Lactylation at the metabolic-epigenetic interface in cardiovascular diseases: context-dependent mechanisms and translational roadmap

Graphical abstract

Highlights

• •Lactylation bridges metabolic dysfunction and gene regulation in heart disease.
• •Histone lactylation regulates immune polarization and cardiomyocyte regeneration.
• •Targeting lactylation pathways offer new precision cardiovascular therapeutics.

Abstract

Background: Lysine lactylation has redefined lactate’s biological role from a metabolic byproduct to a signaling molecule. This post-translational modification directly couples cellular energetics with gene regulation, creating a metabolic-epigenetic axis particularly relevant to cardiovascular pathophysiology. Ischemic and inflammatory stress drive glycolytic reprogramming and lactate accumulation in these diseases. Lactylation modifies both histone and non-histone proteins, enabling metabolic states to reshape chromatin accessibility and protein function. However, therapeutic translation faces critical barriers. These include incomplete characterization of the cardiovascular lactylome, absence of selective pharmacological modulators, and insufficient understanding of how lactylation effects vary across cell types, disease stages, and metabolic contexts.

Aim of Review: We systematically dissect lactylation biology across 5 cardiovascular pathologies to define regulatory mechanisms and therapeutic vulnerabilities. We examine glycolysis-lactylation circuits driving pulmonary arterial smooth muscle hyperproliferation in hypertension; dual roles in atherosclerotic plaque stability versus calcification; M2 macrophage-mediated repair versus fibrotic remodeling in myocardial infarction; the metabolic paradox of lactate accumulation with reduced α-myosin heavy chain lactylation impairing contractility in heart failure; and neonatal glycolytic metabolism enabling histone lactylation-driven cardiomyocyte proliferation with metabolic barriers in diabetic contexts.

Key Scientific Concepts of Review: Lactylation functions through dual substrates: histone modifications orchestrate inflammatory resolution and cell cycle activation, while non-histone modifications (α-myosin heavy chain, Snail1) directly govern contractility and pathological remodeling. Context-dependent dichotomies emerge across diseases, with protective angiogenesis versus maladaptive fibrosis in infarction and plaque stabilization versus calcification in atherosclerosis. Critically, metabolic paradoxes challenge lactate-lactylation correlations: heart failure shows lactate accumulation yet reduced modification, while diabetic advanced glycation end-products competitively inhibit lactylation. Therapeutic strategies require integrating metabolic reprogramming, site-selective targeting, and temporal control. This review systematically dissects these mechanistic complexities to establish a translational framework that guides precision cardiovascular medicine through metabolic-epigenetic intervention strategies.

Introduction

Post-translational modifications have undergone revolutionary expansion with the identification of lysine lactylation (Kla), an epigenetic modification that directly links cellular metabolism to gene regulation. This discovery challenges conventional perspectives on metabolic intermediates and their roles in cardiovascular diseases (CVDs) [1]. In 2019, Zhang and colleagues transformed scientific understanding by revealing that lactate, long dismissed as metabolic waste, serves as an active chromatin modifier. Their investigation of the Warburg effect uncovered histone lactylation as a direct consequence of enhanced glycolytic activity, mapping 28 distinct lactylation sites across mammalian histones [2]. Subsequent research has revealed intricate regulatory networks that control lactylation via multiple pathways. The enzymatic machinery relies on lactyl-coenzyme A (lactyl-CoA) as the primary donor substrate [3], with p300 and CREB-binding protein (CBP) identified as key “writers” installing lactyl groups [4], while class I histone deacetylases (HDAC1-3) function as “erasers” removing these modifications [5]. Beyond enzymatic control, the glyoxalase system contributes significantly to lactylation dynamics. Methylglyoxal conversion to lactoylglutathione (LGSH) via glyoxalase 1 creates alternative lactylation donors [6], [7], [8], with intriguing functional divergence as exemplified by D-lactylation from LGSH to promote inflammation whereas L-lactylation suppresses it [9].

Additional regulatory mechanisms continue emerging, including alanyl-tRNA synthetase (AARS1) acting as both lactate sensor and direct protein modifier [10]. Glyceraldehyde 3-phosphate can induce cysteine lactylation of KEAP1, thereby activating NRF2-mediated oxidative stress responses [11], [12], [13]. Such diversity in lactylation pathways underscores the sophisticated integration of metabolism with cellular regulation. Importantly, lactylation exhibits tissue-specific patterns across diverse pathological contexts, with H3K18 lactylation marking distinct active enhancers in neuroinflammatory and ischemic injury models, suggesting context-dependent regulatory programs that may extend to cardiovascular tissues experiencing metabolic stress [14]. The cardiovascular system offers an ideal context for exploring lactylation's physiological and pathological roles, given its extreme metabolic demands and vulnerability to ischemic insults that elevate lactate levels. Clinically, elevated circulating lactate has been associated with insulin resistance, dyslipidemia, hypertension, and increased cardiometabolic risk, positioning lactate as a potential biomarker for metabolic dysfunction in cardiovascular disease [15], [16], [17]. In cardiovascular inflammation, lactate modulates macrophage behavior through HMGB1 lactylation patterns [4]. The documented links between aberrant glycolysis, methylglyoxal accumulation, and diabetic cardiovascular complications implicate lactylation as a central regulatory node [7], [8]. These discoveries open novel therapeutic avenues. Targeting specific writers and erasers offers precision pharmacological intervention points [18], [19], [20]. Engineering specialized CoA-transferases to manipulate lactyl-CoA levels represents another promising strategy [21], [22].

This comprehensive review capitalizes on the rapidly expanding knowledge on lactylation-mediated processes in cardiovascular disease, with particular emphasis on recent mechanistic advances and their therapeutic implications in different disorders as explained in each section. Through systematic examination of molecular mechanisms, cellular consequences, and clinical potential, we aim to illuminate novel therapeutic targets and accelerate translation into precision cardiovascular medicine. The convergence of metabolic and epigenetic regulation through lactylation represents a paradigmatic shift in cardiovascular therapeutics, positioning this review as an essential resource for advancing patient care through innovative therapeutic strategies targeting metabolic-epigenetic interventions.

Literature search methods and processes

Comprehensive bibliometric analysis of SCOPUS database using search terms 'lactylation' and 'cardiovascular diseases' recieved 1,867 publications (Fig. 1A), demonstrating substantial growth from 25 publications in 2020 to 997 in 2024. VOSviewer network visualization revealed three distinct thematic clusters: genetic mechanisms and pharmacological interventions (231 items, red nodes), metabolic pathways and inflammatory processes (223 items, blue nodes), and cancer biology with tumor microenvironment (199 items, green nodes). Each cluster presented systematic research gaps informing the mechanistic framework for Sections 3-7.

Fig. 1.

Bibliometric network analysis of lactylation research in cardiovascular diseases. (A) Network visualization from VOSviewer analysis of 1,867 SCOPUS publications (keywords: 'lactylation' and 'cardiovascular diseases'; October 2024). Three primary clusters: genetic mechanisms (231 items, red), metabolic pathways (223 items, blue), and cancer biology (199 items, green). Node size reflects keyword frequency; lines represent co-occurrence relationships. (B) Temporal evolution (2020–2024) showing therapeutic applications and disease mechanisms as predominant research foci. Irrelevant literature excluded through manual inspection.

The primary cluster concentrated on histone modifications in immune cells and cancer systems, revealing cardiovascular-specific gaps including limited non-histone protein lactylation investigation in vascular smooth muscle cells, cardiomyocytes, and endothelial cells; sparse evidence linking lactylation enzymes to disease progression; and absent tissue-specific lactylome mapping, directing focus toward VSMC regulation (Section 4.1), contractile protein lactylation (Section 6.3), and cardiomyocyte regeneration (Section 7). The second cluster predominantly interpreted lactate as glycolytic end-product rather than chromatin-modifying substrate, with inflammatory studies focusing on NLRP3/NF-κB pathways without integrating lactylation-mediated transcriptional regulation as mechanistic intermediaries. Temporal focus on acute perturbations over chronic disease dynamics justified examination of immune regulation in atherosclerosis (Section 4.1.2), post-infarction macrophage polarization (Sections 5.2-5.3), and metabolic-epigenetic coupling in cardiac hypertrophy (Sections 6.1-6.2). The third cluster emphasized cancer biology, with tumor microenvironment parallels (hypoxia, acidosis, immune suppression) lacking direct cardiovascular validation, necessitating disease-specific investigations in pulmonary arterial hypertension (Section 3.1), atherosclerotic microenvironment (Section 4), and post-infarction repair (Section 5).

Temporal co-occurrence analysis (Fig. 1B) revealed that despite “therapeutic applications” and “disease mechanisms” constituting prominent network nodes, mechanistic bridges connecting metabolic lactate accumulation to functional lactylation consequences remained underdeveloped. This disconnects between metabolic observations and epigenetic mechanisms exposed gaps in understanding causality, and therapeutic targetability. Recognition of this mechanistic void informed sections 3-7 organizational structure, systematically addressing how lactate dysregulation translates into lactylation-mediated pathology across vascular pressure disorders, atherosclerosis, myocardial infarction, heart failure, and impaired regeneration. By connecting bibliometric gap identification with mechanistic analysis, this review establishes evidence-based framework advancing cardiovascular lactylation research toward therapeutic translation.

Lactate dysregulation in hypertensive vascular diseases

Post-translational lactylation has been identified as a fundamental mechanism linking metabolic alterations to cardiovascular pathophysiology. In abnormal vascular pressure disorders, elevated glycolytic activity generates lactate concentrations that extend beyond metabolic functions, serving as bioactive molecules mediating chromatin remodeling and cellular reprogramming. This reconceptualization of lactate from metabolic byproduct to active regulatory molecules represents a paradigm shift in cardiovascular pathology. However, clinical translation remains challenging due to limited human tissue validation and the complexity of metabolic-vascular interactions.

