Long non-coding RNAs as modulators of metabolic reprogramming for endogenous heart regeneration: Mechanisms and therapeutic potential

Abstract

Myocardial infarction (MI) is one of the leading causes of death worldwide, with its high incidence and mortality posing a significant threat to human health. Despite some progress in the treatment of myocardial infarction, mortality rates remain alarmingly high. Adult mammals have limited myocardial regenerative capacity, and extensive cell death caused by myocardial ischemia severely impairs cardiac function, leading to heart failure or death. In contrast, neonatal myocardium possesses a robust regenerative ability, which gradually diminishes after birth. The loss of cardiomyocyte regenerative capacity is often accompanied by a shift in energy metabolism—from reliance on glucose (glycolysis) to fatty acid oxidation. This metabolic reprogramming significantly impacts CM proliferation. Long non-coding RNAs (lncRNAs) orchestrate cardiac regeneration through epigenetic control (e.g., Bvht/PRC2-mediated silencing), metabolic reprogramming (e.g., GATA6-AS1 suppression of FAO), and miRNA sponging (e.g., CAREL sequestration of miR-296). However, our understanding of the metabolic determinants and pathways that promote myocardial regeneration after myocardial infarction is still insufficient. This review investigates the interplay between lncRNAs and metabolic reprogramming in cardiovascular function, aiming to identify novel therapeutic targets and strategies to enhance myocardial regeneration post-MI.

Graphical abstract

1. Introduction

Myocardial infarction is a leading cause of death globally, with high incidence and mortality rates threatening human health [1,2]. While medications and surgical interventions can mitigate heart disease progression, end-stage heart failure remains a significant challenge. Heart transplantation is a promising solution but is limited by donor availability and rejection risks, prompting intense interest in novel cardiac regeneration strategies [3,4]. A crucial obstacle to regeneration is the dramatic decline in the mammalian heart's regenerative capacity, which occurs primarily within the first week after birth. This loss of regenerative potential coincides with and is critically driven by a fundamental metabolic reprogramming in cardiomyocytes (CMs) [[5], [6], [7]].

During embryonic development, CMs primarily rely on anaerobic glycolysis for energy production. However, shortly after birth, a pivotal metabolic shift occurs: CMs transition towards mitochondrial oxidative phosphorylation (OXPHOS) to meet the heart's escalating energy demands [7]. This metabolic switch is not merely an adaptation for increased energy output; it is a core event intimately linked to CM maturation and terminal differentiation [8]. Critically, this postnatal metabolic maturation is tightly coupled with the exit of most CMs from the cell cycle, effectively shutting down their proliferative capacity and marking the loss of robust cardiac regeneration [5,7,9].

As CMs undergo this metabolic and functional maturation, they experience significant changes in number, structure, and function. Most CMs exit the cell cycle early after birth, leading to hypertrophic growth and changes in cell interactions. High metabolic activity during postnatal maturation often results in oxidative DNA damage, halting CM division. Adult mammals generate only about 1 % of new CMs annually, underscoring the challenges of cardiac regeneration [9]. Following cardiac injury, CMs experience necrosis and apoptosis, while cardiac fibroblasts activate and transform into myofibroblasts, producing excess collagen and extracellular matrix components, leading to myocardial fibrosis and impaired cardiac function.

Regenerative cardiovascular medicine has proposed various strategies for regeneration, including stimulating CM proliferation, recruiting stem cells, converting induced pluripotent stem cells (iPSCs) into new CMs, and reprogramming cardiac fibroblasts into cardiomyocyte-like cells (iCLMs) [10]. These approaches aim to repair damaged hearts by replacing necrotic CMs and minimizing fibrosis.

The complexity of cardiac regeneration involves not only CM differentiation, proliferation, and apoptosis but also the regulation of numerous genes and molecular signals. Current cardiac regeneration strategies often lack robust clinical data, highlighting the need to understand the molecular mechanisms controlling damaged myocardium regeneration. Recently, lncRNAs, which are typically over 200 nucleotides long and do not encode proteins, have gained attention for their regulatory roles in gene expression, cellular metabolism, and signaling pathways, particularly in cardiovascular diseases following myocardial infarction [11].

2. Metabolic reprogramming and lncRNA networks: orchestrating cardiac regeneration

Research indicates that infants with cardiac damage in utero exhibit remarkable self-repair capabilities, attributed to the unique state of CMs during fetal development [12]. However, this regenerative ability declines significantly after birth. Fetal CMs rely on glycolysis, whereas postnatal CMs transition to a more efficient OXPHOS metabolism [13]. These intertwined metabolic transitions, encompassing signaling pathways, epigenetic modifications, and transcriptional regulation, enable distinct cellular processes [14].

Zebrafish, showing exceptional cardiac regeneration, utilize glycolysis while enhancing oxidative metabolism during regeneration [15]. In contrast, mammalian CMs lose regenerative abilities rapidly after birth, with proliferation tightly regulated [16]. Mitochondria-derived reactive oxygen species (ROS) and DNA oxidation play crucial roles [17]. Fatty acid oxidation is associated with high ROS production and cell cycle arrest [18].

Recent research focuses on key molecular axes related to metabolic remodeling and CM proliferation [19,20]. Hypoxia-inducible factors (HIFs), activated under hypoxic conditions, are essential for cellular metabolism [21]. Proper regulation of glucose and fatty acid metabolism impact energy production and CM regenerative capacity. Altering adult CM metabolism may revert them to a more embryonic-like state, facilitating proliferation and cardiac regeneration [22].

