of lncRNA Neat1 and promotes CFs pyroptosis and CF	[247]	
	CF	DNMT1	Lnc-ANRIL	DNMT1 methylation of LncRNA-ANRIL causes myocardial fibrosis pyroptosis by interfering with the NLRP3/Caspase-1 pathway	[248]	
	CF	DNMT1	Lnc-GAS5	DNMT1 Methylation of LncRNA GAS5 Leads to Cardiac Fibroblast Pyroptosis via Affecting NLRP3 Axis	[249]	
	CF	DNMT4	MTHFR	MTHFR epigenetic derepression protects against diabetes CF	[250]	
	DIC	FTO	TLR4/NF-κB	FTO mediates the demethylation of m6A on TLR4, regulating the binding activity of YTHDF1 to TLR4 mRNA, downregulating TLR4, and thereby inhibiting Dox-induced cardiomyocyte apoptosis, inflammation, and oxidative stress through the TLR4/NF-κB pathway.	[251]	
Histone modification	MI	SIRT1	–	Exosomes secreted by hMSCs contain LncRNA KLF3-AS1 acting as ceRNA to sequester miR-138-5p, modulating Sirt1 to inhibit cellular apoptosis and attenuate MI progression.	[252]	
	MI	SIRT3	NLRP3	miR-15b-5p enhances H/R-induced cardiomyocyte apoptosis by targeting SIRT3 and activating the NLRP3 inflammasome.	[253]	
	MIR	SIRT1	Akt	SIRT1 agonists inhibit NLRP3 inflammasome activation during I/R injury through Akt-dependent metabolic regulation.	[254]	
	MIR	SIRT 6	AIM2/GSDMD	Exosomes enriched with Sirt6 modulate MIRI progression by regulating apoptosis-related targets AIM2 and GSDMD, and autophagy-related p62 and Beclin-1.	[255]	
	MIR	KAT5	LATS2/YAP/β-catenin	KAT5 enhances STUB1 transcription through acetylation regulation, leading to LATS2 ubiquitination and degradation, activating the YAP/β-catenin pathway, and inhibiting NLRP3-mediated cardiomyocyte apoptosis, thereby alleviating MIRI.	[256]	
	DCM	SIRT 3	FOXO3a	CD38 deficiency protects mice from diabetes-induced cardiomyopathy by activating the NAD+/Sirt3/FOXO3a signaling pathway, reducing apoptosis.	[257]	
	DCM	SIRT5	GSTP1	SIRT5-mediated depropionylation of GSTP1 lysine helps inhibit cardiomyocyte apoptosis in DCM.	[141]	
	AS	SIRT1	Nrf2	Oxymatrine may alleviate ox-LDL-induced HUVEC damage by activating the SIRT1/Nrf2 pathway and inhibiting NLRP3 inflammasome-mediated apoptosis.	[258]	
	AS	SIRT 3	FOXO3a/ROS	Melatonin mitigates apoptosis by modulating the SIRT3/FOXO3α/ROS axis and interacting with cellular apoptosis in the progression of atherosclerosis.	[259]	
	AS	SIRT6	Lin28b/let-7	Sirt6 inhibits endothelial cell apoptosis by negatively regulating the Lin28b/let-7 pathway in AS.	[260]	
	AS	HDAC11	NLRP3/caspase-1/caspase-3	HDAC11 may promote apoptosis through regulating ERG acetylation in HUVECs, activating NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways.	[153]	
	DIC	SIRT1	Nrf2	Activation of the Sirt1/Nrf2 pathway is a potential mechanism by which melatonin inhibits oxidative stress, apoptosis, and necrosis in DOX-induced cardiomyopathy.	[261]	
	DIC	SIRT3	AMPK	SIRT3 is a direct target of miR-34a-5p; inhibiting miR-34a-5p can restore Sirt3 expression, thus improving DOX-induced cardiomyocyte apoptosis.	[262]	
	SIC	SIRT1	NLRP3/GSDMD	Syringaldehyde (SYR) improves SIC through the ER/SIRT1/NLRP3/GSDMD pathway.	[263]	
	CME	SIRT1	NLRP3	Colchicine alleviates cardiomyocyte apoptosis by increasing AMPK phosphorylation levels, promoting SIRT1 expression, and inhibiting NLRP3 expression.	[264]	
	CME	HDAC2	SMAD7	HDAC2 inhibits SMAD7 expression by catalyzing H3K27 deacetylation at its promoter; miR-30e-3p binds HDAC2 to enhance SMAD7 expression, reducing CME-induced cardiomyocyte apoptosis and inflammation.	[265]	
	CME	HDAC3	NOL3	ATXN1L promotes H3 deacetylation through HDAC3, inhibiting NOL3 expression; the HDAC3/NOL3 axis affects cardiomyocyte apoptosis.	[266]	
	CHK1i-induced CT	SIRT3	–	Mitochondrial CHK1 directly phosphorylates SIRT3, promoting its expression within mitochondria; overexpressed SIRT3 maintains mitochondrial function, thereby ameliorating cardiomyocyte apoptosis and improving cardiac function in mice.	[267]	
	MI	miR-1	FOXO3a/PIK3R1	miRNA-1 promotes cardiomyocyte apoptosis and the release of inflammatory factors by downregulating PIK3R1 expression.	[268]	
Noncoding RNAs	MI	miR-100-5p	FOXO3/NLRP3	miR-100-5p suppresses FOXO3 expression, thereby inhibiting NLRP3 inflammasome activation and cytokine release, protecting cardiomyocytes from H/R-induced apoptosis and damage.	[269]	
	MI	miR-135b	NLRP3/caspase-1/IL-1β	miR-135b inhibits apoptosis through suppression of the NLRP3/caspase-1/IL-1β pathway.	[270]	
	MI	miR-654-3p	–	Overexpression of miR-654-3p prevents myocardial fibrosis and inflammatory infiltration, reducing apoptosis characteristics and alleviating heart damage caused by MI.	[271]	
	MI	miR-378a-3p	NLRP3/Caspase-1/GSDMD	miR-378a-3p in M2-EV encapsulations inhibits HuR expression and cytoplasmic translocation, destabilizing NLRP3 and blocking the NLRP3/Caspase-1/GSDMD pathway, thereby reducing cardiomyocyte apoptosis.	[272]	
	MI	Circ-Helz	miR-133a-3p/NLRP3	Circ-Helz activates the NLRP3 inflammasome and exacerbates myocardial injury by sequestering miR-133a-3p in ischemic mouse hearts.	[273]	
	MI	Circ-Rbms1	miR-142-3p/MST1	Circ-Rbms1 promotes cardiac dysfunction and apoptosis in mice via the miR-142-3p/MST1 axis.	[274]	
	MI	Lnc-FAF	miR-185-5p/PAK2	lncRNA FAF acts as a sponge for miR-185-5p and promotes PAK2 expression in cardiomyocytes, reducing apoptosis, enhancing cellular vitality, and diminishing infarct size.	[275]	
	MI	Lnc-KLF3-AS1	miR-138-5p/SIRT1	LncRNA KLF3-AS1 serves as ceRNA for miR-138-5p, modulating Sirt1 to inhibit cellular apoptosis and attenuate MI progression.	[252]	
	MI	Lnc-H19	PBX3/CYP1B1	H19 may reduce cardiomyocyte apoptosis by inhibiting CYP1B1 expression via a PBX3-dependent mechanism.	[276]	
	MI	Lnc-MIAT	SF1/CGRP	Lnc-MIAT binds SF1 to inhibit CGRP transcription, thereby promoting hypoxia-induced apoptosis in H9C2 cells.	[277]	
	MI	Lnc-TUG1	FUS	HIF-1α-induced TUG1 binds with FUS to promote mitochondrial damage and cardiomyocyte apoptosis, facilitating MI onset.	[278]	
	MI	Lnc-MEG3	TAF15/AIM2	Lnc-MEG3 and AIM2 mRNA interact with TAF15; MEG3 regulates TAF15 to enhance AIM2 mRNA stability.	[279]	
	MIR	miR-29a	SIRT1/NLRP3	Inhibition of miR-29a ameliorates myocardial I/R injury by targeting SIRT1, reducing oxidative stress, and NLRP3-mediated apoptosis.	[280]	
	MIR	miR-29b	FOXO3a/ARC	miR-29b exacerbates apoptosis by inhibiting the FoxO3a/ARC axis.	[281]	
	MIR	miR-148a	TXNIP/TLR4/NF-κB/NLRP3	miR-148a alleviates MIR injury by downregulating TXNIP and inhibiting the TLR4/NF-κB/NLRP3 inflammasome signaling pathway.	[282]	
	MIR	miR-149	FOXO3	MiR-149 exacerbates cardiomyocyte apoptosis in MIR by silencing FoxO3.	[283]	
	MIR	miR-320b	NLRP3	miR-320b targets NLRP3 to inhibit apoptosis and protect the myocardium from ischemia/reperfusion injury.	[284]	
	MIR	miR-383	RP105/AKT	miR-383 promotes apoptosis via the RP105/PI3K/AKT signaling pathway.	[285]	
	MIR	miR-424	CRISPLD2	miR-424 directly targets CRISPLD2 and upregulates caspase-1 and pro-inflammatory cytokines IL-1β and IL-18.	[286]	
	MIR	miR-703	NLRP3/caspase-1	miR-703 prevents H/R-induced cardiomyocyte damage by inhibiting NLRP3/caspase-1-mediated apoptosis.	[287]	
	MIR	miR-22	NLRP3	miR-22 inhibits H/R-induced apoptosis enhanced by EZH2 overexpression in HUVECs.	[288]	
	MIR	miR-15b-5p	SIRT3/NLRP3	miR-15b-5p increases H/R-induced cardiomyocyte apoptosis by targeting SIRT3 and activating the NLRP3 inflammasome.	[253]	
	MIR	miR-182-5p	GSDMD	miRNA-182-5p alleviates myocardial ischemia/reperfusion injury in mice by targeting GSDMD.	[289]	
	MIR	miR-132	SIRT1/PGC-1α/Nrf2	Inhibition of miR-132 improves myocardial I/R injury by activating the PGC-1α/Nrf2 signaling pathway, targeting SIRT1 to reduce oxidative stress and apoptosis.	[290]	
	MIR	Circ-HMGA2	–	Circ-HMGA2 depletion alleviates myocardial tissue damage in MIR mice by reducing oxidative stress and apoptosis.	[291]	
	MIR	Circ-NNT	miR-33a-5p/USP46	Circ-NNT acts as a sponge for miR-33a-5p, regulating USP46 to promote apoptosis and exacerbate myocardial I/R injury.	[292]	
	MIR	Circ-PAN3	miR-29b-3p/SDF4	Circ-PAN3 targets miR-29b-3p through a ceRNA mechanism in MIRI, impacting SDF4 to alleviate myocardial injury and apoptosis.	[293]	
	MIR	Lnc-Neat1	NLRP3	Lnc-Neat1 promotes activation of the NLRP3 inflammasome and apoptosis.	[294]	
	MIR	Lnc-PVT1	GSDMD	Silencing Lnc-PVT1 alleviates myocardial I/R injury by inhibiting GSDMD-mediated apoptosis in vivo and in vitro.	[295]	
	MIR	Lnc-Rian	miR-17-5p/CCND1	Lnc-Rian alleviates cardiomyocyte apoptosis and MIR by regulating the miR-17-5p/CCND1 axis.	[296]	
	MIR	Lnc-ROR	miR-185-5p/CDK6	Inhibition of Lnc-ROR mitigates I/R-induced apoptosis and inflammation through the miR-185-5p/CDK6 axis.	[297]	
	DCM	miR-9	ELAVL1	MiRNA-9 inhibits ELAVL1 targeting, suppressing high glucose-induced apoptosis in human ventricular cardiomyocytes.	[298]	
	DCM	miR-21-3p	AR	miR-21-3p exacerbates STZ-induced diabetic CF by inhibiting AR expression through the caspase-1 pathway.	[299]	
	DCM	miR-30d	FOXO3a	MiRNA-30d directly targets foxo3a, inhibiting its expression and downstream apoptotic inhibitory factor ARC (apoptosis repressor with caspase recruitment domain).	[300]	
	DCM	miR-18a-3p	GSDMD	miR-18a-3p targets GSDMD and alleviates apoptosis in high glucose-treated H9C2 cells.	[301]	
	DCM	miR-135b	Caspase-1	miR-135b directly binds to caspase-1, inhibiting apoptosis and collagen deposition.	[302]	
	DCM	miR-223-3p	SPI1/caspase-1/IL-1β	miR-223-3p promotes cardiomyocyte apoptosis and inflammasome cytokine release by downregulating SPI1 (PU.1).	[303]	
	DCM	Circ-0071269	miR-145/GSDMA	Knockdown of Circ-0071269 prevents diabetes-induced cardiomyopathy damage mediated by the miRNA-145/gasdermin A axis.	[304]	
	DCM	Circ-CACR	miR-214-3p/Caspase-1	Circ-CACR promotes apoptosis in DCM through the CACR/miR-214-3p/caspase-1 pathway.	[305]	
	DCM	Circ-DICAR	VCP/Med12	Circ-DICAR acts as a novel endogenous regulator in DCM and apoptosis; DICAR-VCP-Med12 degradation may underlie its mediated effects.	[306]	
	DCM	Lnc-KCNQ1OT1	miR-214-3p/Caspase-1	Overexpression of Kcnq1ot1 in DCM can be silenced to inhibit apoptosis by affecting miR-214-3p and caspase-1 expression.	[307]	
	DCM	Lnc-GAS5	miR-34b-3p/AHR	Lnc-GAS5 acts as a competitive endogenous RNA by sequestering miR-34b-3p to enhance AHR expression, thereby inhibiting NLRP3 inflammasome-mediated apoptosis to improve DCM.	[308]	
	DCM	Lnc-MALAT1	miR-141-3p	Lnc-MALAT1 promotes high glucose-induced apoptosis in H9C2 cardiomyocytes by downregulating miR-141-3p expression.	[309]	
	DCM	Lnc-MIAT	miR-214-3p/CASP1	Lnc-MIAT regulates apoptosis in DCM by targeting miR-214-3p.	[310]	
	AS	miR-30c-5p	FOXO3a/NLRP3	miR-30c-5p may play a significant role in NLRP3 inflammasome-regulated apoptosis in HAECs by targeting FOXO3.	[311]	