Pulmonary arterial hypertension (PAH)

Glycolytic reprogramming and lactate accumulation

In established PAH, chronic metabolic reprogramming maintains glycolytic phenotypes independent of ongoing hypoxic stress, with vascular cells exhibiting cancer-like metabolism characterized by apoptosis resistance and uncontrolled proliferation [23], [24]. This sustained metabolic dysregulation is orchestrated by the RASSF1A-HIF-1α transcriptional axis (Fig. 2), which forms a self-reinforcing circuit: hypoxia-triggered RASSF1A stabilization (via NOX-1 and PKC-mediated phosphorylation) reciprocally activates HIF-1α-mediated RASSF1A transcription via hypoxia response elements [25]. Once established, this circuit autonomously drives glycolytic enzyme expression through the HIF-1α/PDK1&PDK2/p-PDH-E1α pathway, promoting lactate accumulation and subsequent histone lactylation [26] that reinforces the glycolytic phenotype through epigenetic mechanisms. Critically, while acute hypoxic responses depend on mitochondrial complex III-derived ROS for HIF-1α stabilization [27], chronic PAH maintains HIF-1α activity through alternative mechanisms including succinate accumulation, prolyl hydroxylase inhibition by glycolytic intermediates, and lactylation-mediated positive feedback loops [26], rendering the disease state resistant to normoxic reversal. Complementing these core pathways, the BMPR2-miR-124-PTPB1 axis orchestrates metabolic switching from oxidative phosphorylation towards aerobic glycolysis in pulmonary artery endothelial cells [28], [29], while platelet-derived TGF-β1 stimulates PKM2 upregulation through the mTOR/c-Myc/PTBP-1/hnRNPA-1 cascade in smooth muscle cells [30], further amplifying glycolytic capacity and establishing the metabolic foundation for lactate-driven pathological signaling.

Fig. 2.

Pulmonary hypertension: vascular remodeling driven by lactic acid.

Beyond its role as a metabolic product, lactate functions as a multifaceted signaling molecule that drives vascular remodeling through both direct enzymatic pathways and receptor-mediated mechanisms. Lactate directly promotes PASMC proliferation via the PFKFB3-ERK1/2-calpain-2 pathway [31], while simultaneously exerting context-dependent effects through its cognate receptor GPR81. In inflammatory contexts, lactate-GPR81 signaling negatively regulates TLR-induced NLRP3 inflammasome activation through GPR81-ARRB2 interactions that suppress NFκB activation and IL-1β production in macrophages, establishing an immunomodulatory feedback mechanism that limits sterile inflammation during acute tissue injury [32]. However, in chronic hypoxic microenvironments characteristic of pulmonary vascular remodeling, this pathway assumes a maladaptive role: hypoxia-induced HIF-1α transcriptionally upregulates GPR81 expression while simultaneously enhancing LDHA-mediated lactate production and release, creating a feed-forward loop wherein extracellular lactate activates GPR81 to promote mesenchymal progenitor cell self-renewal and sustained fibrogenic activity [33]. The spatial distribution of GPR81-expressing progenitor cells at sites of active tissue remodeling, coupled with their responsiveness to both endogenous and exogenous lactate, suggests that accumulated lactate functions not merely as a metabolic waste product but as a paracrine signal amplifying pathological cell proliferation [33]. Experimental validation from platelet TGF-β1-deficient mice, which demonstrate reduced glycolytic markers, diminished lactate levels, and improved vascular phenotypes, substantiates the pathogenic relevance of lactate-driven processes. The convergence of glycolytic enzyme upregulation, direct lactate signaling via PFKFB3-ERK1/2 [31], and context-dependent receptor activation through GPR81 establishes a microenvironment that favors persistent cellular activation and vascular remodeling, linking metabolic dysregulation to structural pathology in PAH [32], [33].

The pathological role of glycolytic reprogramming in PAH stands in stark contrast to protective glycolytic adaptations observed in other vascular contexts. In atheroprone arterial regions exposed to disturbed flow, endothelial PRKAA1 (AMPKα1) upregulation drives adaptive glycolysis that sustains endothelial proliferation and barrier integrity; selective Prkaa1 deletion reduces glycolysis and accelerates atherosclerotic lesion formation through compromised endothelial viability [34], [35]. This dichotomy underscores the context-dependent nature of metabolic reprogramming: whereas chronic hypoxia-induced glycolysis in PAH promotes maladaptive PASMC proliferation and vascular remodeling through lactate-GPR81-HIF-1α feedforward circuits [33], disturbed flow-induced glycolysis in atherosclerosis supports adaptive endothelial repair responses [34]. The divergent outcomes likely reflect differences in cellular compartmentalization (smooth muscle versus endothelial), hemodynamic triggers (hypoxia versus disturbed shear stress), and temporal dynamics (chronic pathological activation versus acute adaptive responses). These findings emphasize that therapeutic strategies targeting glycolytic pathways must account for cell-type-specific and context-dependent metabolic requirements to avoid disrupting physiological vascular homeostasis.

Histone lactylation in vascular remodeling

H3K18la ChIP-seq combined with HIF-1α ChIP-seq reveals co-localization at HIF-1α target genes (Bmp5, Trpc5, Kit), suggesting that hypoxia-induced HIF-1α binding creates a chromatin environment conducive to subsequent lactylation-mediated transcriptional activation, or alternatively, that pre-existing lactylation marks facilitate HIF-1α recruitment to these loci [26], establishing a direct mechanistic link between metabolic dysregulation and epigenetic remodeling that perpetuates the disease phenotype. This lactylation-mediated transcriptional activation represents a critical convergence point where metabolic alterations translate into sustained pathological gene expression programs driving vascular remodeling. The self-amplifying nature of this circuit, wherein lactate simultaneously fuels its own production through HIF-1α target activation and propagates proliferative signals through histone modifications, distinguishes PAH from reversible metabolic adaptations.

The systematic identification of lactylation-sensitive gene targets provides mechanistic insight into how transient metabolic stress evolves into stable pathological phenotypes. Unlike reversible metabolic enzyme regulation, histone lactylation establishes persistent chromatin states that maintain glycolytic reprogramming even after initial hypoxic triggers resolve. This epigenetic memory mechanism explains the progressive, treatment-resistant nature of advanced PAH and suggests that early intervention targeting lactate-lactylation circuits may prevent irreversible vascular remodeling.

Therapeutic implications and biomarker potential

Given its unique position at the convergence of multiple dysregulated pathways, including HIF-1α-dependent glycolytic reprogramming, ERK1/2-mediated proliferative signaling, endothelial metabolic switching, and platelet-driven inflammation, lactate emerges as an invaluable integrative biomarker for PAH stratification and management. Critically, pharmacological intervention with lactate dehydrogenase inhibitors diminishes histone lactylation and ameliorates PASMC proliferation and vascular remodeling in hypoxic PH rats [26], providing proof-of-concept for lactate-targeted therapeutic strategies. This validated therapeutic efficacy establishes lactate not merely as a disease marker but rather as a causally relevant therapeutic target whose modulation produces clinically meaningful improvements in experimental models.

Clinically, lactate quantification offers opportunities for non-invasive disease monitoring and treatment response evaluation. The mechanistic foundation linking lactate to histone lactylation, supported by validated therapeutic efficacy of lactate dehydrogenase inhibition in experimental models, provides scientific rationale for lactate measurement as an approach for assessing disease severity and predicting treatment outcomes in clinical PAH management. Furthermore, lactate levels may facilitate identification of patients likely to benefit from metabolic interventions targeting the glycolytic-lactylation axis, including experimental approaches modulating HIF-1α, PDK, PKM2, or PFKFB3 pathways. However, translating these preclinical findings requires addressing fundamental questions regarding optimal therapeutic windows, tissue-specific lactylation patterns, and long-term safety of systemic metabolic interventions.

Renal hypertension and ischemic injury

GPR81-Mediated vascular tone regulation

Beyond its metabolic roles, lactate functions as a vasoactive signaling molecule through GPR81 (G-protein-coupled receptor 81), a lactate-specific receptor that regulates vascular tone independently of lactate metabolism [36]. While GPR81 was initially characterized for its role in adipocyte lipolysis suppression, recent pharmacological and genetic evidence has unveiled an unexpected and physiologically significant function in blood pressure regulation, particularly within the renal microcirculation. This discovery positions GPR81 as a critical mechanistic link between local lactate accumulation and abnormal vascular pressure responses in pathological states.

GPR81 exhibits tissue-selective expression patterns with profound implications for cardiovascular control. In situ hybridization and immunohistochemical studies demonstrate prominent GPR81 localization in renal arterial smooth muscle cells, afferent arterioles, glomerular perivascular cells, and medullary pericyte-like populations [37], establishing the anatomical basis for lactate-mediated regulation of renal hemodynamics (Fig. 3). Pharmacological activation with synthetic GPR81 agonists (e.g., AZ′5538) induces rapid and sustained elevation of systolic and diastolic blood pressure in wild-type mice, accompanied by marked reductions in renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate, effects completely abolished in Gpr81^−/− mice [36], [37].

Fig. 3.

Renal hypertension: GPR81 mediates vasoconstriction.

Critically, these vascular effects exhibit remarkable tissue specificity: GPR81 activation substantially increases renal vascular resistance, with no effect on hindlimb and cardiac vascular beds [36], suggesting sophisticated regional regulatory mechanisms that warrant further mechanistic investigation. The molecular basis for this organ selectivity remains incompletely understood but may reflect differential GPR81 expression levels, distinct downstream signaling effectors in renal versus systemic vasculature, or interactions with kidney-specific regulatory molecules. Understanding these tissue-specific mechanisms is essential for developing targeted therapeutics that modulate renal GPR81 activity without systemic cardiovascular effects.

Lactate-Endothelin axis in pathophysiology

The hypertensive and renal hemodynamic effects of GPR81 activation are mechanistically coupled to the endothelin system, a well-established vasoconstrictor pathway. GPR81 agonist triggers rapid elevation of plasma endothelin-1 (ET-1) levels, and pharmacological blockade with the selective endothelin-A receptor antagonist BQ123 completely prevents GPR81-induced blood pressure elevation, whereas endothelin-B receptor antagonism (BQ788) provides no protection [37]. This receptor-specific dependency implicates endothelin-A receptor-mediated smooth muscle contraction as the primary effector mechanism.