Inactivation of the Cpt1b gene increases α-ketoglutarate (α-KG) levels in CMs. Elevated α-KG enhances KDM5 enzyme activity, thus promoting demethylation in mature CM genes [23]. These changes allow CMs to re-enter the cell cycle, promoting cardiac regeneration. This research underscores the critical role of metabolic reprogramming in cardiac regeneration.

2.1. The Key Role of lncRNAs in cardiomyocyte proliferation

Stimulating the endogenous regenerative capacity of CMs can achieve cardiac regeneration post-myocardial infarction, with numerous non-coding RNAs (ncRNAs) taking on regulatory roles [24].

lncRNAs orchestrate cardiac regeneration through epigenetic control, metabolic reprogramming, and miRNA sponging, influence cell fate, cycle control, and gene expression [11]. They are crucial for cardiac development and function by regulating CM function, impacting CM proliferation, differentiation, and maturation. Their versatile regulatory functions include scaffolds, decoys, or guides for protein complexes.

2.1.1. Epigenetic regulators

LncRNAs like Braveheart (Bvht) act as master epigenetic regulators in early cardiogenesis [25]. Bvht recruits SUZ12/PRC2 to glycolytic genes, maintaining a proliferative state while suppressing maturation markers (HK2, PDK1). It activates a key gene regulatory network of cardiac transcription factors (Showing in [Table 1]). The same function is evolutionarily conserved by linc1405, which recruits WDR5-GCN5 complexes to enhancers of Mesp1 [26]. Glycolysis plays distinct roles in CM differentiation, mediated by precise lncRNAs. uc.457 enhances glycolysis while promoting differentiation through STAT3/GATA1 activation [27]. While ECRAR, a novel fetal lncRNA, is expressed in embryonic and adult rat myocardial cells by day 7 post-birth and promotes DNA synthesis, mitosis, and cytokinesis. Overexpression of ECRAR significantly stimulates cardiac regeneration and restores cardiac function. ECRAR deletion inhibits myocardial cell proliferation and hinders cardiac recovery. ECRAR is upregulated by E2F1, promoting ERK1/2 phosphorylation, activating cyclins D1 and E1, creating a positive feedback loop that enhances myocardial cell proliferation [28].

Table 1.

LncRNAs with characterized and/or potential metabolic targets in the heart.

LncRNA	Metabolic pattern	Tissue/Cell type	Species	Mechanism of action	Target genes	Therapy	Observed Effect	Ref
Braveheart(Bvht)	Glycolysis ↑ (by activating the cardiac gene network)	ESCs nCMs	Mouse	epigenetic regulation	PRC2	shRNA-mediated INH	CM differentiation ↓	[25]
					SUZ12		CM size↓,differentiation↓
linc1405	Glycolysis ↑ (activated by Mesp1)	Heart	Mouse	epigenetic regulation	Eomes	shRNA-mediated INH	CM differentiation ↓, CM proliferation ↓	[26]
uc.457	Glycolysis ↑ (STAT3 HK2 pathway)	P19 cells	mouse	Histone modification	STAT, GATA1	siRNA-uc.457	CM differentiation ↑, CM proliferation ↑	[27]
ECRAR	Glycolysis ↑ (cyclin D1-HK2)	hearts cardiomyocytes	Human rat	Regulated by E2F1	ERK1/2	ECRAR Overexpression	CM proliferation ↑	[28]
lncRNA BANCR	Fatty acid oxidation ↑ (YAP-PPAR α axis)	Heart and neonatal cardiomyocytes	Human, mouse	TEAD/YAP	TBX5	shRNA-mediated INH	CM proliferation↓, CM migration, Ventricular Enlargement	[29]
Fendrr	Unclear	Heart and neonatal cardiomyocytes	mouse	Histone modification	PRC2 and TrxG/MLL complexes	Transgenic KO	CM proliferation ↓,ventricular defects	[30]
Ppp1r1b-lncRNA	Lipid metabolism ↑ (FABP4 regulation)	myoblasts, C2C12	humans.	PRC2	Myogenin, MyoD1, and TBX5	siRNA	Cardiac myogenesis ↑	[31]
			Mouse
Snhg1	Glycolysis ↑ (AKT-GLUT4)	hearts cardiomyocytes	humans	PTEN	PI3K/AKT c-Myc	overexpressing Snhg1	CM proliferation ↑ angiogenesis↑	[32]
			Mouse
CPR	Unclear	hearts cardiomyocytes	humans	DNA replication	MCM3	CPR knockout	CM proliferation ↑	[33]
			Mouse				Improves Cardiac
							Function
lncRNA GATA6	Fatty acid oxidation ↓(GATA6-AS1)	hiPSCs	Human, mouse	epigenetic regulation miRNA	GATA6	shRNA-mediated INH	CM differentiation ↓, CM proliferation ↓	[34]
					Wnt
AZIN2	Lipid metabolism ↑ (Akt activated lipolysis)	Heart and neonatal cardiomyocytes	Human	Sponges miR-214	PTEN/Akt	AZIN2-sv knockdown	CM proliferation ↓	[35]
			Rat
CRRL	Fatty acid oxidation ↑ (CPT2 activation)	CM	Human	Sponges miR-199a-3p	Activates HOPX	SiCRRL	CM proliferation ↑	[36]
			Rat
CAREL	Glycolysis ↑ (Relieve HK2 inhibition)	hearts	mouse	Sponges miR-296	Trp53inp1 and Itm2a	shRNA-mediated INH	CM proliferation ↑	[37]
LncDACH1	Fatty acid oxidation ↑ (YAP1-PGC1 α)	hearts	Human mouse	Inactivates PP1A	YAP1	LncDACH1 gene knockout,	CM proliferation ↑	[38]
lncRNA NR_045363	Glycolysis ↑ (STAT3 activation)	Heart and neonatal cardiomyocytes	HumanMouse	Sponges miR-216a	JAK2-STAT3	overexpressed NR_045363	CM proliferation ↑	[39]
LncSync	Lipid metabolism ↑ (inhibition of ceramides)	hearts cardiomyocytes	mouse	miR-351	HDDC3	LncSync Knockout	CM homeostasis↓	[40]
				miR-181