	AS	miR-125a-5p	TET2	miR-125a-5p post-transcriptionally suppresses TET2 expression, leading to abnormal DNA methylation, mitochondrial dysfunction, increased ROS production, NF-κB activation, inflammasome activation and maturation, release of pro-inflammatory cytokines IL-1β and IL-18, and apoptosis.	[312]	
	AS	miR-181b-5p	STAT3	miR-181b-5p alleviates NLRP3 inflammasome-dependent apoptosis by inhibiting STAT-3 gene expression.	[313]	
	AS	miR-20a	TLR4/TXNIP/NLRP3	miR-20a protects HAECs from inflammatory damage and inhibits atherosclerosis progression by negatively regulating TLR4 and NLRP3 signaling.	[314]	
	AS	miR-9	JAK1/STAT1/NLRP3	miR-9 may reduce atherosclerosis-related inflammation by inhibiting the NLRP3 inflammasome activation via the JAK1/STAT1 signaling pathway.	[315]	
	AS	miR-181a	MEK/ERK/NF-κB/NLRP3	miR-181a regulates the activity of the NLRP3 inflammatory pathway by targeting MEK1 and altering MEK/ERK/NF-κB pathway activity.	[316]	
	AS	miR-33	ABCA1	miR-33 promotes apoptosis by targeting and inhibiting ABCA1, thereby promoting macrophage cholesterol efflux and the development of atherosclerotic plaques.	[317]	
	AS	miR-126-3p	DKK1/LRP6	ERK1/2 inhibition promotes miR-126-3p maturation through AMPKα-mediated p53 phosphorylation, playing a key role in the anti-calcification effects of miR-126-3p in ECs and SMCs under ERK1/2 inhibition.	[318]	
	AS	miR-155	ERK1/2	miR-155 via the ERK1/2 pathway enhances ox-LDL induced NLRP3 inflammasome activation in THP-1 macrophages, exacerbating atherosclerosis in ApoE−/− mice.	[319]	
	AS	miR-145	CD137/NFATc1	Reduced miR-145 via CD137/NFATc1 signaling leads to NLRP3 inflammasome activation.	[320]	
	AS	miR-200a-3p	SIRT1/NF-κB/NLRP3	Inhibition of miRNA-200a-3p alleviates cell apoptosis induced by H2O2 in HAECs through the SIRT1/NF-κB/NLRP3 pathway.	[321]	
	AS	miR-455-5p	ESRRG/NLRP3	miR-455-5p inhibits apoptosis by suppressing ESRRG and NLRP3.	[322]	
	AS	miR-199a-5p	SMARCA4/PODXL/NF-κB	EV-packaged inhibition of miR-199a-5p in macrophages accelerates endothelial cell apoptosis via the SMARCA4/PODXL/NF-κB axis, further accelerating the formation of atherosclerosis.	[323]	
	AS	miR-223-3p	STAT3	STAT3 is a potential target gene of miR-223-3p. Transfection with miR-223 inhibitors upregulates apoptosis-related proteins and ICAM-1 expression in ECs and downregulates NO levels.	[324]	
	AS	miR-302c-3p	NLRP3	MiRNA-302c-3p directly targets NLRP3 to inhibit endothelial cell apoptosis in atherosclerosis.	[325]	
	AS	miR-30b-5p	NLRP3	NLRP3 binds to miR-30b-5p and is negatively regulated by it.	[326]	
	AS	Circ-PPP1CC	HMGB1/TLR9/AIM2	Circ-PPP1CC promotes Pg-LPS-induced vascular smooth muscle cell apoptosis via the HMGB1/TLR9/AIM2 pathway.	[327]	
	AS	Circ-0090231	miR-635/NLRP3	Circ-0090231/miR-635/NLRP3 axis influences the development of AS by regulating cell apoptosis.	[328]	
	AS	Circ-USP9	EIF4A3/GSDMD	Circ-USP9 interacts with EIF4A3 to enhance GSDMD stability, further promoting ox-LDL induced HUVEC apoptosis.	[329]	
	AS	Lnc-00657	miR-106b-5p/TXNIP/NLRP3	Lnc-00657 stimulates macrophage apoptosis via the miR-106b-5p/TXNIP/NLRP3 pathway, exacerbating the progression of AS.	[330]	
	AS	Lnc-MALAT1	miR-30c-5p/Cx43	Lnc-MALAT1 may play a crucial role in TNF-α-mediated apoptosis in RAOEC cells by regulating the miR-30c-5p/Cx43 axis.	[331]	
	AS	Lnc-MALAT1	miR-22	Lnc-MALAT1 promotes high glucose-induced endothelial cell apoptosis partly by competitively binding miR-22 to influence NLRP3 expression.	[332]	
	AS	Lnc-MEG3	miR-223/NLRP3	Lnc-MEG3 enhances apoptosis in HAECs by inhibiting miR-223 function and increasing NLRP3 expression.	[333]	
	AS	Lnc-NEXN-AS1	NEXN	The Lnc-NEXN-AS1/NEXN pathway inhibits apoptosis in human vascular endothelial cells.	[334]	
	AS	Lnc-HCG11	miR-224-3p/JAK1	Knockdown of HCG11 alleviates ox-LDL-induced apoptosis and inflammation via the miR-224-3p/JAK1 axis.	[335]	
	AS	Lnc-RP11-490M8.1	TLR4/NF-κB	Lnc-RP11-490M8.1 inhibits LPS-induced apoptosis through the TLR4/NF-κB pathway.	[336]	
	AS	Lnc-AU020206	CEBPB/NLRP3	Lnc-AU020206 alleviates macrophage apoptosis in atherosclerosis by blocking CEBPB-mediated NLRP3 transcriptional activation.	[337]	
	AS	Lnc-NEAT1	KLF4	NEAT1 induces endothelial cell apoptosis by binding to KLF4, promoting the transcriptional activation of the critical apoptotic protein NLRP3.	[245]	
	AS	Lnc-Gaplinc	SP1	Lnc-Gaplinc promotes vascular endothelial cell apoptosis by enhancing NLRP3 transcription through SP1 binding, thus playing a role in atherosclerosis.	[338]	
	HF	miR-133a-3p	IKKε	miR-133a-3p alleviates myocardial cell hypertrophy induced by Ang II by targeting IKKε to inhibit apoptosis.	[339]	
	HF	miR-351	MLK3	miR-351 improves stress-induced myocardial fibrosis by inhibiting the NF-κB/NLRP3-mediated inflammatory and apoptotic pathways, and the JNK/p53 pathway-mediated oxidative damage and ferroptosis, through MLK3.	[340]	
	HF	Lnc-HOTAIR	miR-17-5p/RORA	HOTAIR competitively binds miR-17-5p, mitigating its repression of RORA transcription, leading to increased RORA expression and inhibiting cardiomyocyte apoptosis in the HF model.	[191]	
	DIC	miR-34a-5p	SIRT3/AMPK	Inhibition of miR-34a-5p mitigates cardiomyocyte apoptosis by regulating the Sirt3-AMPK pathway in DOX-induced autophagy disruption.	[262]	
	SIC	miR-590-3p	AMPK/Mtor/NLRP3	AMPK/mTOR signaling is involved in miR-590-3p-regulated cardiomyocyte autophagy and apoptosis.	[341]	
	SIC	miR-206	RhoB/ROCK	miR-206 inhibits sepsis-induced cardiomyocyte apoptosis through the RhoB/ROCK pathway.	[342]	
	SIC	Lnc-SOX2OT	EZH2/Nrf-2/NLRP3	Lnc-SOX2OT mediates the EZH2/Nrf-2/NLRP3 signaling pathway to inhibit apoptosis and improve sepsis-induced myocardial damage.	[343]	
	AAD	miR-133a	NLRP3	miR-133a inhibits apoptotic pathways and rescues acute aortic dissection.	[344]	
	AAA	LncRNA PVT1	miR-186-5p/HMGB1	M1 Macrophage-Derived Exosome LncRNA PVT1 Promotes Inflammation and Pyroptosis of Vascular Smooth Muscle Cells in AAA by Inhibiting miR-186-5p and Regulating HMGB1	[345]	
	UC	miR-155	FOXO3	miR-155 directly targets FoxO3a, promoting cardiomyocyte apoptosis and uremic cardiomyopathy changes (cardiac hypertrophy and fibrosis).	[346]	
	AF	Lnc-XIST	miR-214-3p/Arl2	Lnc-XIST inhibits myocardial apoptosis in atrial fibrillation by disrupting the miR-214-3p-mediated inhibition of Arl2.	[347]	
	CF	Lnc-GAS5	mir-217/SIRT1	LncRNA GAS5 restrains ISO-induced CF by modulating mir-217 regulation of SIRT1	[348]	
	CME	miR-200a-3p	TXNIP/NLRP3	miR-200a-3p Attenuates Coronary Microembolization-Induced Myocardial Injury in Rats by Inhibiting TXNIP/NLRP3-Mediated Cardiomyocyte Pyroptosis	[349]	
	CME	miR-136-5p	ATXN1L/CIC/PYDC1	miR-136-5p suppressed pyroptosis by upregulating PYDC1 via ATXN1L/CIC axis, thereby attenuating cardiac damage caused by CME	[350]	
	CME	Lnc-TUG1	miR-186-5p/XIAP	Overexpression of Lnc-TUG1 alleviates NLRP3 inflammasome-mediated cardiomyocyte apoptosis through targeting the miR-186-5p/XIAP axis.	[351]	
	CME	Lnc-Sox2OT	miR-23b/TLR4/NF-κB	Silencing Lnc-Sox2OT inhibits CME-induced MI by eliminating Sox2OT/miR-23b binding and downregulating the TLR4/NF-κB pathway.	[352]	
Abbreviations: AAA, Abdominal Aortic Aneurysm; AAD, Acute Aortic Dissection; ABCA1, ATP Binding Cassette Subfamily A Member 1; ACS, Acute Coronary Syndrome; AF, Atrial Fibrillation; AIM2, Absent In Melanoma 2; AS, Atherosclerosis; AHR, Aryl Hydrocarbon Receptor; ALKBH5, AlkB homolog 5; AMPK, AMP-activated Protein Kinase; AMPKα, AMP-activated Protein Kinase Alpha; Arl2, ADP Ribosylation Factor Like GTPase 2; AR, Androgen Receptor; AS, Atherosclerosis; ATXN1L, Ataxin 1 Like; CF, Cardiac Fibrosis; CASP1, Caspase 1; CEBPB, CCAAT Enhancer Binding Protein Beta; CGRP, Calcitonin Gene-Related Peptide; CH, Cardiac Hypertrophy; CHK1, Checkpoint Kinase 1; CHK1i, Checkpoint Kinase 1 Inhibitor; CP, Cardiomyocyte Proliferation; CT, CHK1 inhibition-induced Cardiotoxicity; CYP1B1, Cytochrome P450 Family 1 Subfamily B Member 1; CCND1, Cyclin D1; CDK6, Cyclin-Dependent Kinase 6; CME, Coronary Microembolization; DCM, Diabetic Cardiomyopathy; DGCR8, DiGeorge syndrome critical region gene 8; DIC, DOX-Induced Cardiomyopathy; DKK1, Dickkopf WNT Signaling Pathway Inhibitor 1; EC, Endothelial Cell, EIF4A3, Eukaryotic Translation Initiation Factor 4A3; ELAVL1, ELAV Like RNA Binding Protein 1; ERG, ETS-related gene; ERK, Extracellular Signal-regulated Kinase; ESRRG, Estrogen Related Receptor Gamma; EZH2, Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit; FOXO3a, Forkhead Box O3a; FUS, Fused in Sarcoma; GSDMA, Gasdermin A; GSDMD, Gasdermin D; GSDME, Gasdermin E; GSTP1, Glutathione S-transferase Pi 1; HDAC2, Histone Deacetylase 2; HDAC3, Histone Deacetylase 3; HDAC11, Histone Deacetylase 11; HF, Heart Failure; HMGB1, High Mobility Group Box 1; HUVECs, Human Umbilical Vein Endothelial Cells; IKKε, Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon; IL-1β, Interleukin 1 Beta; JAK1, Janus Kinase 1; JNK, c-Jun N-terminal Kinase; KAT5, K(lysine) Acetyltransferase 5; KCNQ1OT1, KCNQ1 Opposite Strand/Antisense Transcript 1; KLF4, Kruppel Like Factor 4; LATS2, Large Tumor Suppressor Kinase 2; LRP6, Low-density Lipoprotein Receptor-related Protein 6; Med12, Mediator Complex Subunit 12; MEK, Mitogen-activated Protein Kinase Kinase; METTL3, Methyltransferase Like 3; MI, Myocardial Infarction; MIR, Myocardial Ischemia/Reperfusion Injury; MLK3, Mixed Lineage Kinase 3; MST1, Mammalian Sterile 20-like Kinase 1; mTOR, Mammalian Target of Rapamycin; NAD+, Nicotinamide Adenine Dinucleotide; NF-κB, Nuclear Factor Kappa-light-chain-enhancer of activated B cells; NFATc1, Nuclear Factor of Activated T-cells 1; NLRP3, NLR Family Pyrin Domain Containing 3; NOL3, Nucleolar Protein 3; Nrf2, Nuclear Factor Erythroid 2–Related Factor 2; PAK2, p21-activated Kinase 2; PBX3, Pre-B-cell Leukemia Transcription Factor 3; PIK3R1, Phosphoinositide-3-Kinase Regulatory Subunit 1; PODXL, Podocalyxin-like; PRKCE, Protein Kinase C Epsilon; RORA, RAR Related Orphan Receptor A; ROCK, Rho-associated Protein Kinase; ROS, Reactive Oxygen Species; RhoB, Ras Homolog Family Member B; SDF4, Stromal Cell Derived Factor 4; SF1, Steroidogenic Factor 1; SIC, Sepsis-Induced Cardiomyopathy; SIRT, Sirtuin; SMAD7, SMAD Family Member 7; SMARCA4, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 4; SPI1, Spi-1 Proto-Oncogene; SP1, Specificity Protein 1; STAT1, Signal Transducer and Activator of Transcription 1; STAT3, Signal Transducer and Activator of Transcription 3; TAF15, TATA-Box Binding Protein Associated Factor 15; TET2, Tet Methylcytosine Dioxygenase 2; TLR, Toll-Like Receptor; TRAF3, TNF Receptor Associated Factor 3; UC, Uremic Cardiomyopathy; USP46, Ubiquitin Specific Peptidase 46; VCP, Valosin Containing Protein; YAP, Yes-Associated Protein; β-catenin, Beta-Catenin.