The GPR81-ET-1 axis appears particularly relevant under pathophysiological conditions characterized by elevated extracellular lactate, such as renal ischemia–reperfusion injury (IRI). In experimental IRI models, ischemic kidneys exhibit elevated tissue lactate levels correlating with increased expression of ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α, and the macrophage marker F4/80 in wild-type mice, responses entirely absent in Gpr81^−/− animals [37], [38]. This genetic evidence establishes GPR81 as an indispensable mediator linking ischemia-induced lactate accumulation to endothelin-driven vasoconstriction (Fig. 3), inflammatory activation, and profibrotic remodeling that collectively exacerbate acute kidney injury and accelerate progression toward chronic kidney disease.

Therapeutic paradox and Future Directions

The therapeutic implications of GPR81-mediated vascular control present a complex paradox. While GPR81 agonists demonstrate beneficial metabolic effects, improving insulin sensitivity and glycemic control in rodent models of diabetes through antilipolytic mechanisms [36], their concurrent hypertensive properties severely limit clinical applicability for metabolic disorders. Conversely, GPR81 antagonism emerges as a potential renoprotective strategy for ischemic acute kidney injury, which amounts for 5–10 % of ICU patients with mortality rates exceeding 50 % and substantial risk of chronic kidney disease progression in survivors [38]. However, systemic GPR81 blockade risks disrupting beneficial metabolic functions, exemplifying the challenge of isolating pathological from physiological pathway components in precision medicine. Importantly, current evidence for GPR81 antagonism derives primarily from genetic loss-of-function studies (Gpr81^−/− mice) rather than pharmacological studies, as selective small-molecule GPR81 antagonists suitable for systematic vascular profiling remain under development. While genetic deletion provides definitive proof-of-concept for GPR81′s causal role in renal vasoconstriction and ischemic injury, translation to clinical therapeutics requires selective pharmacological antagonists with favorable tissue distribution and safety profiles. The tissue-specific expression patterns and functional responses observed with agonist studies provide a rational mechanistic framework for predicting corresponding organ-selectivity of antagonism, though direct experimental validation across multiple vascular territories represents a critical priority for future research.

Future therapeutic development requires elucidation of concentration–response relationships and temporal dynamics of lactate-GPR81 interactions, identification of tissue-specific regulatory mechanisms underlying selective renal vascular effects, and potential development of organ-targeted GPR81 modulators. Understanding whether GPR81 functions primarily as a sensor of systemic versus local (paracrine) lactate concentrations will be critical for predicting therapeutic windows and off-target effects in clinical translation. The divergent consequences of GPR81 activation in metabolic versus vascular contexts underscore the need for tissue-selective therapeutic strategies that preserve beneficial metabolic signaling while preventing pathological vasoconstriction in ischemic organs.

Lactate and lactylation in atherosclerotic cell regulation

Atherosclerotic plaque development involves complex interactions between metabolic dysregulation, cellular phenotypic transitions, and inflammatory responses. Lactate accumulation within atherosclerotic lesions, driven by hypoxia, glycolytic activation, and inflammatory cell metabolism, creates a microenvironment where lactylation emerges as both a metabolic consequence and regulatory signal. This section presents two complementary aspects (Fig. 4): lactate signaling pathways that have been characterized in atherosclerotic cell models, and lactylation modifications documented primarily in exercise and physiological intervention studies. While lactate's regulatory functions in atherosclerotic cells operate predominantly through receptor-mediated signaling and metabolic pathways, lactylation modifications have been rigorously validated in cardiovascular-relevant tissues under physiological conditions, with their roles in atherosclerotic disease contexts representing an emerging area of investigation.

Fig. 4.

Dual regulatory network of lactic acid in atherosclerotic plaque.

Cell-Type specific lactylation mechanisms

Atherosclerotic plaques comprise heterogeneous cell populations whose phenotypic plasticity determines disease progression and clinical outcomes. Lactate serves as a critical metabolic regulator, orchestrating cellular transitions through both lactate sensing pathways and lactylation-mediated epigenetic modifications. While vascular smooth muscle cells and immune cells constitute primary plaque cellular components, current understanding of lactylation's regulatory roles exhibits significant gaps, particularly regarding histone lactylation's contributions to transcriptional reprogramming governing cell fate decisions.

Lactate signaling and potential lactylation in VSMC phenotypic transitions

Vascular smooth muscle cell (VSMC) plasticity governs atherosclerotic plaque evolution through phenotypic transitions that determine plaque stability [39]. Lineage-tracing studies revealed that VSMCs migrate into plaques and adopt diverse phenotypes, including foam cell-like, macrophage-like, and osteochondrogenic phenotypes, contributing both positively and negatively to disease progression [39]. Lactate drives VSMCs toward a synthetic phenotype through monocarboxylic acid transporter (MCT)-dependent uptake and NDRG3 signaling activation [40]. In lactate-enriched conditions (4–8 mM), MCT1/MCT4-mediated uptake triggers phenotypic conversion characterized by downregulation of contractile markers (myosin heavy chain 11, calponin) and upregulation of synthetic markers (collagen I, vimentin). Lactate stabilizes NDRG3 protein, activating Raf-ERK signaling cascades that govern proliferation, migration, and extracellular matrix production, thereby contributing to fibrous cap formation. Pharmacological MCT inhibition or genetic MCT4 knockdown abolishes these transitions, confirming pathway specificity. Paradoxically, lactate simultaneously accelerates vascular calcification through NR4A1-mediated mechanisms [41]. Lactate upregulates NR4A1, activating the DNA-PKcs/p53 signaling axis that triggers Drp1-mediated mitochondrial fission while suppressing BNIP3-mediated mitophagy, resulting in mitochondrial dysfunction, ATP depletion, and VSMC apoptosis. Surviving VSMCs undergo osteoblastic differentiation marked by RUNX2/BMP-2 upregulation, with genetic NR4A1 silencing preventing these processes while pharmacological activation exacerbates calcification. Apoptotic VSMCs release vesicles serving as nucleation sites for calcium phosphate precipitation, transforming stable fibrous plaques into brittle calcified lesions.

The systematic absence of histone lactylation investigations in VSMCs represents a critical knowledge gap. These lactate-driven phenotypic transitions operate through well-characterized cytoplasmic signal transduction cascades (NDRG3/Raf-ERK and NR4A1/DNA-PKcs pathways). Although NDRG proteins exhibit diverse regulatory functions [42], their lactate-responsive roles may extend beyond cytoplasmic signaling to nuclear chromatin modifications. Whether lactate-driven histone lactylation regulates transcriptional programs governing VSMC dedifferentiation, osteochondrogenic conversion, or foam cell-like transformations [39] remain unexplored, despite compelling rationale linking metabolic lactate accumulation to epigenetic regulation of phenotypic plasticity. Meta-analyses of 218,080 subjects demonstrate that calcification burden correlates significantly with cardiovascular mortality, with coronary artery calcification exhibiting the highest odds ratios [43], yet acute coronary syndromes predominantly arise from rupture of non-calcified, lipid-rich plaques rather than heavily calcified stable plaques. This paradox may be resolvable through temporal targeting: early post-plaque formation, enhancing NDRG3-mediated VSMC synthetic phenotype while blocking NR4A1 could promote fibrous cap formation; in established plaques showing early calcification markers, selective NR4A1 inhibition may prevent progression without compromising existing cap stability. Alternatively, spatial targeting of lactate modulation to cap versus calcification-prone regions may allow differential therapeutic manipulation.

Rational therapeutic development requires comprehensive integration of metabolic signaling, epigenetic regulation, and spatiotemporal resolution of beneficial versus detrimental VSMC phenotypes. Future investigations must determine whether histone lactylation contributes to transcriptional programs governing contractile-to-synthetic transitions versus osteochondrogenic differentiation, whether lactylation patterns differ between plaque-stabilizing matrix-producing VSMCs and plaque-destabilizing calcifying VSMCs, and whether therapeutic modulation of lactylation enzymes or lactate transporters can selectively enhance protective while suppressing pathological VSMC phenotypes within atherosclerotic lesions.

Lactate-Mediated immune Regulation: From acidification to potential lactylation

Lactate-mediated acidification within atherosclerotic plaques generates regulatory networks whose complexity current research inadequately addresses. The plaque microenvironment, characterized by hypoxia, glycolytic metabolism, and inflammatory cell infiltration, creates lactate-rich acidic conditions that influence immune cell function through pH-dependent protein interactions and potentially through lactylation-mediated epigenetic modifications. Enhanced oxidized LDL binding to aortic proteoglycans under acidic conditions has been demonstrated, yet interpretations remain limited to conventional protein interaction models [44], with potential epigenetic implications despite clinical significance as evident in associations between elevated LDL triglycerides and atherosclerotic risk [45]. The acidic microenvironment may simultaneously promote pathological lipid retention while creating conditions favoring lactate uptake and subsequent histone lactylation in infiltrating immune cells, a mechanistic connection systematically neglects. Continuous Ly6Chi monocyte recruitment and STAT6-dependent M2 macrophage conversion during atherosclerosis regression require transcriptional reprogramming likely involving epigenetic mechanisms [46], while microRNA-33 inhibition achieves anti-inflammatory effects through regulatory T cell expansion and M2 polarization via enhanced fatty acid oxidation [47]. While investigations have yet to fully examine lactate-derived histone modifications as mediators of immune transitions in atherosclerosis, evidence from other inflammatory contexts suggests this represents a promising avenue for expanding therapeutic strategies targeting immunometabolism [48]. Future studies should determine whether M2 polarization during plaque regression involves lactylation-dependent transcriptional reprogramming analogous to post-infarction macrophages.

Current results emphasize glycolytic inhibition and TCA cycle modulation while having limited focus on lactate's dual role as metabolic product and chromatin modification substrate regulating immune polarization. Lactate functions as a critical negative regulator of inflammatory activation through GPR81-mediated suppression of TLR-induced NLRP3 inflammasome signaling, with GPR81-ARRB2 interactions inhibiting NFκB activation and reducing IL1β production in macrophages, establishing an immunomodulatory feedback mechanism that limits sterile inflammation during issue injury [32]. Further investigation of traditional inflammatory pathways, particularly NLRP3 inflammasome signaling, together with integration of substrate availability with epigenetic control of inflammatory gene programs may provide more comprehensive mechanistic understanding [49], [50]. The convergence of lactate's receptor-mediated anti-inflammatory effects through GPR81 and its chromatin-modifying functions through lactylation represent a dual regulatory axis that may determine whether plaque-associated inflammation progresses toward resolution or perpetuates chronic pathological remodeling.