During early cardiac morphogenesis, specific lncRNAs act as key regulators of lineage commitment and structural formation, for example, BANCR (BRAF-activated non-coding RNA) is expressed in fetal CMs and acts as a downstream effector of the TEAD/YAP pathway, promoting cell migration and ventricular expansion [29]. Similarly, Fendrr, expressed in the lateral plate mesoderm, functions during embryogenesis to regulate CM differentiation by binding key transcription factors and modulating their activity [30]. Loss of Fendrr results in reduced CM numbers and impaired contractile function, underscoring its role in the transition from mesodermal progenitors to functional myocardium.

Furthermore, lncRNAs such as Ppp1r1b-lncRNA function is mediated by the interaction with the chromatin-modifying complex polycomb repressive complex 2 (PRC2) at the promoter of myogenic differentiation transcription factors, TBX5 and MyoD1 [31]. While Snhg1 promotes myocardial proliferation and angiogenesis via PTEN degradation and PI3K/AKT activation [32]. These diverse functions underscore the importance of lncRNAs as integrated regulators shaping the structural and functional maturation of CMs.

Cardiac cell proliferation regulator (CPR) is a lncRNA highly expressed in neonatal and adult mouse hearts. Knockdown of CPR promotes myocardial cell proliferation, indicating its role in regulating proliferation. CPR deficiency increases myocardial cell proliferation in neonatal and adult mice, while overexpression inhibits neonatal myocardial cell proliferation and reduces adult myocardial cell numbers. CPR suppresses MCM3 expression by regulating its promoter methylation state, modulating myocardial cell proliferation [33] (Showing in [Table 1]).

lncRNAs also regulate processes including structural maturation. During postnatal maturation, they modulate the transition from proliferation to hypertrophy, influencing the development of mature contractile and electrophysiological properties [41]. Targeting specific lncRNAs holds promise for stem cell differentiation, enhancing regeneration, and treating cardiac diseases.

2.1.2. Metabolic modulators

As the heart matures, other lncRNAs continue to coordinate gene networks that influence proliferation and differentiation. In parallel, GATA6-AS1, a nuclear-localized lncRNA, correlates with GATA6 expression and regulates Wnt target genes during CM differentiation [34]. These lncRNAs exemplify the finely tuned gene regulatory architecture ensuring proper cardiac development and maturation.

A fascinating aspect of lncRNA function in cardiac biology is their divergent roles in metabolic reprogramming, which is central to cardiac cell fate decisions. While some lncRNAs, like BANCR [29], promote FAO to meet the energy needs of structurally mature CMs during ventricular expansion, others, such as GATA6-AS1 [34], maintain a glycolytic, fetal-like metabolic state. This dichotomy reflects a broader principle: certain lncRNAs act as molecular switches that promote either maturation-associated FAO or sustain a proliferative, glycolytic phenotype characteristic of embryonic or progenitor states (Showing in [Table 1]). As a result, targeting these lncRNAs could modulate the balance between proliferation and differentiation, which has significant implications for cardiac regeneration strategies. This metabolic bimodality [Fig. 1] suggests stage-specific targeting strategies.

Fig. 1.

The Key Role of lncRNAs in Cardiomyocyte Proliferation. The figure summarizes the function lncRNAs in the process of cardiac Proliferation. lncRNAs orchestrate cardiac regeneration through epigenetic control, metabolic reprogramming, and miRNA sponging, influence cell fate, cycle control, and gene expression.

2.1.3. miRNA sponges

LncRNAs influence CM survival, proliferation, and differentiation through interactions with transcription factors and signaling pathways [Fig. 1]. AZIN2-sv interacts with miR-214 to inhibit Akt/PKB signaling, suppressing proliferation [35]. CRRL promotes neonatal rat CM proliferation by binding to miR-199a-3p [36]. CAREL, a ceRNA, relieves miR-296 mediated repression [37]. In addition, lncRNAs such as LncDACH1 directly bind to phosphatases like PP1A, influencing pathways like YAP1 signaling to promote neonatal heart regeneration and improve ischemic heart recovery [38] (Showing in [Table 1]).Their capacity to modulate distinct signaling axes demonstrates their potential as therapeutic targets for enhancing endogenous regenerative capacity.

Emerging evidence highlights lncRNAs acting as key regulators of myocardial proliferation and maturation across developmental stages. Long non-coding RNA NR_045363 promotes myocardial cell proliferation through the via the miR-216a/JAK2-STAT3 pathway, suggesting that reactivating the regenerative potential [39]. Similarly, LncSync, located on the X chromosome, regulates cardiogenesis through its processed miR-351 cluster, influencing CM differentiation and preventing ferroptosis-related remodeling [40]. These dual roles in promoting proliferation and guiding differentiation exemplify the complex, stage-specific functions of lncRNAs in heart development.