3.3 Ferroptosis

Ferroptosis is cell death caused by excess iron ions entering the cell and inducing the Fenton reaction, leading to the disruption of cellular redox homeostasis, mitochondrial activity, amino acid, and lipid metabolism [353]. Lipid peroxidation triggered by polyunsaturated fatty acid phospholipid (PUFA-PL) synthesis, iron metabolism, and mitochondrial metabolism induces ferroptosis [354]. Conversely, systems such as GPX4-GSH, FSP1-CoQH, GCH1–BH4, and DHODH-CoQH2 can inhibit lipid formation, thus preventing ferroptosis [355] (Fig. 3).Fig. 3 Mechanisms of cellular ferroptosis and Epigenetic Regulation. When the ferroptosis activation system exceeds the ferroptosis inhibition system, the lethal accumulation of lipid peroxides on the plasma membrane leads to membrane rupture, causing ferroptosis-related cell death. The ferroptosis activation system includes the synthesis and peroxidation of PUFA-PL, iron metabolism, and mitochondrial metabolism. The ferroptosis inhibition system includes the GPX4/GSH system, the FSP1/CoQH2 system, and the DHODH/CoQH2 system. At the cellular level, non-heme iron is absorbed and transported intracellularly via TF binding mediated by TFR1. Heme degradation and ferritinophagy mediated by NCOA4 can increase the LIP, making cells sensitive to ferroptosis through the Fenton reaction. Cytosolic GPX4 (GPX4_cyto) works synergistically with FSP1 on the plasma membrane (and other non-mitochondrial membranes), while mitochondrial GPX4 (GPX4_mito) works in tandem with DHODH within mitochondria to neutralize lipid peroxides. ACSL4 and LPCAT3 mediate the synthesis of PUFA-PL. Mitochondria harbor numerous critical metabolic processes, such as the TCA cycle, and are a major source of ROS, which can increase the LIP. The mitochondrial versions of GPX4 or dihydroorotate dehydrogenase (quinone) (DHODH) specifically detoxify mitochondrial lipid peroxides. Additionally, mitochondrial mitoNEET (also known as CISD1) inhibits ferroptosis by limiting mitochondrial iron uptake. In cardiomyocytes, various epigenetic factors regulate ferroptosis by modulating these processes. ACSL4, Acyl-CoA Synthetase Long Chain Family Member 4; ALX5, Arachidonate 5-Lipoxygenase; CH, cardiac hypertrophy; CoQ10, Coenzyme Q10; DIC, DOX-Induced Cardiomyocyte; DCM, Diabetic cardiomyopathy; DMT1, Divalent Metal Transporter 1; FPN1, Ferroportin 1; FSP1, Ferroptosis Suppressor Protein 1; FTH1, Ferritin Heavy Chain 1; FTMT, Ferritin Mitochondrial; GLS, Glutaminase; GPX4, Glutathione Peroxidase 4; GSH, Glutathione; GSSG, Glutathione Disulfide; HO1, Heme Oxygenase 1; LIP, Labile Iron Pool; LOX, Lipoxygenase; METTL3, Methyltransferase Like 3; MI, Myocardial infarction; METTL14, Methyltransferase Like 14; MitoNEET, Mitochondrial Outer Membrane Iron-Sulfur Protein; MIR, Myocardial Ischemia/Reperfusion Injury; MTF1, Metal-Responsive Transcription Factor 1; NADPH, Nicotinamide Adenine Dinucleotide Phosphate; NCOA4, Nuclear Receptor Coactivator 4; NOX4, NADPH Oxidase 4; Nrf2, Nuclear Factor Erythroid 2-Related Factor 2; p53, Tumor Protein p53; PCBP1, Poly (RC) Binding Protein 1; PL, Phospholipid; PL-PUFA-OOH, Phospholipid-Polyunsaturated Fatty Acid Hydroperoxide; POR, Cytochrome P450 Oxidoreductase; PRMT4, Protein Arginine Methyltransferase 4; PUFA, Polyunsaturated Fatty Acid; PUFA-CoA, Polyunsaturated Fatty Acid-Coenzyme A; ROS, Reactive Oxygen Species; SEMA3A-IT1, SEMA3A Intronic Transcript 1; SIRT, Sirtuin; SLC1A5, Solute Carrier Family 1 Member 5; SLC3A2, Solute Carrier Family 3 Member 2; SLC7A11, Solute Carrier Family 7 Member 11; ST6GALNAC4, ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 4; TCA cycle, Tricarboxylic Acid Cycle (Krebs Cycle); TF, Transferrin; TFRC, Transferrin Receptor; TFR-1, Transferrin Receptor 1.

Fig. 3

During HF, cardiomyocyte death exhibits typical features of ferroptosis [356]. MI is a primary cause of HF. METTL3 upregulation in oxygen-glucose deprivation/recovery (OGD/R) cells can inhibit OGD/R-induced ferroptosis [357]. METTL3 interacts with SLC7A11 to enhance its m6A methylation. Silencing SLC7A11 can negate the ferroptosis inhibition caused by METTL3 knockdown. Additionally, YTHDF2, which recognizes m6A methylation on SLC7A11, reduces the stability of SLC7A11 [357]. Silencing METTL3 by inhibiting m6A methylation of SLC7A11 (recognized by YTHDF2) can suppress OGD/R-induced ferroptosis [357]. Knockout of SIRT3 increases p53 acetylation and ferroptosis in mouse hearts, mediated by downregulation of GPX4. The acetylation-induced ferroptosis is partly associated with SIRT3-mediated fibroblast CF activity [131]. The circular RNA FEACR (ferroptosis-related circRNA) regulates cardiomyocyte ferroptosis. Studies show that FEACR directly interacts with nicotinamide phosphoribosyltransferase (NAMPT) to maintain its stability, thereby affecting NAD-dependent deacetylation by SIRT1 on forkhead box O1 (FOXO1), which in turn regulates transcription of ferritin heavy chain 1 (Fth1) [358]. CircSnx12 acts as an endogenous sponge to bind miR-224-5p, while FTH1 in its 3'UTR has a miRNA binding site [218] (Table 6).Table 6 Epigenetic regulation of ferroptosis in cardiovascular diseases.