Resolving this paradox requires integrating measurements of tissue lactate concentrations, cellular lactate transporter expression, histone lactylation patterns, and polarization-specific transcriptional programs within spatially resolved plaque regions. Future investigations should employ multi-dimensional approaches combining spatial metabolomics, single-cell epigenomics, and functional validation to determine whether lactylation-mediated transcriptional reprogramming contributes to atherosclerosis regression or represents an underexploited therapeutic target. Critical inquiries include whether M2 macrophage-enriched stable plaques exhibit distinct lactylation signatures compared to M1-dominant vulnerable plaques, whether lactylation of specific histone residues or transcription factors correlates with pro-resolving versus pro-inflammatory gene expression programs, and whether pharmacological enhancement of lactylation in plaque macrophages promotes efferocytosis, cholesterol efflux, and inflammation resolution.

Physiological modulation of lactylation

Beyond cell-intrinsic lactylation mechanisms operating within atherosclerotic plaques, physiological interventions that systemically alter lactate metabolism exert potential atheroprotective effects. Exercise represents the most extensively studied physiological modulator of lactate dynamics, inducing transient hyperlactatemia that triggers beneficial metabolic and epigenetic adaptations. Understanding how exercise-induced lactylation patterns differ from pathological plaque-associated lactylation may illuminate therapeutic windows for lactylation-targeted interventions.

Exercise-Induced protective lactylation

Exercise demonstrates established cardiovascular protective effects, yet lactylation's mechanistic contributions to atherosclerosis prevention remain incompletely characterized [51]. Exercise-induced lactate accumulation promotes fatty acid synthase (FASN) lactylation at lysine 673, suppressing de novo lipogenesis in adipose tissue during high-intensity interval training [52], [53]. Translation of this metabolic reprogramming to influence arterial wall biology and inflammatory cell recruitment, which are key atherosclerotic progression determinants. Although mitochondrial pyruvate carrier 1 knockout enhances FASN lactylation and reduces hepatic lipid accumulation in nonalcoholic fatty liver disease models, cardiovascular implications remain unexplored [52], the connections between systemic lipogenic suppression and atherosclerotic plaque biology warrant detailed examination. Whether exercise-induced FASN lactylation in vascular cells or plaque-infiltrating immune cells directly suppresses foam cell formation or inflammatory lipid mediator production requires systematic investigation. Exercise-induced lactylation of methylated CpG-binding protein 2 (MeCP2) at lysine 271 in aortic endothelial cells demonstrates anti-atherosclerotic effects through epiregulin/MAPK pathway suppression [54], reducing inflammatory cytokine expression and adhesion molecule production [55], [56]. However, comprehensive examination of whether similar lactylation patterns occur in atherosclerosis-prone arterial segments (e.g., branch points, regions of disturbed flow) or influence established plaque stability, which are processes fundamental to atherosclerotic progression, remains an important research direction.

Reliance on healthy exercise models raises questions about whether lactylation-mediated effects translate to established atherosclerotic disease characterized by distinct metabolic and inflammatory environments. While MeCP2 lactylation enhances repression through chromosome topology-associated mechanisms, dose–response relationships between exercise-induced lactate production and protective lactylation levels in atherosclerotic populations have not been established [57]. Without systematic correlation of exercise parameters (intensity, duration, frequency) with tissue-specific lactylation signatures in vascular beds and circulating immune cells, clinical translation of lactylation-based interventions for atherosclerosis management remains scientifically premature. Critical unresolved questions include: 1) whether exercise-induced transient hyperlactatemia produces similar histone lactylation patterns as chronic plaque-associated lactate accumulation; 2) whether lactylation marks in healthy endothelium persist in atherosclerosis-prone arterial segments under disturbed flow; 3) whether exercise-mediated FASN and MeCP2 lactylation occur in plaque-resident VSMCs and macrophages or remain restricted to circulating cells and healthy vascular beds.

Future Perspectives: Dietary and pharmacological modulation

While exercise remains the primary physiological modulator of systemic lactate metabolism studied to date, emerging evidence suggests additional interventions including dietary lactate supplementation, ketogenic diets altering lactate/ketone body ratios, and pharmacological agents targeting lactate transporters or lactylation enzymes that may represent unexplored therapeutic frontiers with potential cardiovascular implications. However, translating these strategies to atherosclerosis management requires addressing fundamental questions regarding tissue-specific lactylation patterns, dose–response relationships, and temporal dynamics distinguishing beneficial physiological lactylation from pathological plaque-associated lactylation, necessitating systematic investigation to reveal approaches for harnessing lactylation's protective potential while mitigating detrimental effects in atherosclerotic microenvironments. To rigorously evaluate these possibilities, future studies should employ exercise and alternative interventions in preclinical atherosclerosis models such as ApoE^−/− and LDLR^−/− mice, incorporating comprehensive lactylation profiling across plaque regions, arterial wall layers, and immune cell subsets to determine whether intervention-induced lactylation patterns mechanistically contribute to plaque regression or stability. Integrating lactylation mapping with single-cell transcriptomics and spatial metabolomics would reveal cell-type-specific lactylation responses and their transcriptional consequences within atherosclerotic lesions, enabling rigorous evaluation of lactylation-modulating interventions as therapeutic strategies for atherosclerosis management.

Lactate metabolism and lactylation in myocardial infarction

Understanding lactate's role in myocardial infarction has been limited by conventional interpretations that consider this metabolite exclusively through hemodynamic and metabolic perspectives. Despite extensive clinical evidence establishing lactate as a prognostic biomarker, its potential involvement in lactylation-mediated epigenetic regulation has been systematically overlooked, representing a conceptual limitation with therapeutic implications. This section examines mechanistic gaps between clinical applications and molecular discoveries in lactate-related processes during myocardial infarction (Fig. 5). Analysis of histone lactylation mechanisms, immune metabolic reprogramming, post-infarction dysfunction, and translational challenges reveal how viewing lactate solely as metabolic waste obscures chromatin-modifying therapeutic opportunities. A disconnect exists between lactate's clinical utility and limited investigation of lactylation-mediated transcriptional programs governing cellular survival, inflammatory resolution, and tissue repair. Integration of metabolic perspectives with epigenetic insights is required to realize lactate's therapeutic potential in cardiovascular medicine.

Fig. 5.

Dual fate of lactic acid after myocardial infarction-balance between repair and fibrosis.

Clinical significance and prognostic biomarker applications

Lactate as a mortality predictor

Lactate has been established as a prognostic biomarker in acute myocardial infarction, with clinical evidence supporting its predictive value for mortality and adverse outcomes. Clinical significance extends beyond metabolic interpretation, as lactate represents a pathophysiological feature across myocardial infarction, heart failure, and atherosclerosis, with altered metabolism being recognized as integral to cardiovascular pathophysiology [58]. Cardiogenic shock affects 40,000–50,000 patients annually in the United States and represents the leading cause of in-hospital mortality following myocardial infarction, with 30-day mortality approaching 40 % and 1-year mortality near 50 % [59]. These outcomes have prompted investigation into lactate's prognostic utility. Admission lactate levels exceeding 1.8 mmol/L independently correlate with 30-day mortality in ST-segment elevation myocardial infarction, with mortality rates of 2.0 % for levels ≤ 1.1 mmol/L, 1.5 % for 1.2–1.7 mmol/L, and 6.5 % for ≥ 1.8 mmol/L [60]. These clinical associations establish lactate measurement as a practical and accessible prognostic tool in acute coronary care settings.

Beyond acute myocardial infarction, lactate's biomarker utility extends to cardiac transplantation settings where graft quality assessment remains challenging under hypothermic preservation conditions. In experimental hypothermic oxygenated perfusion (HOPE) models for donor heart preservation, perfusate lactate levels demonstrated negative correlation with coronary flow indices, alongside troponin I, ammonia, and YES1 kinase as candidate biomarkers predicting post-reperfusion cardiac function [61]. These findings suggest that lactate monitoring during organ preservation may enable real-time graft viability assessment, potentially improving transplant outcomes through enhanced donor heart selection, particularly in donation after circulatory death contexts where warm ischemia complicates quality evaluation. The convergence of lactate's prognostic value across acute infarction and transplantation underscores its versatility as a metabolic indicator of cardiac injury and functional reserve.

Risk stratification systems

Risk stratification has been refined through scoring systems incorporating lactate measurements. The CLIP score, combining cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide, achieves c-statistics of 0.82 in cardiogenic shock populations with external validation. The IABP-SHOCK II risk score identifies arterial lactate > 5 mmol/L as an independent mortality predictor, discriminating between low (23.8 %), intermediate (49.2 %), and high (76.6 %) mortality risk [62]. Temporal lactate dynamics provide additional prognostic information suggesting biological processes beyond hypoperfusion markers. Lactate measurements at 8 h post-admission demonstrates superior mortality prediction compared to baseline, with 3.1 mmol/L showing optimal discrimination for early prognosis in cardiogenic shock [63]. Point-of-care testing emphasizes practical importance in risk stratification [64].