2.2. Metabolic reprogramming in cardiac regeneration

Under the influence of myocardial ischemia, local tissues often experience insufficient blood supply, leading to cardiac diseases characterized by disturbances in myocardial contractile function, fibrotic scar formation, and overall heart remodeling. This remodeling affects not only the infarcted myocardial layers but also extends to distal regions, resulting in pathological cardiac hypertrophy and significant changes in energy metabolism. Specifically, myocardial ischemia reduces fatty acid metabolism while increasing glycolysis, leading to decreased ATP production, essential for CM function. This reduction exacerbates cardiac injury and accelerates the progression to heart failure. The regulation of FAO by lncRNAs is tightly linked to distinct phases of cardiac development and repair. For example, Pro-regenerative (glycolytic) state: LncRNAs like GATA6-AS1 suppress FAO to maintain a proliferative, less differentiated state reminiscent of fetal CMs, where glycolysis dominates [34]. Maturation (FAO-dependent) state, LncRNAs such as BANCR enhance FAO to meet the energy requirements of contracting mature CMs, coinciding with cell-cycle exit and structural stabilization [29]. Therapeutic strategies targeting these lncRNAs may thus require precise temporal control—promoting glycolysis (via GATA6-AS1 inhibition) early in regeneration to boost proliferation, followed by FAO activation (via BANCR) to support functional recovery. Therefore, finely regulating cardiac metabolism homeostasis is crucial, and recent years have seen growing interest in the role of lncRNAs in this regulation.

2.2.1. The pivotal role of glycolysis

LncRNAs are vital in regulating biological processes closely related to metabolism and mitochondrial function. Glycolysis is a key pathway for energy acquisition in the heart. Disruptions in lncRNA regulation can lead to metabolic disorders and cardiovascular complications. For instance, LncHrt is significantly downregulated after myocardial infarction, increasing the interaction between CDK5 and SIRT2, inhibiting the LKB1-AMPK signaling pathway. LncHrt promotes LKB1-AMPK pathway activation, thus regulating cardiac energy metabolism and alleviating pathological remodeling post-infarction. Knockdown of LncHrt impairs mitochondrial respiratory function, reducing fatty acid oxidation and complex I oxidative phosphorylation capacity [42]. The LKB1-AMPK signaling pathway, a central regulator of cellular energy homeostasis, highlights metabolic lncRNA function (Showing in [Table 2]).

Table 2.

The regulatory role of lncRNA in cardiac metabolic reprogramming.

lncRNA	Target/pathway	Cell type/Model	Metabolic effects	Proliferation/Regeneration Effect	Disease model	Ref
LncHrt	CDK5/SIRT2 → LKB1-AMPK	cardiomyocyte	Fatty acid oxidation ↑, mitochondrial respiratory function restored	↑Proliferation (AMPK activation promotes division)	myocardial infarction	[42]
H19	LIN28a/let-7 → PDK1	cardiomyocyte	Glycolysis increases, ↑ATP production increases	↑Regeneration (simulating embryonic metabolic state)	myocardial infarction	[43,44]
Linc00092	Unclear (regulation of glycolytic enzymes)	cardiac fibroblast	Glycolysis ↓ inhibits fibroblast activation	↓ Fibrosis (inhibits fibroblast activation)	myocardial fibrosis	[45]
MEG3	p53/FUS → Mitochondria	Cardiomyocyte	Mitochondrial dysfunction↓	↓ Apoptosis (reducing hypoxia damage)	Hypoxic myocardial injury	[46]
H19	MOXI peptide/MTP complex	cardiomyocyte	Fatty acid beta oxidation ↑	↑ Survival (reduces lipotoxicity)	Metabolic cardiomyopathy	[47]
LINC00116	MTLN peptide/CPT1B-CYB5B	cardiomyocyte	Accumulation of VLCFA ↓, insulin sensitivity ↑	↑ Proliferation (improves metabolic flexibility)	Insulin resistant cardiomyopathy	[48]
LIPTER	Lipid droplet transporter protein	cardiomyocyte	Lipid transport ↑, reducing lipid toxicity	↑ Function (Reducing Lipotoxicity)	High fat diet induces cardiomyopathy	[49]
GAS5	miR-26a-5p/PDE4B	cardiomyocyte	Regulation of fatty acid transporter expression	↑Hypertrophy (related to pathological hypertrophy)	Metabolic syndrome related heart failure	[50]
CPAL	Glucose/lipid metabolism related proteins	cardiomyocyte	ATP ↓ promotes metabolic disorders and pyroptosis	↓ Survival (promotes pyroptosis)	myocardial ischemia	[51]
CARL	miR-539/PHB2	cardiomyocyte	Mitochondrial homeostasis ↑ inhibits apoptosis	↑Regeneration (inhibition of apoptosis)	myocardial infarction	[52]
Caren	Mitochondrial DNA damage response	cardiomyocyte	Mitochondrial function protection ↑	↑ Survival (resistance to stress injury)	Stress-Induced Cardiomyopathy	[53]
KCND1	YBX1	cardiomyocyte	Inhibit pathological hypertrophy	↓ Hypertrophy (protective effect)	Pressure overload induced myocardial hypertrophy	[54]
LARP7	7SK complex/SIRT1	cardiomyocyte	Mitochondrial synthesis ↑	↑Function (Improving Energy Supply)	heart failure	[55]
CAIF	p53	cardiomyocyte	Autophagy inhibition ↑	↓ Apoptosis (reducing autophagic death)	Ischemia-reperfusion injury	[56]
lncRNA-TUG1	HIF-1α/FUS	cardiomyocyte	Mitochondrial damage ↓, anti necrosis	↑ Survival (anti necrosis)	myocardial infarction	[57]

(Note: ↑ indicates upregulation/activation, ↓ indicates inhibition).