Table 6Types of epigenetic	Diseases	Major regulator	Targets	Role in CVD	Ref	
Methylation	DIC	PRMT4	Nrf2/GPX4	Upregulation of PRMT4 can promote its enzymatic methylation through interaction with Nrf2, thereby inhibiting GPX4 and promoting ferroptosis, exacerbating DIC.	[359]	
DIC	METTL14	TFR1	METTL14, by stabilizing KCNQ1OT1 through IGF2BP1 m6A modification, absorbs miR-7-5p, thus increasing the levels of the transferrin receptor and promoting DOX-induced ferroptosis in cardiomyocytes.	[360]	
DIC	METTL3	TFRC	METTL3 promotes the m6A modification of TFRC and enhances its stability by recognizing the m6A reading protein IGF2BP2, regulating cardiac iron metabolism and ferroptosis.	[361]	
DIC	FTO	P53–P21/Nrf2	Overexpression of FTO mediates the demethylation of m6A on p53, positioned upstream of P21. Additionally, FTO activates the P21/Nrf2 pathway by directly mediating the demethylation of its mRNA m6A. This signaling is crucial for FTO's anti-ferroptosis effects.	[73]	
MI	METTL3	SLC7A11	Silencing METTL3 inhibits OGD/R-induced ferroptosis by suppressing the m6A methylation of SLC7A11, recognized by YTHDF2.	[357]	
Aortic dissection	METTL3	SLC7A11	Upregulated METTL3 promotes ferroptosis in HASMC by enhancing the degradation of SLC7A11 and FSP1 mRNA.	[362]	
SIC	METTL3	SLC7A11	METTL3 regulates the high m6A methylation level on SLC7A11 mRNA. Additionally, YTHDF2 directly binds to the m6A modification sites on SLC7A11 to mediate its mRNA degradation, thereby upregulating ferroptosis in sepsis-induced myocardial injury.	[363]	
	SIC	FTO	BACH1	FTO alleviated ferroptosis in septic cardiomyopathy via mediating the m6A modification of BACH1	[364]	
Histone modification	MIR	SIRT6	AIM2/GSDMD	Enhanced mitophagy and inhibited AIM2-pyroptosis in vitro and in vivo	[255]	
DCM	Kat2a	Tfrc/Hmox1	Kat2a enhances the expression of Tfrc and Hmox1 by increasing the enrichment of H3K27ac and H3K9ac in their promoter regions, thus promoting ferroptosis.	[365]	
DCM	SIRT1	SLC7A11/GPX4	Treatment with irisin increases SIRT1 and reduces p53 K382 acetylation, thereby reducing p53 protein expression through increased degradation, and upregulates SLC7A11 and GPX4 expression. Consequently, the irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes from high glucose damage.	[366]	
HF	SIRT1	GPX4	Supplementing AKG by raising NAD + levels activates the SIRT-PINK1 and SIRT1-GPX4 signaling pathways, promotes mitochondrial autophagy, inhibits cardiomyocyte ferroptosis, and ultimately mitigates myocardial cell damage.	[367]	
SIC	SIRT1	p53/SLC7A11	QUE exerts anti-ferroptosis effects by activating the SIRT1/p53/SLC7A11 signaling pathway, thereby inhibiting systemic and in vitro SIC.	[368]	
SIC	SIRT3	p53	The ANXA1sp inhibits ferroptosis-induced cell death through SIRT3-dependent p53 deacetylation, thus protecting cells from LPS-induced myocardial cell injury.	[369]	
CF	SIRT3	p53	Knocking out SIRT3 leads to increased p53 acetylation and ferroptosis in mouse hearts, achieved by downregulating GPX4. SIRT3-mediated CF partly occurs through a mechanism involving p53 acetylation-induced ferroptosis in myofibroblasts.	[131]	
Noncoding RNAs	MIR	Circ-FEACR	NAMPT/Sirt1/FOX1/FTH1	CircRNA FEACR inhibits ferroptosis by interacting with NAMPT, thereby alleviating MIRI. This increases NAMPT-dependent Sirt1 expression, then by reducing FOXO1 acetylation levels, it enhances FOXO1 transcriptional activity, ultimately upregulating FTH1 transcription.	[358]	
MIR	Circ-HMGA2	undetermined	CircHMGA2 enhanced MIR injury via promoting ferroptosis and pyroptosis	[291]	
MIR	Lnc-SEMA5A-IT1	SLC7A11	Upregulated LncRNA SEMA5A-IT1, by absorbing miR-143-3p, upregulates SLC7A11 to inhibit ferroptosis, thus preventing hypoxia/reoxygenation injury in cardiomyocytes.	[370]	
MIR	miR-210-3p	TFR1	MiR-210-3p inhibits ferroptosis by downregulating TfR1, alleviating hypoxia/reoxygenation-induced cardiomyocyte injury.	[371]	
MIR	miR-190a-5p	GLS2	MiR-190a-5p promotes ferroptosis by inhibiting GLS2.	[372]	
MIR	MiR-199a-5p	GPX4	MiR-199a-5p induces ferroptosis by downregulating GPX4 through the Akt/eNOS signaling pathway, promoting cardiomyocyte death in OGD/R-treated H9c2 cells.	[373]	
MIR	miR-214-3p	ME2	Upregulated miR-214-3p induces ferroptosis by inhibiting ME2, thus promoting MIRI.	[374]	
MIR	miR-15a-5p	GPX4	Egr-1-mediated upregulation of miR-15a-5p induces ferroptosis by inhibiting GPX4, promoting MIRI.	[375]	
HF	miR-351	MLK3	miR-351 improves pressure overload-induced myocardial fibrosis by inhibiting NF-κB/NLRP3-mediated inflammation and pyroptosis via MLK3, and oxidative damage and ferroptosis mediated by the JNK/p53 signaling pathway	[340]	
MIR	Lnc-SEMA5A-IT1	SLC7A11	SEMA5A-IT1 regulates the expression of BCL2 and SLC7A11 by absorbing miR-143-3p, thereby inhibiting ferroptosis.	[370]	
Myocardial lipotoxicity	Circ-005077	CyPA/p47PHOX	Circ-005077 interacts with CyPA and inhibits its degradation through the UBS, thus promoting the interaction between CyPA and p47phox, enhancing the activity of the NADPH oxidase responsible for ROS production, and thereby inducing ferroptosis.	[376]	
Cardiac hypertrophy	Lnc-Snhg7	Tbx5/GLS2	LncRNA Snhg7 transcriptionally regulates Tbx5/GLS2/ferroptosis in cardiomyocytes.	[377]	
Cardiac hypertrophy	Circ-Cmiss1	TFR1	Circ-Cmss1 interacts with the transcription factor EIF4A3, inducing the expression of TfR1, thereby activating ferroptosis in cardiomyocytes.	[378]	
DCM	Lnc- ZFAS1	CCND2	LncRNA-ZFAS1 acts as a ceRNA to absorb miR-150-5p and downregulate CCND2, promoting ferroptosis in cardiomyocytes and the development of DCM.	[379]	
HF	Circ-Snx12	FTH1	CircSnx12 acts as an endogenous sponge with miR-224-5p, with the 3'UTR region of FTH1 also having miRNA binding sites, regulating ferroptosis.	[218]	
Abbreviations: AKG, Alpha-Ketoglutarate; ANXA1sp, Annexin A1 Small Peptide; BCL2, B-cell CLL/Lymphoma 2; CCND2, Cyclin D2; CF, Cardiac Fibrosis; CyPA, Cyclophilin A; DCM, Diabetic Cardiomyopathy; DIC, DOX-Induced Cardiomyopathy; FSP1, Ferroptosis Suppressor Protein 1; FTO, Fat Mass and Obesity-Associated Protein; GLS2, Glutaminase 2; GPX4, Glutathione Peroxidase 4; H3K27ac, Histone H3 Acetylated at Lysine 27; H3K9ac, Histone H3 Acetylated at Lysine 9; HASMC, Human Aortic Smooth Muscle Cells; HF, Heart Failure; Hmox1, Heme Oxygenase 1; IGF2BP1, Insulin-Like Growth Factor 2 mRNA-Binding Protein 1; IGF2BP2, Insulin-Like Growth Factor 2 mRNA-Binding Protein 2; KCNQ1OT1, KCNQ1 Opposite Transcript 1; LPS, Lipopolysaccharide; METTL14, Methyltransferase Like 14; METTL3, Methyltransferase Like 3; MIR, Myocardial Ischemia/Reperfusion Injury; miRNA, MicroRNA; NAD+, Nicotinamide Adenine Dinucleotide; NADPH, Nicotinamide Adenine Dinucleotide Phosphate; Nrf2, Nuclear Factor Erythroid 2–Related Factor 2; OGD/R, Oxygen-Glucose Deprivation/Reoxygenation; P21, Cyclin-Dependent Kinase Inhibitor 1A; p47phox, Neutrophil Cytosol Factor 1; P53, Tumor Protein P53; PINK1, PTEN-Induced Kinase 1; PRMT4, Protein Arginine Methyltransferase 4; QUE, Quercetin; ROS, Reactive Oxygen Species; SIC, Sepsis-Induced Cardiomyopathy; SIRT, Sirtuin; SLC7A11, Solute Carrier Family 7 Member 11; TfR1, Transferrin Receptor 1; TFRC, Transferrin Receptor; TFR1, Transferrin Receptor 1 (repeated with different abbreviation); TFRC, Transferrin Receptor; Tbx5, T-box 5; UBS, Ubiquitin-Proteasome System; YTHDF2, YTH N6-Methyladenosine RNA Binding Protein 2.

3.4 Cuproptosis

Under normal conditions, copper in the body is maintained in a dynamic, stable balance through processes of copper absorption, storage, transport, and output [380](Fig. 4). In 2022, Peter Tsvetkov and colleagues discovered a novel type of cell death induced by copper (Cu), distinct from apoptosis, necroptosis, pyroptosis, and ferroptosis, and named it "cuproptosis" [381]. Typically, intracellular copper concentrations are relatively low. When cellular copper levels rise, excess copper ions bind to mitochondrial proteins, leading to protein lipoylation, membrane permeability, cellular disruption, and cell death [381].Fig. 4 Cellular copper homeostasis and cuproptosis in CVDs. (a) Copper Absorption: Extracellular Cu2⁺ is reduced to Cu⁺ by STEAP and taken up by the cell via the CTR1 transporter. Cu⁺ is then delivered to cytoplasmic chaperones like COX17, CCS, and ATOX1, and transported to mitochondria, the TGN, and the nucleus; (b). Copper Distribution: CCS channels copper to SOD1, which converts superoxide radicals into oxygen and hydrogen peroxide, stabilizing ROS and protecting against oxidative stress. In mitochondria, Cu contributes to the respiratory and redox pathways via CCO and is shuttled by COX17 to SCO1 or COX11, influencing cytochrome oxidase activity. In the nucleus, Cu binds transcription factors, affecting gene expression through the “GGAA” and “TTCC” motifs [512]; (c). Copper Export: Within the TGN, Cu⁺-ATPase transport proteins ATP7A and ATP7B transfer Cu from the cytosol into the TGN lumen, activating secretion pathways that rely on copper-dependent enzymes. When cytoplasmic Cu levels are elevated, ATP7A and ATP7B vacate the TGN to facilitate copper excretion; (d). Copper Sequestration: Copper storage is mediated by the copper-binding protein MT, which plays a pivotal role in copper homeostasis by storing and releasing excess copper as needed; (e). Cuproptosis: Elesclomol ferries copper into cells, where FDX1 reduces Cu [2]⁺ to Cu⁺ and targets DLAT in the TCA cycle. Cu⁺ increases aggregation of acylated proteins and reduction of iron-sulfur clusters, leading to cell death through proteotoxic stress. Excessive copper also promotes catecholamine oxidation by oxidizing GSH, disrupting lipid metabolism and causing DNA damage. AAA, Abdominal Aortic Aneurysm; ATP7A, ATPase Copper Transporting Alpha; ATP7B, ATPase Copper Transporting Beta; CCO, Cytochrome c Oxidase; CCS, Copper Chaperone for Superoxide Dismutase; COX11, Cytochrome c Oxidase Assembly Homolog 11; COX17, Cytochrome c Oxidase Assembly Protein 17; CTR1, Copper Transporter 1; DLAT, Dihydrolipoamide S-Acetyltransferase; DVC, Diabetic Vascular Complications; FDX1, Ferredoxin 1; GSH, Glutathione; MT, Metallothionein; ROS, Reactive Oxygen Species; SCO1, Synthesis of Cytochrome C Oxidase 1; SOD1, Superoxide Dismutase 1; STEAP, Six Transmembrane Epithelial Antigen of the Prostate; TCA, Tricarboxylic Acid Cycle; TGN, Trans-Golgi Network.