Beyond cardiogenic shock, lactate and pH demonstrate robust prognostic utility in out-of-hospital cardiac arrest (OHCA), a condition sharing ischemic-hypoxic pathophysiology with acute myocardial infarction but presenting distinct challenges in neurological outcome prediction. Systematic review and meta-analysis encompassing 21,120 patients across 49 studies established that mean lactate levels of 7.24 mmol/L associate with favorable survival, while 7.15 mmol/L correlates with favorable neurological recovery, with the narrower threshold for neurological outcomes reflecting greater metabolic sensitivity of neural tissue to ischemic injury [65]. Complementing lactate, pH exhibited direct positive correlation with both survival and neurological function, with mean pH of 7.22 predicting favorable outcomes across both domains [65]. The inverse relationship between lactate elevation and outcome severity, coupled with pH's positive predictive value, underscores the dual metabolic assessment approach wherein acidosis and lactate accumulation synergistically reflect tissue hypoperfusion severity and cellular metabolic dysfunction. Critically, these biomarkers enable identification of patients likely to benefit from resource-intensive post-cardiac arrest interventions including targeted temperature management, early coronary angiography, and extracorporeal cardiopulmonary resuscitation, addressing the challenge that return of spontaneous circulation (ROSC) alone does not ensure meaningful neurological recovery. The convergence of lactate and pH as independent prognostic markers across acute coronary syndromes, cardiogenic shock, and cardiac arrest establishes these readily available metabolic markers as universal tools for risk stratification in ischemic cardiovascular emergencies.

Therapeutic potential of exogenous lactate

Clinical evidence supports therapeutic potential beyond prognostic applications. A pilot randomized trial demonstrated that half-molar sodium lactate infusion improves cardiac performance in acute heart failure, increasing cardiac output from 4.05 ± 1.37 to 5.49 ± 1.9 L/min and tricuspid annular plane systolic excursion from 14.7 ± 5.5 to 18.3 ± 7 mm without organ dysfunction [66]. Molecular mechanisms underlying these cardioprotective effects extend beyond lactate's role as an energy substrate. Exogenous lactate supplementation may promote beneficial cellular responses through multiple pathways: direct oxidative metabolism providing ATP for stressed cardiomyocytes, modulation of cellular signaling cascades, and potentially through lactylation-mediated epigenetic modifications that enhance expression of cardioprotective genes. Experimental evidence indicates that lactate can induce histone lactylation in immune cells, promoting anti-inflammatory gene expression programs [67]. These multilevel mechanisms suggest that exogenous lactate administration represents a promising therapeutic approach warranting further clinical investigation to determine optimal dosing strategies and patient populations most likely to benefit from such interventions [66], [67].

Molecular mechanisms of Lactate-Mediated cardiac responses

Histone lactylation in reparative gene regulation

Studies have provided direct experimental evidence for histone lactylation's pivotal role in myocardial infarction pathophysiology, validating lactate's function as a chromatin-modifying substrate in cardiac contexts. Groundbreaking research demonstrates that histone H3K18 lactylation increases significantly in monocyte-macrophages during early post-infarction period, regulating critical reparative genes including Lrg1, Vegf-a, and IL-10 through direct transcriptional mechanisms [67]. The divergent outcomes of lactylation in post-infarction hearts reflect cell-type-specific substrate availability and enzymatic machinery. Macrophages exhibit high MCT1 expression and robust p300/GCN5 activity, favoring histone lactylation and reparative gene activation. Conversely, endothelial cells express CBP preferentially over GCN5, and Snail1′s nuclear localization during TGF-β stimulation positions it for CBP-mediated lactylation that stabilizes its pro-fibrotic activity. Thus, the same metabolic stress produces beneficial versus detrimental lactylation depending on cellular context. Mechanistically, monocytes undergo metabolic reprogramming in early stages of myocardial infarction, with dysregulated glycolysis and MCT1-mediated lactate transport promoting histone lactylation through IL-1β-dependent GCN5 recruitment. The functional significance of lactylation-regulated genes extends beyond immediate cardiac repair, with VEGF-A and LRG1 playing crucial roles in angiogenic processes that support tissue regeneration, while their dysregulation contributes to pathological conditions when inappropriately activated [68]. These findings establish histone lactylation as a central epigenetic mechanism governing transition from inflammatory damage to reparative responses in post-infarction hearts.

Endothelial-to-Mesenchymal transition and fibrosis

However, lactylation-mediated processes exhibit dual functionality that complicates therapeutic applications. While lactylation promotes beneficial effects, lactate simultaneously induces detrimental endothelial-to-mesenchymal transition (EndoMT) via Snail1 lactylation, exacerbating cardiac fibrosis and dysfunction [69]. This paradoxical effect involves lactate-induced association between CBP/p300 and Snail1, leading to TGF-β/Smad2 pathway activation and enhanced cardiac fibrosis through MCT-dependent mechanisms. EndoMT represents a core pathological process where endothelial cells transdifferentiate into mesenchymal cells, contributing significantly to cardiac fibrosis development [70], [71]. This process mirrors developmental programs occurring during cardiac valve formation but becomes pathologically activated in disease states. TGF-β emerges as a central mediator inducing endothelial cells to undergo EndoMT, while BMP-7 preserves endothelial phenotype, suggesting therapeutic opportunities through pathway modulation [71].

Critically, snail transcription factor serves as an essential mediator for TGF-β-induced EndoMT, with snail knockdown abrogating TGF-β-induced mural differentiation of endothelial cells [72]. The integration of lactylation mechanisms with EndoMT pathways reveals sophisticated regulatory networks where lactate simultaneously promotes beneficial macrophage polarization while driving detrimental endothelial transdifferentiation. The MCT-dependent nature of both processes suggests that lactate transport regulation could provide therapeutic targets for modulating lactylation's beneficial versus detrimental effects, emphasizing critical importance of understanding tissue-specific and temporal contexts when developing lactylation-based interventions.

Immune cell metabolic reprogramming

Myocardial infarction triggers inflammatory responses essential for repair but implicated in post-infarction remodeling and heart failure [73]. This cascade involves interactions between cardiac macrophages, recruited monocytes, and metabolic reprogramming determining outcomes through lactylation pathways. Cardiac macrophages remain active throughout post-infarction phases including cardio protection, inflammation, and tissue repair [74]. Resident cardiac macrophages, derived from yolk sac progenitors and maintained through self-renewal, exhibit distinct cardioprotective properties compared to recruited monocyte-derived populations. Post-infarction remodeling involves local macrophage proliferation and monocyte recruitment, with mechanical strain stimulating proliferation through mitogen-activated protein kinase activation [75].

Glucose transporter 1 (GLUT1) serves as the rate-limiting transporter for proinflammatory macrophage glucose uptake, with overexpression inducing hyperinflammatory phenotypes characterized by reactive oxygen species production and inflammatory mediator secretion [76]. Sodium lactate administration post-infarction improves cardiac performance through M2 macrophage polarization, reduced cardiomyocyte apoptosis, and neovascularization via STAT3 phosphorylation [77]. The therapeutic mechanisms of exogenous sodium lactate extend beyond direct metabolic effects. While lactate serves as an oxidative fuel substrate, its ability to promote M2 macrophage polarization likely involves modulation of gene expression programs. Recent studies demonstrate that lactate-induced M2 polarization is accompanied by increased expression of anti-inflammatory markers (Arg1, Ym1, TGF-β, IL-10), effects that may be mediated through histone lactylation at these gene loci [67], [78].

Clinical relevance appears in NSTEMI patients exhibiting GLUT-1/pyruvate kinase M2 (PKM2) loop dysregulation, with aberrant PKM2 nuclear translocation activating proinflammatory genes [78]. PKM2 complexes with Hif-1α bind IL-1β promoters, promoting inflammation while inhibiting M2 polarization [79]. Lactate secretion can promote immunosuppressive phenotypes with elevated IL-1β, IL-10, and IL-6, demonstrating context-dependent effects [80]. Exogenous IL-10, a lactylation-regulated gene, improves ventricular function by promoting M2 polarization and reducing inflammation [81]. This modulates 410 macrophage genes involved in assembly and repair, illustrating regulatory networks between lactate metabolism, immune cell function, and cardiac repair. Notably, IL-10 is among the genes directly regulated by histone H3K18 lactylation in macrophages exposed to elevated lactate, suggesting that therapeutic IL-10 administration may partially compensate for insufficient endogenous lactylation-dependent IL-10 production in failing hearts [67], [81].

Translation challenges and Future Directions of lactylation in myocardial infarction

Endogenous metabolic dysfunction and compensatory tolerogenic responses

Temporal dynamics of post-infarction lactate metabolism reveal endogenous processing dysregulation despite benefits from exogenous administration. Analysis of lactate oxidation complex (LOC) gene expression in post-infarction hearts shows impaired lactate's capacity to modulate LOC expression and enhance blood flow under pathological stress [82]. Chronic post-infarction exhibits elevated reactive oxygen species, increased NADPH oxidase activity, and reduced antioxidant enzyme activities following lactate perfusion, indicating altered metabolic capacity. Lactate perfusion shows no additional effects on reactive oxygen species while partially reducing MCT1 expression, suggesting impaired transport mechanisms. Lactate decreases superoxide dismutase and catalase activities in post-infarction hearts, indicating compromised antioxidant capacity. This dysfunction may reflect not only impaired oxidative metabolism but also dysregulation of lactylation-dependent gene regulatory mechanisms. In healthy hearts, lactate modulates LOC gene expression potentially through lactylation-mediated chromatin modifications, but chronic oxidative stress and inflammation in failing myocardium may impair the cellular machinery required for effective lactylation, thereby disrupting lactate's gene regulatory functions even when substrate availability is maintained [82], [83]. These observations suggest that the post-infarction heart develops metabolic dysfunction that limits endogenous lactate processing, potentially necessitating alternative therapeutic approaches.

Paradoxically, this dysfunction coincides with emergence of therapeutically beneficial tolerogenic responses involving lactate-dependent mechanisms. Autologous tolerogenic dendritic cells suppress T cell proliferation and expand regulatory T cells through lactate production, modulating glycolytic capacity and promoting tolerance [83]. Mechanistically, tolerogenic dendritic cells generate high lactate levels that modulate T cell metabolism and function. Studies demonstrate that dendritic cell-derived lactate is taken up by T cells, reducing their glycolytic capacity and proliferation [84]. Infarcted myocardium-primed tolerogenic dendritic cells administered to post-infarction mice activate myocardial infarction-specific regulatory T cells, promoting inflammatory-to-reparative macrophage shifts preserving systolic function. This aligns with regulatory T cell therapies enhanced through biotechnology, though optimal timing for lactate-mediated interventions considering post-infarction metabolic dynamics remains undefined [85]. Clinical significance encompasses immunoregulatory strategies transforming post-infarction care through inflammatory resolution and tissue repair [86].