Research by Mohsin Khan's team revealed a new role for LIN28a in cardiac repair, showing that reintroducing LIN28a in adult cardiac tissue-derived stem cells (CTSCs) enhances cell proliferation and survival while reducing senescence. LIN28a inhibits let-7 and activates PDK1, promoting a metabolic shift from oxidative phosphorylation to glycolysis, enhancing cell survival post-infarction. Overexpression of LIN28a in neonatal rat ventricular myocytes increases glycolysis and ATP production, with lncRNA-H19 identified as a target of LIN28a [43,44]. LIN28a and its target lncRNA-H19 has been established as critical links between RNA regulation and metabolic reprogramming in cardiac repair [44].

In human cardiac tissue, Linc00092 is primarily expressed in cardiac fibroblasts and inhibits their activation by altering glycolysis. Knocking down Linc00092 activates cardiac fibroblasts and enhances glycolysis, while its overexpression rescues activated fibroblasts and downregulates glycolysis, indicating its potential as a therapeutic target for cardiac fibrosis [45]. Linc00092 reveals that lncRNAs regulating cardiac fibroblast metabolism is a novel target to impede cardiac fibrosis.

Beyond its role in glycolysis, other lncRNAs also participate in metabolic regulation through different mechanisms. LncRNA MEG3 modulates energy metabolism by affecting mitochondrial function. Initially recognized for its tumor-suppressive effects, MEG3 plays a significant role in cardiac metabolic regulation and mitochondrial function. Under hypoxic conditions, Meg3 is upregulated by p53, participating in apoptosis regulation by binding to FUS, influencing cardiovascular disease development. Loss of MEG3 leads to mitochondrial dysfunction and energy metabolism imbalance [46]. MEG3's influence over p53 and FUS suggests it is a vital component in hypoxic responses and metabolic equilibrium in the heart.

In summary, lncRNAs significantly regulate glycolytic enzymes and CM energy metabolism, enhancing our understanding of their roles in cardiac diseases and providing potential therapeutic targets.

2.2.2. The double-edged sword of fatty acid oxidation

In the adult heart, FAO is the primary energy source, accounting for approximately 70 % of ATP production. While FAO is efficient in energy generation, it also produces a higher amount of reactive oxygen species (ROS) compared to glycolysis. Elevated ROS levels can induce oxidative stress, DNA damage, and cell cycle arrest, limiting CM proliferation and regenerative capacity.

lncRNAs have emerged as pivotal modulators in the regulation of cardiac FAO, balancing its beneficial and detrimental effects through influencing lipid uptake, transport, and β-oxidation pathways. For example, H19, an extensively studied lncRNA, interacts with multiple proteins involved in metabolic regulation [47] (Showing in [Table 2]). Notably, Makarewich et al. identified that H19 encodes a mitochondrial micropeptide named MOXI, which binds to mitochondrial trifunctional protein (MTP), a key enzyme complex catalyzing the final steps of long-chain fatty acid β-oxidation in mitochondria [58]. By modulating MTP activity, MOXI influences mitochondrial fatty acid fluxes, energy homeostasis, and reactive oxygen species (ROS) production, thereby affecting cardiac mitochondrial function and overall myocardial energetics.

Similarly, the microprotein Mitoregulin (MTLN), encoded by the lncRNA LINC00116, directly interacts with enzymes such as CPT1B (carnitine palmitoyltransferase 1B), a rate-limiting enzyme in FAO, and CYB5B, involved in electron transport and lipid metabolism [48]. MTLN deficiency results in the accumulation of very long-chain fatty acids (VLCFAs), which can cause lipotoxicity and mitochondrial dysfunction. Interestingly, MTLN deficiency also appears to confer protection against insulin resistance in cardiac tissue, suggesting that transient suppression of FAO pathways could mitigate lipotoxic damage and improve cardiac metabolic flexibility in disease contexts [48].

In addition to endogenous modulators, lncRNA-mediated regulation of lipid droplet dynamics plays a vital role in managing cardiac lipid homeostasis. LIPTER, a recently characterized lncRNA associated with lipid droplet transport in CMs, facilitates the mobilization of lipid stores. Overexpression of LIPTER in high-fat diet-fed mice alleviates cardiac lipotoxicity, preserves mitochondrial integrity, and improves cardiac function—highlighting its protective role against lipid overload and metabolic stress [49]. This underscores the importance of proper lipid trafficking in preventing lipotoxic heart failure.

Complementary to lipid transport, lncRNAs also regulate fatty acid oxidation through post-transcriptional mechanisms. LncRNA-GAS5 further influences FAO through its regulation of fatty acid transport proteins. It modulates the expression of fatty acid transporters via interactions with microRNAs such as miR-26a-5p and proteins like PDE4B, thereby impacting lipid uptake and oxidation [50]. Dysregulation of GAS5 may contribute to abnormal lipid accumulation and metabolic derangements associated with cardiac hypertrophy and ischemic injury (Showing in [Table 2]).