Fig. 4

Serum copper levels can often predict disease prevalence and are closely related to cardiac metabolic risk factors such as atherosclerosis (AS), coronary heart disease (CHD), ischemic heart disease, HF, type 2 diabetes, and obesity (Table 7). In clinical epigenetic studies, DNA methylation is one of the key biological mechanisms through which copper exposure impacts acute coronary syndrome (ACS). A genome-wide meta-analysis involving 1243 Chinese individuals showed that higher methylation levels at cg05825244 are associated with increased risk of ACS (odds ratio [OR], 1.23; 95 % CI 1.02–1.48; P = 0.03) [382]. Additionally, higher DNA methylation levels at the cg05825244 site correlate with lower levels of high-density lipoprotein cholesterol and higher levels of C-reactive protein [382].Table 7 Summary of clinical epigenetic studies.

Table 7Gene	Title	Types of epigenetic	Diseases	Ref	
SBNO2/BCL3/EBF4, cg05825244	Profile of copper-associated DNA methylation and its association with incident ACS	DNA methylation	ACS	[382]	
CD274/CP/VEGFA/COX11/CCL8/MAP2K1/AOC3	Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis	m6A methylation	SIC	[387]	
CXCL2/DDIT3/DUSP1/CDKN1A/TLR4/STAT3	Potential diagnostic biomarkers: 6 cuproptosis- and ferroptosis-related genes linking immune infiltration in acute myocardial infarction	Non-coding RNAs	AMI	[388]	
SLC31A1/SLC31A2/SOD1	Identification of Three Cuproptosis-specific Expressed Genes as Diagnostic Biomarkers and Therapeutic Targets for AS	Non-coding RNAs	AS	[389]	
CoroMarker/MALAT1/CDR1as/LINC00460	The human long noncoding RNAs CoroMarker, MALAT1, CDR1as, and LINC00460 in whole blood of individuals after controlled short-term exposure with ultrafine metal fume particles at workplace conditions, and in human macrophages in vitro	Long noncoding RNAs	CVD	[390]	
Abbreviations: ACS, Acute Coronary Syndrome; AMI, Acute Myocardial Infarction; AS, Atherosclerosis; CVD, Cardiovascular Disease; SIC, Sepsis-Induced Cardiomyopathy.

Preclinical studies suggest that cuproptosis may promote the pathogenesis of CVD [383]. ASH2L, a regulator of H3K4me3, triggers gene transcription [384]. Research reports that high glucose-induced ASH2L in endothelial cells (ECs) by regulating copper absorption causes diabetic endothelial dysfunction. ASH2L expression leads to activation of STEAP4 transcription, subsequently increasing the delivery of Cu(I) to ECs by CTR1. This causes an overload of copper in cells, thereby promoting endothelial dysfunction [385]. Additionally, research reports that endogenous ATP7A by restricting the expression of pro-inflammatory miR-125b (targeting Suv39h1 and TNFAIP3) in a copper-dependent manner, inhibits vascular inflammation, MMP activity, elastin fragmentation, and vascular apoptosis, thereby preventing the formation of abdominal aortic aneurysm (AAA) [386].

4 Medications targeting novel cell death pathways

As the understanding of cell death mechanisms deepens, novel forms of RCD are recognized as playing significant roles in cardiovascular diseases. Consequently, many drugs targeting these novel RCDs have emerged in the cardiovascular field (Table 8). However, direct regulation of these RCD pathways presents several challenges and limitations: ①Specificity and Selectivity: Many RCD pathways also play essential roles in normal physiological processes; direct manipulation could interfere with normal cellular functions and cause side effects [391]; ②Resistance: Prolonged use of certain drugs could lead to the development of resistance, diminishing therapeutic effectiveness; ③Complexity of Pathological Mechanisms: Many diseases involve multiple RCD pathways, and single-target drugs may not comprehensively control the condition. Research in epigenetics offers a broader and deeper perspective for comprehensively regulating cell functions and disease progression. Various cells within cardiac tissue exhibit distinct epigenetic modification patterns across the entire genome or at specific genes, and the reversibility of abnormal epigenetic modifications is a crucial target for salvaging cells in various cardiovascular diseases [392] (see Table 9).Table 8 Summarizes preclinical studies on drugs targeting novel RCD pathways in cardiovascular diseases.