Metabolomics heterogeneity in acute coronary syndromes

Translation of lactylation insights into clinical practice faces obstacles from heterogeneous acute coronary syndromes and complex therapeutic integration. Metabolomic investigations reveal heterogeneous signatures across acute coronary syndrome subtypes requiring patient-specific optimization. Metabolomic profiling demonstrates distinct STEMI and NSTEMI metabolic fingerprints, with differential expression of branched-chain amino acids, lysophosphatidylcholines, and lactate among 163 altered metabolites [87], [88]. Twenty-five metabolites including lactic acid, succinate, and malonic acid were identified as biomarker candidates differentiating STEMI from NSTEMI, indicating alterations in oxidative phosphorylation, the tricarboxylic acid cycle, and glycolysis pathways [88]. The identification of lactate among these discriminatory metabolites underscores its potential not only as a prognostic marker but also as a mechanistic indicator of differential metabolic reprogramming between ACS subtypes. This heterogeneity reflects multifaceted pathophysiology encompassing ischemic extent, metabolic demand, and systemic responses. Patients with acute coronary syndromes exhibit characteristic metabolic shifts reflecting tissue ischemia, cellular stress, and systemic adaptation to reduced coronary perfusion [87].

This metabolomic heterogeneity presents both challenges and opportunities for lactate-targeted interventions. The variability in lactate levels across different ACS presentations suggests that lactylation-mediated processes may exhibit differential activation patterns depending on severity and duration of ischemia. Therapeutic strategies targeting lactate metabolism or lactylation pathways must therefore account for this heterogeneity through personalized approaches based on metabolomic profiling. Future clinical trials investigating lactate-based interventions should incorporate metabolomic stratification to identify patient populations most likely to benefit from such therapies and to determine optimal therapeutic windows based on individual metabolic states [87], [88]. Complementing metabolomic approaches, bioinformatics analysis of lactate metabolism-related genes (LMRGs) in MI identified three candidate biomarkers, OLIG1, LIN52, and RLBP1, associated with 'ribosome' and 'carbon metabolism' pathways, with OLIG1 exhibiting strong correlations with monocyte infiltration [89]. However, critical gaps remain in connecting these computationally identified LMRGs to lactylation-mediated epigenetic mechanisms governing immune cell polarization and reparative gene expression in post-infarction hearts. Future integrative studies combining transcriptomic profiling with proteomic mapping of lactylation sites are needed to bridge genomic biomarker discovery with mechanistic understanding of lactylation-dependent cardiac repair [89].

Reperfusion Injury: Implications for Lactate-Based therapies

Ischemia-reperfusion injury represents a critical pathophysiological challenge during acute myocardial infarction treatment, with important implications for lactate-targeted therapeutic development. Reperfusion-induced cardiomyocyte death is estimated to contribute significantly to final infarct size, despite restoration of coronary blood flow being essential for myocardial salvage [90]. Experimental evidence demonstrates that ischemia–reperfusion injury is mediated by oxidative stress, calcium overload, mitochondrial permeability transition, and inflammatory responses that develop paradoxically during flow restoration.

The temporal dynamics of lactate accumulation and clearance during reperfusion create a complex metabolic environment that may influence lactylation-mediated processes. During ischemia, lactate accumulates due to anaerobic glycolysis, potentially priming cells for lactylation-dependent gene expression changes. Upon reperfusion, rapid lactate washout coincides with oxidative burst and inflammatory cell infiltration, suggesting that the transition from high to low lactate environments may trigger specific transcriptional programs through dynamic changes in histone lactylation status. Studies employing lactate-consuming therapies show promise, with polyhemoglobin-superoxide dismutase-catalase formulations protective in ischemia–reperfusion models [91].

Lethal reperfusion injury from coronary flow restoration after ischemia necessitates cardioprotective strategies during percutaneous coronary intervention [92]. The integration of lactate-targeted therapies with established reperfusion strategies requires consideration of several key factors. First, temporal coordination is critical, interventions aimed at modulating lactate metabolism or lactylation must be timed to coincide with specific phases of the ischemia–reperfusion sequence. Second, the tissue-specific effects of lactylation require targeted delivery approaches that maximize beneficial effects in cardiomyocytes and reparative immune cells while minimizing detrimental effects on endothelial cells prone to EndoMT. Third, the metabolic heterogeneity across different patient populations necessitates stratification approaches to identify those most likely to benefit from lactate-based cardioprotection. Addressing these considerations will be essential for translating mechanistic insights into clinically effective interventions that reduce reperfusion injury and improve outcomes following myocardial infarction [90], [91], [92].

Lactate metabolism and protein lactylation in heart failure

Transition from compensated cardiac hypertrophy to heart failure involves metabolic reprogramming that reshapes cellular energy landscapes and introduces regulatory mechanisms extending beyond bioenergetic pathways [93]. Cardiac aging encompasses metabolic alterations affecting cardiomyocytes and non-cardiomyocytes through autophagy, oxidative stress, epigenetic modifications, and inflammation. Recognition of lactylation as a post-translational modification has advanced understanding of metabolic intermediates' influence on cardiac structure and function. At this metabolic-epigenetic interface, lactate functions as a signaling molecule modifying contractile proteins and regulatory networks rather than merely serving as glycolytic end-product or fuel source (Fig. 6). Therapeutic strategies targeting lactate metabolism and lactylation pathways could address metabolic dysfunction and structural remodeling simultaneously, integrating traditionally separated metabolic and structural interventions.

Fig. 6.

Metabolic-structure remodeling in heart failure.

Metabolic Reprogramming: From hypertrophy to failure

Ldha-mediated adaptive hypertrophy

Initial heart failure development involves metabolic reprogramming establishing foundations for structural and functional alterations. Lactate dehydrogenase A (LDHA) governs cardiac hypertrophic growth responses, with metabolic enzymes functioning as regulators of cellular adaptation and pathological remodeling [94]. LDHA expression increases in hearts under hemodynamic stress, while cardiomyocyte-restricted LDHA deletion causes defective hypertrophic growth and accelerated heart failure progression during pressure overload. In cultured cardiomyocytes, LDHA silencing suppresses growth responses to pro-hypertrophic stimulation, whereas LDHA overexpression drives growth without external stimuli. Lactate rescues growth defects from LDHA knockdown, establishing relationships between LDHA activity, lactate production, and cellular growth.

LDHA-derived lactate stabilizes N-myc downregulated gene family 3 (NDRG3) and stimulates extracellular signal-regulated kinase (ERK) signaling, creating an LDHA/NDRG3/ERK axis determining adaptive growth responses to hemodynamic stress. ANKRD1 selectively mediates specific hypertrophic stimuli, illustrating signaling complexity [95]. ANKRD1 forms sarcomeric complexes with ERK1/2 and GATA4, with phenylephrine treatment inducing phosphorylation and nuclear translocation. While chronic phenylephrine infusion induces hypertrophy with fetal gene reactivation in wild-type mice, this response is absent in ANKRD1 null mice. However, ANKRD1-deficient mice develop normal hypertrophy following transverse aortic constriction, indicating stimulus-specific involvement. Distinct metabolic-transcriptional circuits govern different hypertrophic stimuli, suggesting targeted therapeutic approaches preserving adaptive while inhibiting maladaptive responses.

Glycolysis-Oxidation uncoupling in Decompensation

Progression to heart failure involves glycolytic-oxidative metabolism uncoupling that compromises cardiac energetics. This uncoupling represents a metabolic abnormality providing insights into heart failure energy inefficiency [96], [97]. Coronary artery ligation (CAL) models demonstrate profound energy utilization inefficiencies in failing hearts, with impaired ventricular function showing reduced ejection fraction (49 %) and work capacity (46 %) versus controls. CAL hearts exhibit elevated glycolysis, glucose oxidation, and proton production per unit of ventricular work, indicating inefficient substrate utilization. This metabolic uncoupling arises from glycolysis proceeding faster than pyruvate oxidation, resulting in excess pyruvate being reduced to lactate and generating protons that contribute to intracellular acidosis [97], [98]. Consequently, failing hearts exhibit net lactate production despite adequate oxygen availability, representing a cardiac Warburg-like phenomenon where glycolytic pyruvate is preferentially converted to lactate rather than being oxidized in mitochondria [99], [100]. In heart failure with preserved ejection fraction (HFpEF), Dahl salt-sensitive rats demonstrate progressive diastolic deterioration over nine weeks of high salt diet [97]. Metabolic uncoupling increases proton production, potentially contributing to HFpEF through altered pH homeostasis. Glycolytic enhancement accompanies increased GLUT1 expression, while fatty acid oxidation decreases and ATP production declines occur with progression to reduced ejection fraction.

Mitochondrial pyruvate carrier (MPC) function mediates transition from adaptive to pathological remodeling [98], [99], [100]. The MPC serves as a critical metabolic branch point determining pyruvate fate, either mitochondrial oxidation or cytosolic metabolism to lactate [99]. Decreased MPC expression in failing hearts limits mitochondrial pyruvate uptake, directly contributing to cytosolic lactate accumulation that characterizes the diseased myocardium [100], [101]. This pyruvate-lactate axis dysfunction represents an early and fundamental feature of cardiac hypertrophy, preceding contractile impairment [99]. Cardiac assistance-induced recovery coincides with increased myocardial MPC expression, suggesting restoration of the pyruvate-lactate balance underlies functional improvement as hearts shift from net lactate production back toward mitochondrial pyruvate oxidation [99]. MPC ablation in cardiomyocytes induces hypertrophy and failure, while overexpression attenuates drug-induced hypertrophy. Cardiac-specific MPC2-deficient mice developing progressive dysfunction are rescued by ketogenic dietary intervention [101]. Genetic deletion of MPC recapitulates the hypertrophic metabolic phenotype, with pyruvate being shunted into lactate production and pentose phosphate pathway rather than entering the tricarboxylic acid cycle, demonstrating that impaired MPC-mediated pyruvate import causally drives pathological remodeling. Importantly, the accumulation of lactate resulting from glycolysis-oxidation uncoupling and reduced MPC activity provides elevated cytosolic substrate availability for subsequent protein lactylation modifications that contribute to cardiac dysfunction [101].