In the setting of myocardial infarction, certain lncRNAs exacerbate metabolic disturbances. For instance, lncRNA CPAL is upregulated post-injury and correlates with decreased ATP production, as well as reduced expression of enzymes involved in glucose and lipid metabolism. CPAL appears to promote metabolic dysfunction and pyroptosis—an inflammatory form of programmed cell death—in CMs [51]. Silencing CPAL restores energetic competence and mitigates inflammatory damage, suggesting that targeting such lncRNAs may represent a novel therapeutic strategy for ischemic heart disease (show in [Fig. 2]).

Fig. 2.

lncRNAs in cardiac regeneration by regulating metabolic reprogramming. The figure summarizes the function lncRNAs in the process of cardiac regeneration (including cardiomyocyte differentiation, cardiomyocyte proliferation, cardiomyocyte apoptosis) by regulating cardiac metabolism. PDK, pyruvate dehydrogenase kinase; MDH2, malate dehydrogenase; Myh10, non-muscle myosin IIB; MTP, mitochondrial trifunctional protein; LDH, lactic dehydrogenase; PDH, pyruvate dehydrogenase complex; OXPHOS, oxidative phosphorylation; TCA cycle, tricarboxylic acid cycle; Ac, acetylation; SIRT3, sirtuin 3.

In summary, lncRNAs intricately regulate cardiac FAO, with both protective and maladaptive consequences depending on the context. Their modulation affects mitochondrial function, ROS production, and lipotoxicity, illustrating how FAO can be both a vital energy source and a potential contributor to cardiac injury if dysregulated. Understanding these dual roles is paramount for developing precise interventions that harness the energy-providing capacities of FAO while preventing its harmful effects.

2.2.3. Mitochondrial dynamic homeostasis

Maintaining the integrity and function of mitochondria is paramount for CM survival and performance, given their central role in energy production, calcium signaling, and apoptosis regulation. Cardiomyocytes are highly dependent on mitochondrial oxidative phosphorylation to meet their energy demands, making them particularly vulnerable to mitochondrial dysfunction. Accordingly, a complex interplay of regulatory mechanisms, including lncRNAs, orchestrates mitochondrial biogenesis, dynamics (fusion and fission), mitophagy, and overall homeostasis within the heart. These mechanisms are crucial for maintaining cardiac health and preventing the onset of heart failure.

Emerging evidence suggests that mitochondrial translation itself influences CM proliferation and adaptation to stress. For example, in a mouse model with a heterozygous deletion of the Mrps5 gene, reduced mitochondrial translation stimulated CM proliferation via the ATF4 signaling pathway, thereby facilitating cardiac regeneration [59]. These findings highlight how cells can sense and respond to disruptions in mitochondrial proteostasis, activating compensatory pathways that promote cell survival and tissue repair.

Furthermore, recent studies have identified several lncRNAs that directly regulate mitochondrial function and protect against CM injury under stress conditions. The antibiotic doxycycline, for instance, can trigger the mitochondrial stress response and enhance cardiac regeneration post-myocardial infarction. This effect involves lncRNA CARL, interacting with microRNA-539 to release its inhibitory effect on PHB2, which is a known regulator of mitochondrial homeostasis. The increase in PHB2 prevents CM apoptosis during myocardial infarction, suggesting a protective role for the CARL/miR-539/PHB2 axis [52] (Showing in [Table 2]).

Similarly, the novel lncRNA Caren is highly expressed in mouse CMs under normal conditions but is significantly reduced under stress. This reduction is associated with mitochondrial dysfunction and DNA damage responses, suggesting that Caren plays a protective role against heart failure by safeguarding mitochondrial integrity [53]. LncKCND1, which is downregulated in pathological cardiac hypertrophy, interacts with YBX1 and protects against TAC-induced cardiac hypertrophy, emphasizing its role in maintaining mitochondrial function and preventing maladaptive remodeling [54].

Other lncRNAs regulate mitochondrial processes through different mechanisms, such as modulating protein activity. LARP7, for example, associates with the 7SK ribonucleoprotein complex and regulates mitochondrial synthesis by controlling SIRT1 activity. LARP7 knockout leads to reduced SIRT1 expression and impaired mitochondrial function, showcasing the importance of LARP7 in maintaining mitochondrial biogenesis [55].

Moreover, lncRNAs are also involved in regulating autophagy, a crucial process for removing damaged mitochondria and maintaining cellular homeostasis. LncRNA-CAIF inhibits autophagy in CMs by binding to p53, suggesting a role in modulating the cellular response to stress and potential as a therapeutic target in heart diseases [56]. The HIF-1α/TUG1/FUS signaling pathway also plays a pivotal role in myocardial infarction, with TUG1 silencing showing protective effects against mitochondrial damage and necrosis, thus implicating TUG1 as a regulator of mitochondrial integrity under ischemic conditions [57] (Showing in [Table 2]).

In summary, lncRNAs play multifaceted roles in the maintenance of mitochondrial dynamic homeostasis in CMs. They influence mitochondrial translation, biogenesis, autophagy, and protect against stress-induced mitochondrial dysfunction. These functions highlight their potential significance as therapeutic targets for preventing or treating heart failure and other cardiac pathologies related to mitochondrial impairments.