Table 8Cell Death-Related	Mediator	Classification	Mechanism	Effects	Diseases	Ref	
Necroptosis induction	sCD74	Cytokines	Inhibiting MIF-mediated survival pathways via the CXCR4/AKT axis to activate necroptosis in a CD74/RIP3-dependent manner.	Anti-fibrosis	HF	[393]	
Necroptosis inhibition	Hydrogen sulfide	Gaseous signaling molecule	Suppressing necroptosis mediated by the RIP1/RIP3/MLKL pathway.	Anti-necroptosis of cardiomyocytes	HF	[394]	
Melatonin	Small compound	Inhibiting necroptosis induced by RIP3-MLKL/CaMKII signaling.	Anti-necroptosis of cardiomyocytes	MIR	[395]	
Resveratrol	Phytonutrient	Suppressing necroptosis through the TNF-α/RIP1/RIP3/MLKL signaling pathway.	Anti-necroptosis of cardiomyocytes	MIR	[396]	
DIMO	Small compound	Reducing RIP1K activation and restoring impaired autophagic flux.	Anti-necroptosis of cardiomyocytes	MIR	[397]	
Metformin	FDA-approved drug	Disrupting the p62-RIP1-RIP3 complex.	Inhibiting autophagy defects and necroptosis	MIR	[398]	
Inhibiting the phosphorylation of RIPK3 and MLKL.	Anti-necroptosis of cardiomyocytes	DCM	[399]	
GSK2795039	Small compound	Preventing RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis by inhibiting NADPH oxidase-derived oxidative stress.	Anti-oxidative stress and necroptosis	DIC	[400]	
Donepezil	Small compound	Inhibiting the recruitment of RIP1 to autophagosomes by p62, thereby preventing the formation of necrosomes and the phosphorylation of MLKL.	Regulating mitochondrial homeostasis, apoptosis, and necroptosis	DIC	[401]	
AM1241/JWH-133	Small compound	Overactivating CB2R inhibits the expression and phosphorylation of RIP1, RIP3, and MLKL. Upon activation, CB2R promotes the translocation of BACH2 from the cytoplasm to the nucleus by inhibiting the activity of S6K (S6 kinase). In the nucleus, BACH2 functions as a transcription factor, binding with its partner MafK to suppress the transcription of RIP1 and RIP3 genes.	Reducing cardiac inflammation and fibrosis	DCM	[402]	
Empagliflozin	FDA-approved drug	Inhibiting the phosphorylation of RIPK3 and MLKL.	Anti-necroptosis of cardiomyocytes	DCM	[399]	
GSK'074	Small compound	Dual targeting of RIP1 and RIP3 to inhibit necroptosis.	Anti-necroptosis of cardiomyocytes and macrophage infiltration	AAA	[403]	
Necrosulfonamide	Small compound	Inhibiting necroptosis dependent on the RIP1-RIP3-MLKL pathway.	Anti-pyroptosis and necroptosis	Cardiac arrest	[404]	
Anti-oxidative stress	PIC	[405]	
Anti-oxidative stress, apoptosis, and necroptosis	DIC	[406]	
Donepezil	Small compound	Inhibiting RIP3 and MLKL levels and calcium overload.	Anti-oxidative stress and necroptosis	Cardiomyocyte injury	[407]	
Pyroptosis inhibition	Hydrogen gas	Gaseous signaling molecule	Inhibiting the NLRP3 inflammasome.	Anti-pyroptosis	MI	[408]	
Kanglexin	Small compound	Inhibiting the NLRP3 inflammasome.	Anti-pyroptosis	MI	[409]	
Melatonin	Small compound	Modulating the TLR4/NF-κB/NLRP3 pathway.	Anti-pyroptosis	MI	[410]	
Nicorandil	Small compound	Modulating the TLR4/NF-κB/NLRP3 pathway.	Anti-pyroptosis	MI	[411]	
LCZ696	FDA-approved drug	Regulating the TAK1/JNK/NLRP3 pathway.	Anti-pyroptosis	MI	[412]	
Metformin	FDA-approved drug	Modulating the AMPK/NLRP3 inflammasome pathway.	Anti-pyroptosis	MIR	[413]	
Panaxynol	Phytonutrient	Regulating the HMGB1/TLR4/NF-κB pathway to inhibit the NLRP3 inflammasome.	Anti-pyroptosis and apoptosis	MIR	[414]	
Dexmedetomidine	FDA-approved drug	Modulating the miR-665/MEF2D/Nrf2 axis.	Anti-pyroptosis	MIR	[415]	
Oxytocin	Hormone	Regulating the AMPK/NLRP3 signaling pathway.	Anti-pyroptosis	MIR	[416]	
β-Asarone	Phytonutrient	Inhibiting the NLRP3 inflammasome.	Anti-pyroptosis	MIR	[417]	
Cinnamaldehyde	Phytonutrient	Inhibiting the NLRP3 inflammasome.	Anti-pyroptosis	MIR	[418]	
Piperazine ferulate	Small compound	Inhibiting the NLRP3 inflammasome.	Anti-pyroptosis	MIR	[419]	
Cinnamic acid	Phytonutrient	Modulating the NLRP3/Caspase-1/GSDMD pathway.	Anti-pyroptosis and oxidative stress	MIR	[420]	
Gastrodin	Phytonutrient	Inhibiting the NLRP3 inflammasome.	Anti-pyroptosis	MIR	[421]	
Emodin	Phytonutrient	Regulating the TLR4/MyD88/NF-κB/NLRP3 pathway.	Anti-pyroptosis	MIR	[422]	
Exendin-4	FDA-approved drug	Modulating the AMPK-TXNIP pathway.	Anti-pyroptosis	DCM	[423]	
Aloe-Emodin Derivative	Phytonutrient	Inhibiting NLRP3 inflammasome activation.	Anti-pyroptosis	DCM	[424]	
Pyrroloquinoline quinone	Phytonutrient	Suppressing NF-κB/NLRP3 inflammasome activation.	Inhibiting mitochondrial dysfunction-induced pyroptosis	DCM	[425]	
Berberine	Phytonutrient	Modulating the miR-18a-3p/Gsdmd pathway.	Anti-pyroptosis	DCM	[301]	
Astragaloside IV	Phytonutrient	Regulating the SIRT1/NLRP3 pathway.	Anti-pyroptosis	DIC	[426]	
Mitochonic acid 5	Small compound	Modulating the TNF-α/NF-κB/NLRP3 pathway.	Anti-pyroptosis	DIC	[427]	
MCC950	Small compound	Inhibiting NLRP3 inflammasome activation.	Anti-pyroptosis	DIC	[428]	
Amentoflavone	Phytonutrient	Modulating the STING/NLRP3 pathway.	Anti-pyroptosis	DIC	[429]	
Calycosin	Phytonutrient	Inhibiting the NLRP3 inflammasome.	Anti-pyroptosis	DIC	[430]	
Fucoxanthin	Phytonutrient	Regulating the PI3K/AKT and TLR4/NF-κB signaling pathways.	Anti-pyroptosis	AS	[431]	
Rosuvastatin	FDA-approved drug	Inhibiting NLRP3 inflammasome activation.	Anti-pyroptosis and regulating mitochondrial ROS	CME	[432]	
Colchicine	FDA-approved drug	Modulating the AMPK/SIRT1/NLRP3 pathway.	Anti-pyroptosis	CME	[264]	
Resveratrol	Phytonutrient	Regulating the TLR4/MyD88/NF-κB pathway.	Anti-pyroptosis	CME	[433]	
Tanshinone IIA	Phytonutrient	Modulating the TLR4/MyD88/NF-κB/NLRP3 pathway.	Anti-pyroptosis	CME	[434]	
MI	[435]	
VR	[436]	
Cortistatin	Polypeptide	Modulating the SSTR2/AMPK/NLRP3 pathway.	Anti-oxidative stress and pyroptosis	SIC	[437]	
Carvacrol	Phytonutrient	Regulating the NLRP3/Caspase1/Gasdermin D pathway.	Anti-oxidative stress and regulating autophagy	SIC	[438]	
Irisin	Myokine	Activating MITOL and inhibiting GSDMD.	Anti-pyroptosis	SIC	[439]	
Regulating mitochondrial homeostasis and pyroptosis	DCM	[440]	
Ferroptosis inhibition	Ferrostatin 1	Small compound	Restoring glutathione (GSH) levels and countering lipid peroxidation.	Anti-ferroptosis in cardiomyocytes	HF	[441]	
Inhibiting mitochondrial ROS production and ferroptosis	SIC	[442]	
Inhibiting endothelial dysfunction	AS	[443]	
Modulating the Nrf2/Hmox1 pathway.	Reducing mitochondrial iron accumulation and/or inhibiting lipid peroxidation	DIC	[444]	
Activating Nrf2 signaling.	Anti-ferroptosis	MI	[445]	
Regulating TLR4/Trif-dependent signaling.	Inhibiting the recruitment of neutrophils to damaged myocardium	Heart transplantation	[446]	
Liproxstatin 1	Small compound	Reducing VDAC1 levels and restoring GPX4 levels.	Anti-ferroptosis and mitochondrial ROS	MIR	[447]	
Deferoxamine	FDA-approved drug	Inhibiting iron overload.	Anti-ferroptosis	MIR	[448]	
Compound 968	Small compound	Inhibiting glutaminolysis.	Anti-ferroptosis	MIR	[449]	
P22077	Small compound	Regulating the USP7/p53/TfR1 pathway.	Anti-ferroptosis	MIR	[450]	
Nec-1f	Small compound	Inhibiting RIPK1.	Inhibiting necroptosis and ferroptosis	Heart transplantation	[451]	
Dexrazoxane	FDA-approved drug	Inhibiting lipid peroxidation.	Inhibiting mitochondrial ROS production and ferroptosis	SIC	[442]	
Atorvastatin	FDA-approved drug	Inhibiting ferritinophagy.	Anti-ferroptosis	HF	[452]	
MitoTEMPO	Small compound	Scavenging mitochondrial ROS.	Inhibiting oxidative stress and ferroptosis	DIC	[444]	
Mito-FerroGreen	Small compound	Inhibiting mitochondrial iron overload.	Inhibiting ferroptosis and apoptosis	DIC	[453]	
CeO2	NPs	Activating GPX4.	Anti-oxidative stress and ferroptosis	DIC	[454]	
Metformin	FDA-approved drug	Activating AMPKα2 phosphorylation.	Inhibiting ferroptosis	DIC	[455]	
		Promoting AMPKα to reduce NOX4 expression.	Inhibiting ferroptosis	MIR	[456]	
6-Gingerol	Phytonutrient	enhancing the Nrf2/HO-1 pathway	Inhibiting ferroptosis	DCM	[457]	
Astragaloside IV	Phytonutrient	Inhibiting CD36 and lipid peroxidation.	Anti-ferroptosis	DCM	[458]	
Sulforaphane	Phytonutrient	Preventing ferroptosis through AMPK-mediated NRF2 activation.	Anti-oxidative stress; removing excess iron	DCM	[459]	
Canagliflozin	FDA-approved drug	Activating the AMPK pathway.	Regulating inflammation, ferroptosis, and lipotoxicity	DCM	[460]	
N-Acetyl cysteine	Small compound	Activating Nox2 in an AMPK-dependent manner.	Inhibiting oxidative stress and ferroptosis	DCM	[461]	
Vas2870	Small compound	Inhibiting NOX2.	
Acadesine	Purine nucleoside analog	Activating AMPK.	
Elabela	Peptide hormones	Regulating the IL-6/STAT3/GPX4 signaling pathway.	Anti-ferroptosis, adverse myocardial remodeling, and fibrosis	Hypertension	[462]	
Dexmedetomidine	FDA-approved drug	Activating GPX4.	Anti-ferroptosis	SIC	[463]	
Cuproptosis inhibition	Sleep continuity	Behavioral therapy	Improving VPS35 expression inhibition caused by sleep fragmentation, leading to impaired ATP7A-related copper transport and myocardial copper overload.	Inhibiting cuproptosis and apoptosis	MIR	[464]	
Ammonium tetrathiomolybdate	Small compound	Chelating copper.	Mitochondrial function and reducing ROS production	MIR	[465]	
Triethylenetetramine	FDA-approved drug	Reducing intracellular copper ion accumulation and enhancing antioxidant defense mechanisms.	Anti-cuproptosis	DCM	[466,467]	
Restoring myocardial copper transport and promoting Pgc-1α expression.	Restoring myocardial copper homeostasis and normalizing mitochondrial processes disrupted by copper dysregulation	HF	[468]	
Tetrathiomolybdate	Small compound	Reducing bioavailable copper.	Vascular inflammation	AS	[469]	
Decreasing free copper concentration.	Preventing vascular inflammation and copper accumulation	AAA	[386]	
Paeoniflorin	Phytonutrient	Increasing FDX1/DLAT expression and serum copper, enhancing pyruvate levels.	Inhibiting cuproptosis, inflammation, apoptosis, and fibrosis	RV	[470]	
Abbreviations: AAA, Abdominal Aortic Aneurysm; AF, Atrial Fibrillation; AKT, Protein kinase B; AM1241/JWH-133, Specific CB2 receptor agonists; AMPK, AMP-activated protein kinase; CaMKII, Calcium/calmodulin-dependent protein kinase II; CB2R, Cannabinoid receptor type 2; CeO2 NPs, Cerium oxide nanoparticles; CME, Coronary Microembolization; CXCR4, C-X-C chemokine receptor type 4; DCM, Diabetic cardiomyopathy; DIC, DOX-Induced Cardiomyocyte; DLAT, Dihydrolipoamide S-acetyltransferase; DIMO, Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1; FDA, Food and Drug Administration; FDX1, Ferredoxin 1; GPX4, Glutathione peroxidase 4; GSK2795039, GlaxoSmithKline 2795039 (a small molecule); GSDMD, Gasdermin D; HF, Heart failure; Hmox1, Heme oxygenase 1; HMGB1, High mobility group box 1; IL-6, Interleukin 6; JNK, c-Jun N-terminal kinase; MEF2D, Myocyte enhancer factor 2D; MITOL, Mitochondrial ubiquitin ligase; MLKL, Mixed lineage kinase domain-like pseudokinase; MIR, Myocardial Ischemia Reperfusion; NADPH, Nicotinamide adenine dinucleotide phosphate; Nec-1f, Nec-1 analog; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-like receptor family pyrin domain containing 3; NOX2, NADPH oxidase 2; Nrf2, Nuclear factor erythroid 2-related factor 2; NPs, nanoparticles; Pgc-1α, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PIC, Paraquat-Induced Cardiomyocyte; RIP1, Receptor-interacting serine/threonine-protein kinase 1; RIP1K, RIP1 kinase; RIP3, Receptor-interacting serine/threonine-protein kinase 3; ROS, Reactive oxygen species; S6K, Ribosomal protein S6 kinase; sCD74, soluble CD74; SIC, Sepsis-Induced Cardiomyopathy; SIRT, Sirtuin; SSTR2, Somatostatin receptor 2; STAT3, Signal transducer and activator of transcription 3; STING, Stimulator of interferon genes; TAK1, Transforming growth factor-beta-activated kinase 1; TfR1, Transferrin receptor 1; TLR4, Toll-like receptor 4; TNF-α, Tumor necrosis factor alpha; Trif, TIR-domain-containing adapter-inducing interferon-β; TXNIP, Thioredoxin-interacting protein; USP7, Ubiquitin-specific-processing protease 7; VDAC1, Voltage-dependent anion-selective channel 1; VPS35, Vacuolar protein sorting 35 homolog; VR, ventricular remodeling.

Table 9 Mechanisms of cardiovascular epigenetic drugs targeting cell death pathways.