Intercellular lactate transport networks

Metabolic reprogramming occurs within altered fatty acid metabolism and intercellular lactate transport networks reshaping cardiac energetics. Cardiac insulin resistance and decreased mitochondrial production precede systolic dysfunction, suggesting primary causation [102]. Early dysfunction establishes energy deficits contributing to hypertrophy-failure progression, with ATP production decreasing 37 % and 47 % at two and three weeks respectively, due to reduced mitochondrial oxidation without compensatory glycolysis. Fatty acid oxidation downregulation characterizes heart failure, with enzyme mRNA reductions exceeding 40 % in failing human hearts [103]. This inflexibility favors alternative pathways and intercellular cooperation.

Cell-to-cell lactate shuttles between fibroblasts and cardiomyocytes represent multicellular metabolic networks [104]. Co-culture demonstrates orchestrated enzyme and transporter changes regulated by microvesicles and soluble factors, resembling astrocyte-neuron shuttles relevant in age-related failure where matrix deposition and hypoxia favor lactate-mediated communication (Fig. 7) [105]. Differential monocarboxylate transporter expression serves cardioprotective functions during ischemia–reperfusion [106]. MCT4 increases during ischemia facilitating extrusion, while MCT1 increases during reperfusion enabling bidirectional transport. Flux analyses reveal lactate as primary TCA cycle carbon, with turnover exceeding glucose 1.1-fold fed and 2.5-fold fasting [107]. However, chronic lactate exposure reduces CPT I/II activities, alters cardiolipin, enhances ROS, and decreases mitochondrial ATP [108]. These findings emphasize complex dose- and time-dependent effects of lactate, highlighting importance of optimal homeostasis over simple availability maximization and setting stage for understanding lactate's role in pathological tissue remodeling.

Fig. 7.

Changes in subcellular localization and immunostaining intensity of Ki-67, FBP2 and FBP2-regulating kinase GSK3 evoked by cardiomyocytes-fibroblasts co-culture [105]. Copyright 2020, The Authors.

Lactate-Driven pathological remodeling

Myofibroblast metabolic reprogramming

Metabolic alterations and disrupted lactate homeostasis promote pathological remodeling through myofibroblast-mediated mechanisms creating persistent secretomes generating pro-fibrotic mediators and self-perpetuating matrix deposition [109], [110]. Cardiac fibrosis centers on transformed myofibroblasts activated following cardiomyocyte loss [110]. While preserving initial integrity, persistent myofibroblasts generate angiotensin II, receptors, and growth factors, creating signal-transducer-effector pathways sustaining collagen synthesis through autocrine/paracrine networks involving tissue angiotensin II and TGF-β1-Smad pathways [111]. TGF-β1 receptor kinase inhibition promotes myofibroblast dedifferentiation, demonstrating plasticity [112].

Cardiac myofibroblast differentiation and activation are accompanied by profound metabolic reprogramming characterized by decreased fatty acid oxidation and increased glycolysis [113]. This metabolic shift is regulated through AMPK-dependent pathways, wherein suppression of the PGC1α-CPT1A axis reduces fatty acid oxidation, while activation of the HIF1α-HK2 pathway enhances glycolytic flux. In fibroblasts isolated from explanted hearts of end-stage heart failure patients (both ischemic and dilated cardiomyopathy), the myofibroblast phenotype exhibits constitutive activation of the TGF-β1 signaling pathway alongside elevated expression of profibrotic cytokines and mature α-smooth muscle actin stress fibers, confirming sustained metabolic and phenotypic transformation [113]. This glycolytic reprogramming inevitably results in elevated intracellular lactate production, establishing a metabolic environment conducive to lactate-dependent signaling and potentially to lactylation-mediated processes.

Lactate-Mediated fibrotic activation

Lactate directly promotes fibrosis, as demonstrated in idiopathic pulmonary fibrosis where elevated lactic acid induces myofibroblast differentiation via pH-dependent TGF-β activation [114]. Physiologic lactate levels suffice for differentiation through TGF-β-induced LDH5 expression via HIF1α, creating positive feedback perpetuating progression. The interconnection between glycolytic reprogramming, lactate accumulation, and TGF-β pathway activation in cardiac myofibroblasts mirrors mechanisms established in other fibrotic diseases, suggesting that lactate serves dual functions: as a pH-modulating signaling molecule activating TGF-β and as a potential substrate for protein lactylation modifications [113], [114].

The established connection between metabolic reprogramming and fibroblast activation, combined with evidence from other fibrotic contexts where lactate-TGF-β circuits drive myofibroblast persistence, provides a mechanistic framework linking the metabolic dysfunction characterized in section 6.1 (glycolysis-oxidation uncoupling, reduced MPC activity, elevated cardiac lactate production) to the lactate-rich microenvironment that defines fibrotic cardiac tissue. This lactate accumulation, whether originating from metabolically reprogrammed cardiomyocytes or from glycolytic myofibroblasts themselves, creates conditions favoring both lactate-mediated signaling and potential lactylation-dependent epigenetic or post-translational modifications that could sustain the fibrotic phenotype [109], [113], [114].

Protein lactylation and contractile dysfunction

Metabolic reprogramming, altered lactate homeostasis, and structural remodeling culminate in contractile apparatus modification through protein lactylation. α-myosin heavy chain (α-MHC) undergoes lactylation at lysine 1897 maintaining titin interactions, linking metabolism to contractile integrity [115]. Paradoxically, reduced α-MHC K1897 lactylation occurs in experimental models and human heart failure despite elevated tissue lactate levels, connecting metabolic dysfunction to contractile impairment. This apparent paradox reflects subcellular lactate compartmentalization and enzymatic dysfunction in failing hearts. While cytosolic lactate accumulates due to glycolysis-oxidation uncoupling, enhanced MCT4-mediated lactate efflux reduces intracellular substrate availability for lactylation. Simultaneously, oxidative stress-induced p300 dysfunction and enhanced SIRT1 delactylase activity create an enzymatic environment favoring delactylation despite elevated bulk tissue lactate. Thus, heart failure exhibits a disconnect between total lactate production and functional lactylation capacity at contractile protein targets. Significance extends beyond α-MHC to thick filament networks including myosin, myosin binding protein-C, titin, myomesin, and obscurin, suggesting lactylation coordinates contractile function with metabolic status [116]. This metabolic-structural integration through lactylation provides mechanistic foundations for therapeutic approaches targeting the metabolic-structural interface in heart failure.

Lactate metabolism and lactylation in cardiomyocyte regeneration

Neonatal mammalian hearts possess regenerative capacity that is lost during postnatal maturation, creating a fundamental challenge in cardiovascular medicine. While neonatal hearts regenerate through cardiomyocyte proliferation following injury, this ability diminishes with shifts in metabolism, epigenetic programming, and cell cycle regulation [117]. Protein lactylation has emerged as a metabolic-epigenetic regulatory mechanism whereby lactate modifies regulatory proteins and transcriptional networks essential for proliferation. This metabolic-epigenetic interface indicates that regenerative capacity loss results from coordinated changes in lactate metabolism and lactylation-mediated gene regulation. Therapeutic strategies targeting lactate homeostasis and lactylation pathways could restore intrinsic repair capacity, moving beyond damage prevention toward tissue regeneration.

Metabolic foundations of cell cycle regulation

During the neonatal proliferative window (P1-P7), TLR3-mediated signaling enhances glycolytic metabolism and YAP1 activation promoting cardiomyocyte proliferation [118]. However, transition to normoxia triggers ROS production and DDR activation that ultimately override pro-proliferative signals, establishing permanent cell cycle arrest [117]. Therapeutic strategies aim to reactivate this TLR3-glycolysis-YAP1 axis while suppressing ROS-DDR pathways in adult hearts. Cardiomyocyte proliferative capacity links to metabolic state, with reduced oxygen, ROS scavenging, or DDR inhibition prolonging the proliferative window. Hyperoxemia and ROS generation accelerate post-mitotic transition, trading proliferative capacity for aerobic metabolism. The Hippo pathway regulates cardiomyocyte proliferation through YAP1 nuclear effector, stimulating growth via proliferation rather than hypertrophy [119], [120]. YAP1 activation stimulates postnatal cardiomyocyte proliferation in culture and intact hearts through YAP1-TEAD interactions. Integration with metabolism occurs through cellular energy status response, as Hippo signaling responds to mechanical cues, cell contact, and energy status via AMPK [121]. Cell cycle machinery reveals metabolic-proliferative connections through inhibitors including p27Kip1 [122]. This cyclin-dependent kinase inhibitor associates with cyclin E-Cdk2 complexes, preventing activation and S phase entry, with regulation tied to metabolic signaling. TLR3-mediated signaling enhances glycolytic metabolism and YAP1 activation for cardiomyocyte proliferation [118]. This operates through glycolysis-dependent YAP1 activation increasing miR-152 expression, which represses p27Kip1, linking metabolic flux to cell cycle progression. Glycolysis inhibition with 2-deoxyglucose prevents proliferation and functional recovery, establishing glycolytic metabolism as regenerative requirement.

Glycolytic reprogramming and regenerative signaling

Glycolytic pathways position lactate as a critical metabolic intermediate bridging glucose metabolism with epigenetic regulation. Glycolysis converts glucose to lactate, which accumulates in regenerative microenvironments and serves dual functions: fueling cellular metabolism and acting as substrate for protein lactylation [123]. Lactate dehydrogenase A (LDHA) catalyzes this conversion, with LDHA expression strongly correlating with cardiomyocyte proliferative capacity, high in neonatal regenerative hearts and declining during maturation. Lactate-derived lactylation modifies histone proteins, particularly H3K18la, creating an epigenetic landscape permissive for cell cycle gene expression [124], [125]. This metabolic-epigenetic axis operates through transcription factor networks that coordinate glycolytic flux with chromatin remodeling: enhanced glycolysis increases lactate availability, promoting lactylation at gene loci encoding proliferative regulators while suppressing maturation programs. By connecting glucose metabolism through lactate to histone modifications that control cell cycle gene accessibility, lactylation establishes a regulatory circuit whereby metabolic state directly determines proliferative competence.