3. Epigenetic roles of lncRNAs in cardiac development and remodeling

The roles of lncRNAs in epigenetics have gained increasing recognition as critical regulators of cardiac development and remodeling, marking them as a significant focus in cardiovascular biology. These insights challenge the conventional understanding of gene expression regulation and underscore the importance of lncRNAs in influencing cardiac structure and function. Once considered transcriptional “dark matter,” lncRNAs are now understood to exert profound effects on cardiac development and disease through epigenetic mechanisms, including chromatin modification, histone modification, and transcriptional regulation [57] (Showing in [Table 3]).This is crucial given the limited regenerative capacity of the adult heart, making understanding the epigenetic factors that affect CM proliferation and differentiation is critical for developing regenerative therapies.

Table 3.

Epigenetic and metabolic reprogramming roles of lncRNAs in cardiac development and pathological remodeling.

lncRNA	Target/Pathway	Epigenetic Mechanism	Cell Type	Metabolic Mode	Biological Function	Disease Model	Ref
linc1405	Mesp1 (cardiac progenitor differentiation)	Mediates WDR5/GCN5 complex, opens chromatin	Cardiac progenitors	Glucose metabolism: May support differentiation via energy	Promotes early cardiac development	Cardiac developmental defects	[26]
ANRIL	p15 (cell cycle)/PRC1/PRC2	PRC1/2-dependent H3K27me3 silencing of p15	Cardiomyocytes, vascular cells	Lipid metabolism: Promotes atherosclerosis (lipid deposition); Glucose metabolism: Indirectly affects via inflammatory signaling	Promotes proliferation, exacerbates vascular pathology	Atherosclerosis, cardiac hypertrophy	[60]
NPPA-AS1	SFPQ-NONO (DNA repair)	Competitively inhibits SFPQ-NONO complex	Cardiomyocytes	Glucose metabolism: DNA repair requires ATP; FAO: May enhance energy supply during regeneration	Promotes post-injury proliferation and regeneration	Myocardial infarction	[61]
Chaer	Hypertrophy genes (ANP/BNP)	Inhibits PRC2-mediated H3K27me3, activates hypertrophy genes	Cardiomyocytes	FAO: Pathological hypertrophy involves metabolic remodeling; Glucose metabolism: Shifts to glycolysis (Warburg effect)	Promotes pathological hypertrophy and fibrosis	Cardiac hypertrophy, heart failure	[62]

LncRNAs participate in complex regulatory networks that impact the epigenetic landscape of cardiac cells. These lncRNAs often function by recruiting chromatin-modifying complexes to specific genomic loci, thus modulating gene expression programs that are crucial for cardiac development and remodeling in response to injury or stress.

For example, the lncRNA linc1405 serves as a scaffold to mediate the formation of a transcriptional regulatory complex involving WDR5 and GCN5, thereby directly impacting the expression of the master developmental gene Mesp1 [26]. This suggests that linc1405 is essential for establishing and maintaining the transcriptional identity of cardiac progenitor cells during early cardiogenesis.

Another prominent lncRNA, ANRIL (antisense non-coding RNA in the INK4 locus), exemplifies the epigenetic regulation of cell proliferation. ANRIL forms complexes with Polycomb Repressive Complex 1 (PRC1) and PRC2, leading to the repression of the tumor suppressor gene p15/CDKN2B, promoting cell proliferation [60]. Notably, ANRIL expression correlates with atherosclerosis severity in humans, implying a link to smooth muscle and endothelial cell proliferation in vascular lesions. Deletion of ANRIL in mice significantly impacts cardiac development, indicating its critical role in regulating CM proliferation and cardiac maturation via epigenetic mechanisms.

NPPA-AS1, a unique lncRNA transcribed antisense to the natriuretic peptide precursor type A (NPPA) gene, influences CM proliferation and cardiac regeneration [61]. While NPPA-AS1 absence does not affect normal cardiac development, it promotes CM proliferation after injury, improving cardiac function, and reducing infarct size in mouse models of myocardial infarction. Mechanistically, NPPA-AS1 competes with SFPQ, preventing it from binding to NONO, thereby inhibiting efficient DNA repair mechanisms and leading to cell cycle arrest [61]. The deletion of NPPA-AS1 enhances SFPQ-NONO binding, facilitating DNA repair processes and enabling CMs to proliferate after cardiac injury, highlighting the therapeutic potential of manipulating NPPA-AS1 levels to induce cardiac regeneration.

Cardiac Hypertrophy-Associated Epigenetic Regulator (CHARE) is another crucial lncRNA involved in the development of cardiac hypertrophy [62]. Chaer interacts with PRC2, inhibiting trimethylation of histone H3 lysine 27 (H3K27me3) at cardiac hypertrophy-related gene promoters, which is essential for epigenetic reprogramming and the induction of those genes. By antagonizing H3K27me3 deposition, Chaer promotes the transcriptional activation of genes involved in cardiac hypertrophy, suggesting that targeting Chaer and its interactions with PRC2 may represent a promising approach for reversing cardiac remodeling and preventing heart failure (Showing in [Table 3]).

In conclusion, lncRNAs play pivotal roles in shaping the epigenetic landscape of the heart. By modulating chromatin structure, recruiting chromatin-modifying complexes, and regulating histone modifications, these lncRNAs significantly influence cardiac development, CM proliferation, and the response to cardiac injury. Recognizing the intricate epigenetic mechanisms mediated by lncRNAs offers new avenues for developing targeted therapeutic strategies to promote cardiac regeneration, prevent adverse remodeling, and treat heart failure.