Table 9Classification of Epigenetic Mechanisms	Epidrug	Classification	Mechanism	Cell death pathways	Ref	
AS	
DNA methylation	Melatonin	Small compound	TET2/UQCRC1	Pyroptosis inhibition	[471]	
SIRT3	SIRT3/FOXO3α/ROS	Pyroptosis inhibition	[259]	
Lnc-MEG3	Lnc-MEG3/miR-223/NLRP3	Pyroptosis inhibition	[333]	
HDAC11	Hydroxytyrosol acetate	Phytonutrient	HDAC11	Pyroptosis inhibition	[500]	
mRNA methylation	Exercise	physiotherapy	METTL14/Lnc-NEAT1/KLF4	Pyroptosis inhibition	[245]	
HDAC6	Nicotine	Small compound	HDAC6/NF-κB/NLRP3	Pyroptosis induction	[472]	
Lnc-01272	Lnc-01272/miR-515/KLF6	Pyroptosis induction	[501]	
SIRT1	Oxymatrine	Small compound	SIRT1/Nrf2	Pyroptosis inhibition	[258]	
SIRT1	Paeonol	Phytonutrient	SIRT1/NRF2/GPX4	Ferroptosis inhibition	[473]	
SIRT1	Colchicine	FDA-approved drug	AMPK/SIRT1	Pyroptosis inhibition	[474]	
SIRT6	Isoliquiritigenin	Phytonutrient	SIRT6/NLRP3	Pyroptosis inhibition	[475]	
Lnc-NEXN-AS1	Atorvastatin	FDA-approved drug	Lnc-NEXN-AS1/NEXN	Pyroptosis inhibition	[334]	
Lnc-MALAT1	Sinapic Acid	Phytonutrient	Downregulation of Lnc-MALAT1	Pyroptosis inhibition	[476]	
Lnc-AU020206	BMSC-Exos	Exosome	Lnc- AU020206/CEBPB/NLRP3	Pyroptosis inhibition	[337]	
Circ-HIPK3	H₂O₂	Small compound	Circ-HIPK3/DRP1	Necroptosis induction	[238]	
miR-429	Hydroxysafflor yellow A	Small compound	miR-429/SLC7A11	Ferroptosis inhibition	[477]	
miR-199a-5p	Macrophage-derived extracellular vesicles	Exosome	miR-199a-5p/SMARCA4/PODXL/NF-κB	Pyroptosis inhibition	[323]	
miR-125a-5p	OxLDL	Lipoprotein particles	miR-125a-5p/TET2	Pyroptosis induction	[312]	
MIR/MI	
DNA methylation	5-aza-CdR	Small compound	NCOA4-ferritinophagy	Ferroptosis inhibition	[479]	
mRNA methylation	HNEAP	piRNAs	HNEAP/DNMT1/ATF7/CHMP2A	Necroptosis inhibition	[482]	
SIRT1	SRT1720	Small compound	Pyruvate dehydrogenase/NLRP3 inflammasome	Ferroptosis inhibition	[254]	
SIRT1-SIRT3	Resveratrol	Phytonutrient	SIRT1-SIRT3/PINK1/Parkin	Ferroptosis inhibition	[480]	
SIRT1-SIRT3	Honokiol	Phytonutrient	SIRT1-SIRT3/PINK1/Parkin	Ferroptosis inhibition	[480]	
SIRT5	Quercetin	Phytonutrient	DNA-PKcs-SIRT5	Necroptosis inhibition	[140]	
SIRT5	S-ASC-Exo	Exosome	SIRT3/AIM2	Pyroptosis inhibition	[255]	
Lnc-MEG3	EGCG	Phytonutrient	Lnc-MEG3/TAF15/AIM2	Pyroptosis inhibition	[279]	
Circ-PAN3	Sevoflurane	FDA-approved drug	Circ-PAN3/miR-29b-3p/SDF4	Pyroptosis inhibition	[293]	
miR-144-3p	Ginsenoside Re	Phytonutrient	miR-144-3p/SLC7A11	Ferroptosis inhibition	[502]	
miR-23a-3p	HUCB-MSC	Exosome	miR-23a-3p/DMT1	Ferroptosis inhibition	[503]	
miR-665	Dexmedetomidine	FDA-approved drug	miR-665/MEF2D/Nrf2	Pyroptosis inhibition	[415]	
miR-29b	miR-29b/FOXO3a/ARC	Pyroptosis inhibition	[281]	
miR-141-3p	miR-141-3p/Lnc- TUG1	Ferroptosis inhibition	[504]	
miR-383	Piperine	Phytonutrient	miR-383/RP105/AKT	Pyroptosis inhibition	[285]	
miR-143-3p	SEMA5A-IT1	Exosome	miR-143-3p/SLC7A11	Ferroptosis inhibition	[370]	
miR-155	Melatonin	Small compound	MT2/miR-155/FOXO3a/ARC	Ferroptosis inhibition	[505]	
miR-450b-5p	EGCG	Phytonutrient	miR-450b-5p/ACSL4	Ferroptosis inhibition	[506]	
HF	
SIRT1	Resveratrol	Phytonutrient	SIRT1/p53	Ferroptosis inhibition	[120]	
SIRT1	α-ketoglutarate	Small compound	SIRT-PINK1 and SIRT1-GPX4	Ferroptosis inhibition	[367]	
Lnc-GAS5	BMSC-Exos	Exosome	Lnc-GAS5/UL3/Hippo	Ferroptosis inhibition	[484]	
DCM	
SIRT1	Irisin	Myokine	SIRT1-p53-SLC7A11/GPX4	Ferroptosis inhibition	[366]	
SIRT3	Baicalin	Phytonutrient	SENP1/SIRT3	Ferroptosis inhibition	[486]	
miR-18a-3p	miR-18a-3p/GSDMD	Pyroptosis inhibition	[301]	
Lnc-MALAT1	Pomegranate peel extract	Phytonutrient	Lnc-MALAT1/NLRP3/caspase-1/IL-1β	Pyroptosis inhibition	[487]	
miRNA-223-3p	Mesenchymal stem cell	Cell therapy	miRNA-223-3p/NLRP3	Pyroptosis inhibition	[488]	
miR-135b	Ranolazine	FDA-approved drug	miR-135b/caspase-1	Pyroptosis inhibition	[302]	
DIC	
SIRT1	Melatonin	Small compound	SIRT1/Nrf2	Pyroptosis inhibition	[261]	
SIRT1	Astragaloside IV	Phytonutrient	SIRT1/NLRP3	Pyroptosis inhibition	[426]	
SIRT3	LCZ696	FDA-approved drug	AKT/SIRT3/SOD2	Ferroptosis inhibition	[491]	
SIRT3	Pinocembrin	Phytonutrient	Nrf2/Sirt3	Pyroptosis inhibition	[492]	
CME	
SIRT1	Colchicine	FDA-approved drug	AMPK/SIRT1/NLRP3	Pyroptosis inhibition	[264]	
SIC	
SIRT1	Resveratrol	Phytonutrient	SIRT1/Nrf2	Ferroptosis inhibition	[493]	
SIRT1	Quercetin	Phytonutrient	SIRT1/p53/SLC7A11	Ferroptosis inhibition	[368]	
AAA	
Lnc-PVT1	Curcumin nicotinate	Phytonutrient	Lnc-PVT1/miR-26a/KLF4/PI3K/AKT	Pyroptosis inhibition	[496]	
Lnc-PVT1	M1φ-exos	Exosome	Lnc-PVT1/miR-186-5p/HMGB1	Pyroptosis inhibition	[345]	
miR-17-5	ADSC-exos	Exosome	miR-17-5p/TXNIP-NLRP3	Pyroptosis inhibition	[495]	
miR-146a-5p	Pterostilbene	Phytonutrient	miR-146a-5p/TRAF6	Pyroptosis inhibition	[497]	
CF	
SIRT3	Hydrogen Sulfide	Gaseous signaling molecule	SIRT3	Necroptosis inhibition	[498]	
AF	
SIRT1	Icariin	Phytonutrient	SIRT1/Nrf-2/HO-1	Ferroptosis inhibition	[499]	
miR-214-3p	AMSC-exos	Exosome	miR-214-3p/Arl2	Pyroptosis inhibition	[347]	
Abbreviations: 5-aza-CdR, 5-Aza-2'-deoxycytidine; AAA, Abdominal Aortic Aneurysm; ACSL4, Acyl-CoA Synthetase Long Chain Family Member 4; ADSC, Adipose-Derived Mesenchymal Stem Cells; AF, Atrial Fibrillation; AIM2, Absent In Melanoma 2; AKT, Protein Kinase B; AMSC, Adipose Tissue-Derived Mesenchymal Stem Cells; AMPK, AMP-Activated Protein Kinase; ARC, Activity-Regulated Cytoskeleton-Associated Protein; Arl2, ADP Ribosylation Factor Like GTPase 2; AS, Atherosclerosis; ATF7, Activating Transcription Factor 7; CME, Coronary Microembolization; CEBPB, CCAAT Enhancer Binding Protein Beta; CF, Cardiac Fibrosis; CHMP2A, Charged Multivesicular Body Protein 2A; DCM, Diabetic Cardiomyopathy; DIC, DOX-Induced Cardiomyopathy; DMT1, Divalent Metal Transporter 1; DNA-PKcs, DNA-Dependent Protein Kinase, Catalytic Subunit; DNMT1, DNA Methyltransferase 1; DRP1, Dynamin Related Protein 1; EGCG, Epigallocatechin Gallate; FOXO3α, Forkhead Box O3 Alpha; GSDMD, Gasdermin D; GPX4, Glutathione Peroxidase 4; HF, Heart Failure; HDAC6, Histone Deacetylase 6; HMGB1, High Mobility Group Box 1; HO-1, Heme Oxygenase 1; HNEAP, Homocysteine Inducible ER Protein With Ubiquitin Like Domain 1; HUCB-MSC, MSCs Derived from Human Umbilical Cord Blood; KLF, Kruppel Like Factor; M1φ-exos, Exosomes from M1 Macrophages; MEF2D, Myocyte Enhancer Factor 2D; MEF-Exos, Mouse Embryonic Fibroblast-Exosomes; METTL14, Methyltransferase Like 14; MI, Myocardial Infarction; MIR, Myocardial Ischemia/Reperfusion Injury; NCOA4, Nuclear Receptor Coactivator 4; NEXN, Nexilin F-Actin Binding Protein; NF-κB, Nuclear Factor Kappa B; NLRP3, NLR Family Pyrin Domain Containing 3; Nrf2, Nuclear Factor Erythroid 2-Related Factor 2; PINK1, PTEN Induced Kinase 1; Parkin, Parkin RBR E3 Ubiquitin Protein Ligase; PI3K, Phosphoinositide 3-Kinase; PODXL, Podocalyxin Like; ROS, Reactive Oxygen Species; RP105, Radioprotective 105 kDa; SENP1, SUMO1/sentrin specific peptidase 1; SIC, Sepsis-Induced Cardiomyopathy; SIRT, Sirtuin; SLC7A11, Solute Carrier Family 7 Member 11; SMARCA4, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 4; SOD2, Superoxide Dismutase 2; SDF4, Stromal Cell Derived Factor 4; TAF15, TATA-Box Binding Protein Associated Factor 15; TET2, Tet methylcytosine dioxygenase 2; TRAF6, TNF Receptor Associated Factor 6; TXNIP, Thioredoxin Interacting Protein; UQCRC1, Ubiquinol-Cytochrome C Reductase Core Protein I; piRNAs, PIWI-interacting RNAs.

4.1 Atherosclerosis

Studies have shown that melatonin can inhibit EC pyroptosis by upregulating and demethylating UQCRC1 to improve mitochondrial function, regulating the SIRT3/FOXO3α/ROS pathway, and modulating the long non-coding RNA MEG3/miR-223/NLRP3 pathways [259,333,471]. Research by Yang et al. suggests that exercise-induced significant downregulation of m6A modification and METTL14, with METTL14 binding to m6A sites on NEAT1 and promoting NEAT1 expression through subsequent recognition by YTHDC1 (YTH domain-containing 1), thus inducing EC pyroptosis [245].

Histone acetylation is crucial for treating AS. HDAC11 may promote cell pyroptosis through the NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways by regulating the acetylation of ERG in HUVECs, making it a potential target for AS therapy [153]. HDAC6 is involved in macrophage pyroptosis induced by nicotine in AS [472]. Additionally, SIRT1 and SIRT6 are key regulators in multiple therapeutic agents such as Oxymatrine, Paeonol, Colchicine, and Isoliquiritigenin, which inhibit cell pyroptosis and ferroptosis in AS [258,[473], [474], [475]].

Non-coding RNAs are also primary therapeutic targets in AS. Long non-coding RNAs such as Lnc-NEXN-AS1, Lnc-MALAT1, and Lnc-AU020206 are key targets in the treatment of AS cell pyroptosis with Atorvastatin, Sinapic Acid, BMSC-Exos, and others [334,337,476]. CircRNA circHIPK3 interacts with DRP1, participating in H2O2-induced mitochondrial damage and necroptosis in VSMCs. In vivo silencing of circHIPK3 reduces the formation of vulnerable atherosclerotic plaques [238]. miR-429 and miR-199a-5p are involved in Hydroxysafflor yellow A and macrophage-derived extracellular vesicles' inhibition of iron death and cell pyroptosis in AS [323,477]。

4.2 MIR/MI

The interaction between epigenetics and metabolism has been identified as a potential target for treating cardiovascular diseases. Wang et al.'s study reveals that endogenous adenosine accumulation in cardiomyocytes induces protective mechanisms against myocardial I/R injury through epigenetic mechanisms [478]. Adenosine kinase (ADK) deficiency leads to cellular adenosine accumulation, reducing cell death and increasing IGF-1 expression through decreased DNMT1-dependent methylation of the IGF-1 promoter, thus improving MIR [478]. In diabetic MIR models, inhibition of DNMT-1 using 5-azacytidine (5-aza-CdR) alleviates ferroptosis via nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy [479] (Fig. 5).Fig. 5 The Role of m6A Modification in Regulated Cell Death within the MIR Framework. CBL, Cbl proto-oncogene; FTO, fat mass and obesity-associated protein; KLF6, Kruppel-like factor 6; m6A, N6-methyl-adenosine; METTL3, Methyltransferase-like protein 3; WTAP, WT1 associated protein.