Single-cell analysis of regenerating zebrafish hearts shows proliferating border zone cardiomyocytes exhibit distinct transcriptomes resembling embryonic cardiomyocytes, with reduced mitochondrial gene expression and activity alongside increased glycolysis genes and glucose uptake [126]. This reprogramming, induced by Nrg1/ErbB2 signaling and conserved in murine hearts, establishes glycolysis as a cross-species regulator. Neuregulin1 (Nrg1) couples metabolic reprogramming with proliferative activation. Nrg1 expression increases in perivascular cells following cardiac injury in adult zebrafish, with Erbb2 inhibition disrupting proliferation [127]. Myocardial Nrg1 overexpression induces dedifferentiation, hyperplasia, epicardial activation, and vascularization in uninjured hearts, identifying Nrg1 as a mitogen coordinating regenerative programs with glycolytic reprogramming.

LDHA orchestrates regenerative processes, connecting lactate metabolism with proliferation [123]. LDHA expression decreases during development, coinciding with regenerative capacity loss. Cardiomyocyte-specific LDHA knockout inhibits proliferation and impairs function in neonatal resection models, while overexpression promotes proliferation and repair following infarction. LDHA-mediated succinyl coenzyme A reduction inhibits succinylation-dependent ubiquitination of thioredoxin reductase 1, alleviating ROS and promoting proliferation. This lactate-centered network is modulated by Tp53 suppression, with damage inducing mdm2 expression and Tp53 fluctuations in regenerating cardiomyocytes [128]. BMP10 deficiency elevates p57Kip2 and reduces proliferation, establishing regulatory hierarchies where metabolic reprogramming, growth factor signaling, and cell cycle regulation converge [129].

Lactylation-Mediated epigenetic regulation

Metabolic reprogramming and regenerative signaling converge through epigenetic modifications orchestrating proliferative-to-post-mitotic transitions via lactylation. Lactate-rich environments stimulate cell cycle progression and modulate gene expression in neonatal and human iPSC-derived cardiomyocytes, though the precise molecular mechanisms linking lactate to transcriptional changes remain incompletely understood [124]. This is manifested via increased Ki67 and Aurora-B kinase expression, upregulation of BMP10, LIN28, and TCIM, while downregulating GRIK1 and DGKK (Fig. 8). Lactate modulates inflammatory cytokine production in cardiac fibroblasts, creating regenerative microenvironments potentially through hypoxia signaling pathways in addition to, or instead of, direct lactylation-dependent transcriptional reprogramming. In somatic cell reprogramming contexts, an epigenome-metabolome-epigenome signaling cascade coordinates histone modifications with metabolic flux [125]. Transcription factor Glis1 binds and opens chromatin at glycolytic genes while closing chromatin at somatic genes, upregulating glycolysis. Enhanced glycolytic flux increases acetyl-CoA and lactate levels, promoting acetylation (H3K27Ac) and lactylation (H3K18la) at 'second wave' pluripotency gene loci (Oct4, Sall4, Mycn). This demonstrates metabolic reprogramming creating conditions for epigenetic remodeling, with lactylation linking glycolytic flux to transcriptional regulation during cell fate transitions.

Fig. 8.

Effect of lactate on mouse cardiomyocyte cell cycle activity [124]. Copyright 2022, The Authors.

Therapeutic potential of targeting metabolic control of epigenetic landscapes becomes evident in studies of cardiomyocyte maturation reversal. Fatty acid oxidation inhibition through Cpt1b inactivation enables adult heart regeneration by altering the metabolic-epigenetic axis that restricts proliferation [130]. This metabolic intervention leads to α-ketoglutarate accumulation, activating KDM5 which demethylates H3K4me3 domains in cardiomyocyte maturation genes, shifting cells toward proliferation-competent states. Practical feasibility of pharmacological interventions is demonstrated by a five-molecule cocktail (5C) that promotes adult cardiomyocyte proliferation through lactate-LacRS2 signaling pathways, inducing metabolic switching toward glycolysis and cardiomyocyte dedifferentiation [131]. These findings establish lactylation as a druggable target that bridges metabolic reprogramming with epigenetic regulation, providing mechanistic foundations for therapeutic approaches that harness microenvironmental factors.

Microenvironmental regulation and therapeutic translation

Translating lactylation-mediated regenerative mechanisms requires understanding microenvironmental modulation and pathological disruptions. Inflammatory microenvironment determines regenerative outcomes, with M2 macrophages providing paracrine signals promoting proliferation, suppressing myofibroblast differentiation, and stimulating endothelial tube formation [132]. Cytokines IL-4 and IL-6 in M2-conditioned media recapitulate regenerative effects, establishing immune-metabolic crosstalk for lactylation-mediated processes. Pathological conditions interfere with lactylation-dependent signaling. Advanced glycation end-products (AGEs) accumulating in diabetes may compete with beneficial modifications including lactylation, as both involve lysine residue modification [133]. Whether AGEs directly prevent lactylation at specific sites (e.g., histones, Snail1) or indirectly impair lactylation through altered cellular energetics requires experimental validation.

Successful translation requires combination approaches optimizing lactate availability, modulating competing post-translational modifications, and creating supportive inflammatory microenvironments [132], [133]. Strategies must address temporal dynamics and dose-dependent effects, enabling lactylation-mediated programs to overcome barriers to adult regeneration while accounting for pathological states that impede regenerative success. Understanding these regulatory layers provides foundations for therapeutic interventions that harness endogenous repair mechanisms through metabolic and epigenetic modulation.

Conclusion and future respective

This review examined lysine lactylation as a metabolic-epigenetic regulatory mechanism in cardiovascular disease, demonstrating lactate's function beyond glycolytic metabolism as a signaling molecule modifying chromatin structure and gene expression. Analysis across vascular pressure disorders, atherosclerosis, myocardial infarction, heart failure, and cardiac regeneration reveals therapeutic potential alongside translational challenges. Mechanistic insights have established a regulatory network involving enzymatic writers (p300/CBP) and erasers (class I HDACs), with functional consequences ranging from α-myosin heavy chain regulation to histone modifications controlling immune polarization. Clinical translation is complicated by lactylation's dual nature with dichotomous effects: in regenerative contexts, lactate-induced histone lactylation promotes cardiomyocyte proliferation and M2 macrophage polarization facilitating tissue repair; conversely, in pathological settings, snail1 lactylation drives endothelial-to-mesenchymal transition perpetuating post-infarction fibrosis, while reduced α-MHC K1897 lactylation impairs contractile function in heart failure. These opposing outcomes necessitate tissue-specific and temporally controlled interventions.

Future therapeutic strategies will require integrating metabolic reprogramming, site-selective targeting, and temporal control, pending resolution of critical knowledge gaps in tissue-specific lactylation patterns and context-dependent efficacy. For example, targeting Snail1 lactylation during days 3–7 post-myocardial infarction when EndoMT peaks while preserving later macrophage lactylation-dependent repair. Tissue-specific lactylome profiling using cell-type-resolved proteomics should map beneficial versus detrimental lactylation across cardiomyocytes, fibroblasts, and immune populations to guide selective modulation strategies. For heart failure with reduced α-MHC lactylation, cardiomyocyte-targeted delivery of p300 activators or SIRT1-selective inhibitors could restore contractile protein modifications without affecting other cell types. Conversely, endothelial-selective inhibition of Snail1 lactylation through VE-cadherin promoter-driven expression of lactylation-resistant mutants may prevent post-infarction fibrosis. Understanding resistance mechanisms including dysregulated lactylation enzyme expression, compensatory metabolic pathways, and epigenetic memory maintaining pathological programs will determine whether therapeutic failures reflect irreversible remodeling or modifiable dysfunction amenable to combination strategies integrating MCT inhibitors, HDAC modulators, and metabolic reprogramming agents. These disease-specific approaches should guide development of precision cardiovascular medicine addressing both metabolic dysfunction and structural remodeling through lactylation pathway targeting.

CREDIT Author Statement

Conceptualization, Project administration. Supervision, Writing − original draft. Writing − review & editing, B.X., M. A. F.; Writing − original draft. Investigation. G.L.C., Z.W.S., Y.L., Y.K.X. and S.H.J.; Investigation and Funding acquisition, Z.W. S. All authors have read and agreed to the published.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Guilin Cheng First Author() is an Associate Professor at Zhejiang Chinese Medical University. She earned her M.S. degree in Biochemical Engineering and Ph.D. in Chemistry from Zhejiang University. Her research team primarily focuses on the modification and application of pharmaceutical-related materials.

Yan Liu is currently pursuing her undergraduate studies at Jiyang College of Zhejiang A&F University. Her research interests include the enzymatic synthesis antibacterial and anti-inflammatory biodegradable stent.

YangkunXing is currently pursuing her undergraduate studies at Jiyang College of Zhejiang A&F University. His current research focuses on the preparation of antimicrobial peptides.

ZheweiShi obtained his master’s degree from Wenzhou Medical University and is currently serving as an attending physician in the Department of Cardiovascular Medicine at Zhuji People's Hospital.

Mohamed AliFarag research work focuses on applying (metabolomics) in biodiversity studies involving multi-organisms including plants, marine corals, soil, and gut bacteria for improved quality, alongside better sustainability of organisms under stressed conditions. Dr. Farag research in metabolomics offers improved insights into multi-organisms’ adaptation to stress responses that are crucial for biodiversity conservation.

Songheng Jin is a Professor at Jiyang College, Zhejiang A&F University. He earned his Ph.D. in Biology from Zhejiang University. His research work focuses on plant physiology and biochemistry.

Bo Xia is an Associate Professor at the Jiyang College of Zhejiang A&F University. He received his B.S. degree in Chemistry and his M.S. degree in Agricultural Pesticide Science from Zhejiang University of Technology. In 2015, he earned his Ph.D. in Chemistry from Zhejiang University. To date, he has authored 10+ peer-reviewed articles in leading journals, including Advanced Science, Biotechnology Advances, Organic Letters, Green Chemistry, ACS Catalysis, Biomacromolecules, ACS Macro Letters, Critical Review in Food Science and Nutrition, Food Bioprocess Technol and iScience.