4. Metabolic reprogramming and lncRNA biology: milestones in cardiac regeneration

Over the past decade, the intersecting fields of cardiac metabolism and lncRNA biology have yielded several landmark discoveries, advancing our understanding of cardiac regeneration mechanisms and opening new therapeutic avenues. As summarized in [Table 4], these milestone breakthroughs—ranging from metabolic reprogramming to lncRNA-mediated epigenetic regulation—have elucidated key metabolic switches and lncRNA functions that enable cardiomyocyte proliferation, survival, and functional recovery post-injury.

Table 4.

Milestone Discoveries in Metabolic Reprogramming and lncRNA Regulation for Cardiac Regeneration.

Discovery	Key Mechanism	Impact	Reference
OSKM Reprogramming	Reverts adult CMs to fetal-like state	Enables CM renewal in mammals	[19,20]
α-KG/KDM5 Axis	Cpt1b inactivation → H3K4me3 demethylation	Promotes CM cell cycle re-entry	[23]
LIN28a-lncRNA-H19 Cascade	Metabolic shift to glycolysis in CTSCs	Enhances stem cell survival post-MI	[43,44]
Mitochondrial Stress-Induced Regeneration	Doxycycline → ATF4 activation → CM proliferation	Non-invasive regeneration strategy	[59]
NPPA-AS1/SFPQ Interaction	Competes with SFPQ to enable DNA repair in CMs	Improves post-injury regeneration	[61]

For instance, the OSKM reprogramming approach reverts adult CMs to a fetal-like state, enabling CM renewal in mammals [19,20], while the α-KG/KDM5 axis promotes CM cell cycle re-entry through Cpt1b inactivation and subsequent H3K4me3 demethylation [23]. The LIN28a-lncRNA-H19 cascade drives a metabolic shift toward glycolysis in cardiac stem cells, enhancing their survival after myocardial infarction [43,44]. Meanwhile, mitochondrial stress-induced regeneration via doxycycline-dependent ATF4 activation offers a non-invasive strategy to stimulate CM proliferation [59], and the NPPA-AS1/SFPQ interaction competitively enables DNA repair in CMs, improving post-injury regeneration [61].

These breakthroughs, detailed in [Table 4], collectively emphasize the central theme that precise metabolic reprogramming—both at the level of substrate utilization and epigenetic remodeling—along with tightly controlled lncRNA networks underlie CM proliferation and regeneration. They also provide a proof of principle for targeting metabolism and lncRNA pathways as promising therapeutic strategies in cardiac repair interventions. Looking forward, integrating these insights with emerging single-cell and epigenomic technologies will deepen mechanistic understanding and streamline the development of lncRNA and metabolism-based regenerative therapies. Further exploration of temporal regulation—balancing glycolytic activation for proliferation with timely FAO for maturation—remains a critical objective to optimize clinical translation.

5. Therapeutic potential and clinical translation

The insights gained from studying metabolic reprogramming and lncRNA regulation in cardiac regeneration have significant therapeutic implications. By identifying key metabolic targets and lncRNA regulators, researchers can develop novel strategies for promoting cardiac repair and regeneration after myocardial infarction. These strategies may involve pharmacological interventions that modulate metabolic pathways such as glycolysis and FAO, or gene therapies that target specific lncRNAs.

Gene therapy approaches targeting lncRNAs and downstream effectors could provide a much more specific and adjustable avenue for promoting cardiac regeneration.

6. Challenges and future directions

Despite the significant progress in understanding the role of lncRNAs in cardiac metabolism and regeneration, several challenges remain: ①Mechanism of action: Elucidating the precise mechanisms by which lncRNAs regulate cardiac metabolism and regeneration. ②Target specificity: Improving the specificity of lncRNA-based therapies to minimize off-target effects.③Delivery: Developing efficient and targeted delivery systems for lncRNAs to CMs. New targeted nanotechnologies are important for future lncRNA studies [63]. ④Clinical trials: Conducting well-designed clinical trials to evaluate the safety and efficacy of lncRNA-based therapies in patients with heart disease.

Future research should focus on addressing these challenges to accelerate the clinical translation of lncRNA-based therapies for cardiac regeneration. This includes exploring the roles of novel lncRNAs in cardiac metabolism, developing innovative delivery strategies, and conducting rigorous preclinical and clinical studies to evaluate the therapeutic potential of lncRNAs in heart disease. Exploring new machine learning methodologies to identify lncRNAs for cardiac regeneration is also critical for the progress of this field.

Authors' contributions

Conceptualization, Xueping WU, Yehui Lv, Zhihong LI and Zhifang YANG; Formal analysis, Yehui Lv; Writing–original draft, Xueping WU; Writing–review & editing, Zhihong LI and Zhifang YANG.All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate

The study was permitted by the Law of the People's Republic of China on the Protection of Wildlife, and the protocol was approved by the Institutional Animal Care Committee of Shanghai University of medicine & Health Sciences, China (Permit Number: 2022-GZR-08).

Availability of data and materials

The original contributions presented in the study are included in the article, and further inquiries can be directed to the corresponding authors.

Funding

This work was supported by the construction project of high-level local universities, Shanghai University of Medicine and Health Sciences(E1-2601-23-201006).2024 Shanghai University of Medicine & Health Sciences Research Fund(SSF-24-08-01). Self assembled nano biomaterials for myocardial infarction repair(HXXM-20-08-002).

Declaration of competing interest

The authors declare that they have no competing interests.