Fig. 5

Various Sirtuin proteins are involved in the treatment of MIR, such as the SIRT1 agonist SRT1720, which regulates cardiac NLRP3 inflammasomes via pyruvate dehydrogenase in MIR [254]. Additionally, SIRT1, SIRT3, SIRT5, and SIRT6 act as epigenetic mediators regulating cell death in MIR through various drugs 140 255 480. Moreover, numerous non-coding RNAs participate in the regulatory mechanisms of therapeutic drugs on cell death.

Additionally, PIWI-interacting RNAs (piRNAs) have been discovered in recent years and are highly expressed in various cardiovascular diseases [481]. Research by Wang et al. found that a cardiac necroptosis-associated piRNA (HNEAP) targets DNMT1 to attenuate methylation of Atf7 mRNA transcripts, thereby increasing Atf7 expression levels. ATF7 further downregulates the necroptosis inhibitor Chmp2a transcription, leading to decreased Chmp2a levels and progression of cardiomyocyte necroptosis [482]. This study reveals that piRNA-mediated m5C methylation is involved in the regulation of cardiomyocyte necroptosis. Another study shows that piRNA HAAPIR promotes myocardial cell death post-MI by facilitating NAT10-mediated ac4C acetylation of Tfec mRNA [483].

4.3 Heart failure

The m6A methylation plays a significant role in the progression of HF. METTL3 modulates iron death in cardiac cells during HF; silencing METTL3 via the YTHDF2 pathway can inhibit cardiomyocyte iron death through m6A modifications on SLC7A11 [357]. SIRT3 can exacerbate myocardial fibrosis in HF by inducing p53 acetylation in myofibroblasts, contributing to HFwith preserved ejection fraction (HFpEF) [131]. Research by Zhang et al. indicates that the SIRT activator resveratrol mitigates HFprogression by inhibiting iron death via the Sirt1/p53 pathway [120]. Another dietary supplement, α-ketoglutarate, activates the SIRT-PINK1 and SIRT1-GPX4 signaling pathways, promoting mitochondrial autophagy and inhibiting cardiomyocyte iron death, thereby reducing myocardial cell damage [367]. In non-coding RNA, bone marrow-derived mesenchymal stem cell exosomal lncRNA GAS5 alleviates HFby inhibiting iron death mediated by the UL3/Hippo pathway [484]. Furthermore, piRNA-mediated RNA epigenetic mechanisms participate in regulating cardiac hypertrophy, with the CHAPIR-METTL3-PARP10-NFATC4 signaling axis serving as a potential therapeutic target for pathological hypertrophy and adverse cardiac remodeling [485].

4.4 Diabetic cardiomyopathy

The role of m6A in diabetic cardiomyopathy (DCM) is somewhat limited. According to Meng et al., METTL14 suppresses cell pyroptosis and DCM by downregulating the TINCR lncRNA [44]. Iristectorigenin is a peptide derived from the type III fibronectin domain, which mitigates type 1 DCM by anti-ferroptosis through SIRT1-mediated p53 deacetylation [366]. Baicalin (BAI), a bioactive compound, improves DCM by activating the SENP1/SIRT3 pathway and the miR-18a-3p/Gsdmd pathway, addressing both iron death and cell pyroptosis [301,486]. Non-coding RNA regulators such as pomegranate peel extract prevent the development of rat DCM by inhibiting cell pyroptosis and downregulating LncRNA-MALAT1 [487]. Cell therapy with mesenchymal stem cells improves cell pyroptosis through miRNA-223-3p [488]. Rilmenidine in the treatment of diabetic cardiac fibrosis regulates miR-135b to inhibit cell pyroptosis [302].

4.5 DOX-induced cardiotoxicity

The application of doxorubicin (DOX) is hindered by severe cardiac toxicity, characterized by ventricular dilation, progressive deterioration of cardiac function, and eventual HF [489,490]. Iron death is a crucial mechanism in DOX-mediated cardiac toxicity [453]. m6A methylation, involved in DOX-induced iron death, is an important intervention target. Research by Wu et al. reported that METTL3 promotes cardiac cell iron death in DOX-Induced Cardiotoxicity (DIC) by enhancing TFRC mRNA m6A modification through an IGF2BP2-dependent mechanism, thereby maintaining TFRC stability [361]. Therefore, inhibiting METTL3 could be a potential therapeutic approach for DIC. Regarding m6A demethylase regulation, Yang et al. indicated that FTO mediates p53 or P21/Nrf2 m6A demethylation in a HuR-dependent manner, inhibiting DOX-induced iron death and forming a positive feedback loop with HuR and P53–P21 [73]. Additionally, FTO can alleviate DOX-induced HF by blocking the TLR4/NF-κB pathway [251]. According to Wang et al., protein arginine methyltransferase 4 (PRMT4) catalyzes the enzymatic methylation of Nrf2, restricting its nuclear translocation and reducing the expression of downstream iron death-related gene GPX4, accelerating iron death in DIC [359].

Sirtuins, particularly SIRT1 and SIRT3, may play a protective role in DIC. Zhang et al. reported that activation of the Sirt1/Nrf2 pathway is a potential mechanism by which melatonin inhibits oxidative stress, cell pyroptosis, and apoptosis induced by DOX in cardiomyopathy [261]. Astragaloside IV (AS IV), a major compound in Astragalus water extract, prevents DIC by inhibiting cell pyroptosis through the SIRT1/NLRP3 pathway [426]. LCZ696 reshapes the myocardial structure and improves ventricular function in rats treated with DOX by inhibiting iron death triggered by the activation of the AKT/SIRT3/SOD2 signaling pathway [491]. Piceatannol, a flavonoid compound initially isolated from bee propolis and Boesenbergia pandurata rhizomes, protects the heart from DOX-induced cardiotoxicity by activating the Nrf2/Sirt3 signaling pathway, reducing myocardial cell pyroptosis [492].

4.6 Coronary Microembolism

Coronary Microembolism (CME) is a common complication of ACS and percutaneous coronary intervention. Colchicine pretreatment can improve cardiac function impairment and myocardial damage caused by CME by inhibiting myocardial cell pyroptosis through the AMPK/SIRT1/NLRP3 signaling pathway [264].

4.7 Sepsis-Induced Cardiomyopathy

In Sepsis-Induced Cardiomyopathy (SIC), two phytonutrients, resveratrol and quercetin, can inhibit iron death through SIRT1-mediated pathways [368,493].

4.8 Abdominal aortic aneurysm

AAA, with the highest incidence and rupture rate among all aortic aneurysms [494], involves cell pyroptosis inhibition by extracellular vesicles from M1 macrophages and adipose-derived mesenchymal stem cells through Lnc-PVT1 and miR-17-5 [345,495]. Additionally, curcumin nicotinate and pterostilbene regulate AAA cell pyroptosis through Lnc-PVT1 and miR-146a-5p [496,497].

4.9 Cardiac fibrosis

SIRT proteins are potential targets for cardiac fibrosis (CF) and heart failure. Lack of SIRT3 enhances iron death and promotes cardiac fibrosis through p53 acetylation [131]. Hydrogen sulfide (H2S), a gaseous signaling molecule with multiple physiological functions, mitigates hypoxia-induced proliferation of cardiac fibroblasts through SIRT3, inhibiting necroptotic cell death [498].

4.10 Atrial fibrillation

Cell death is one of the mechanisms in the pathogenesis of atrial fibrillation (AF). Icariin can reverse the increased susceptibility to AF induced by excessive ethanol administration, changes in atrial conduction patterns, atrial enlargement, and enhanced fibrosis markers, through the inhibition of iron death by the SIRT1 signaling pathway, thereby preventing atrial damage [499]. Research by Yan et al. showed that extracellular vesicles from adipose-derived mesenchymal stem cells shuttle LncRNA XIST, which inhibits atrial fibrillation-associated myocardial pyroptosis through disrupting miR-214-3p-mediated Arl2 inhibition [347]。

5 Conclusion and future perspectives

As terminally differentiated cells, the death of cardiomyocytes leads to a reduction in their numbers, so strict regulation of RCD is undoubtedly the correct direction for therapy. However, does blocking one death pathway really bring benefits in clinical practice? Theoretically, yes! But in reality, not always. In terms of intrinsic cell death pathways, the only successful story is the development of the BCL-2 inhibitor Venetoclax for treating certain hematologic malignancies [507]. What's the problem? Is our understanding of the intrinsic mechanisms of cell death not deep enough? Despite researchers attempting substantial changes in experimental design and reinterpretation of results at different levels, the outcomes are often not as expected. The main issue is that RCD itself is an endogenous regulatory mechanism, and multiple RCD pathways within the cell are functionally overlapping and interactive. This means that when one RCD is inhibited, cells might initiate other death mechanisms as a compensatory mechanism [507]. In this context, it is crucial to consider the complex interplay between different types of epigenetic and epitranscriptomic modifications, as they collectively influence RCD pathways. This review has emphasized not only the role of traditional epigenetic modifications such as DNA methylation and histone modifications but has also highlighted the dynamic regulatory roles of RNA modifications, notably m6A methylation, in shaping the landscape of novel RCD pathways in cardiovascular diseases.

However, RCD regulation mediated by epigenetic modifications is still an emerging field and in its infancy. First, how epigenetic modifications control the expression of RCD-related genes in cardiovascular diseases is not fully understood. Determining whether these novel epigenetic mechanisms are specific to different diseases and cell types requires more systematic and comprehensive investigations. Second, besides known modifications such as methylation, acetylation, and non-coding RNA regulation, whether other epigenetic modifications like ubiquitination, phosphorylation, SUMOylation, O-GlcNAcylation, ISGylation, and lactylation participate in regulating RCD in cardiovascular diseases remains unclear. Third, more emphasis needs to be placed on the regulatory networks among various RCDs and on how different epigenetic and epitranscriptomic modifications collaborate with diverse signaling pathways to regulate RCD, which is currently not well-defined but vital for understanding the full spectrum of RCD regulation.

It is imperative for future research to extend beyond the predominant focus on cardiomyocytes to include other cell types within the cardiovascular system, such as endothelial cells and smooth muscle cells [508,509,511]. The interactions and crosstalk between these cells under various pathological conditions can significantly influence the dynamics of RCD and may unveil novel regulatory mechanisms that are obscured when only a single cell type is considered [510,511]. Understanding how different cell types collectively respond to epigenetic modifications and contribute to the pathology of cardiovascular diseases will provide a more comprehensive view of disease mechanisms and potentially reveal new therapeutic targets. Emphasizing the interconnectedness of cellular responses within the cardiovascular system will help to delineate more detailed and sophisticated regulatory networks essential for advancing our understanding of RCD regulation.

CRediT authorship contribution statement

Cong Chen: Writing – original draft. Jie Wang: Conceptualization. Shan Zhang: Writing – review & editing. Xueying Zhu: Methodology. Jun Hu: Resources. Chao Liu: Visualization. Lanchun Liu: Writing – original draft.

Declaration of competing interest

All authors declare no competing interests.

Data availability

No data was used for the research described in the article.

Acknowledgements

The authors thank to the support by the 10.13039/501100001809 National Natural Science Foundation of China (Key Program) (No. 82230124 ), High Level Chinese Medical Hospital Promotion Project (No. HLCMHPP2023083 ), State Administration of Traditional Chinese Medicine 2nd National Traditional Chinese Medicine Inheritance Studio Construction Project (Official Letter of the State Office of Traditional Chinese Medicine ❲2022❳No. 245), State Administration of Traditional Chinese Medicine National Traditional Chinese Medicine Experts Inheritance Studio Construction Project (National Letter of Traditional Chinese Medicine Practitioners❲2022❳No. 75), National Natural Science Foundation of China Youth Project (No. 82305211 ).
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