Metabolic regulation of macrophage polarization in myocardial infarction: from mechanisms to targeted therapies

Abstract

Background

Myocardial infarction (MI) elicits a tightly staged immune response in which macrophages coordinate early inflammation, subsequent tissue repair, and long-term ventricular remodeling. Growing evidence indicates that macrophage polarization is directed by immunometabolic reprogramming; however, the metabolic circuits that connect immune function to durable cardiac recovery remain incompletely defined.

Content

This review integrates current insights into the spatiotemporal, metabolic, and functional regulation of macrophages after MI. We summarize how glucose metabolism (glycolysis and the pentose phosphate pathway), TCA cycle rewiring and immunometabolic intermediates, lipid and amino-acid metabolism, iron handling and ferroptosis, purinergic and NAD⁺-dependent signaling, oxidative stress pathways, and vitamin-dependent regulation shape inflammatory versus reparative macrophage states. We highlight drug-targetable mediators—including lactate, succinate, α-KG, itaconate, kynurenine, and NAD⁺-linked pathways—and discuss how stage-specific targeting may suppress early injurious inflammation while promoting reparative remodeling. We also review advances in nanotechnology- and exosome-based delivery platforms that enable cardiac macrophage–directed interventions.

Outlook

Clinical translation will require deeper characterization of human macrophage heterogeneity, development of in vivo metabolic biomarkers, and validation in prospective multi-omics–anchored human studies. Temporally controlled combination therapies coupled with precision delivery systems may maximize cardiac repair while minimizing systemic metabolic toxicity.

Conclusions

Macrophage immunometabolism is a central determinant of post-MI healing and remodeling. Therapeutic reprogramming of macrophage metabolism represents a promising precision-immunotherapy strategy to improve repair, limit heart failure progression, and expand future cardiovascular treatment options.

Clinical trial number

Not applicable.

Introduction

Cardiovascular disease (CVD) remains a major global public health challenge, with mortality from coronary atherosclerotic heart disease and acute myocardial infarction (MI) remaining high. In the United States alone, CVD accounted for 941,652 deaths in 2022, of which coronary heart disease (CHD) represented approximately 39% [1]. MI, a common and severe manifestation of CHD, is characterized by extensive cardiomyocyte loss accompanied by robust inflammatory activation. The pathological course of MI involves acute inflammatory injury triggered by ischemic cell death and tissue necrosis, followed by a coordinated process of tissue healing and ventricular remodeling [2]. Over recent decades, therapeutic strategies for MI have markedly improved, particularly through early reperfusion interventions.These include primary percutaneous coronary intervention and coronary artery bypass grafting [3], alongside evidence-based pharmacological therapies such as antiplatelet agents (e.g., aspirin and P2Y12 inhibitors) [4], parenteral anticoagulants (unfractionated or low-molecular-weight heparin), and long-term neurohormonal modulation with angiotensin-converting enzyme inhibitors, angiotensin receptor–neprilysin inhibitors, β-blockers, and mineralocorticoid receptor antagonists. Despite these advances, MI-associated morbidity and mortality remain substantial. Infarct expansion, maladaptive ventricular remodeling, and subsequent heart failure continue to limit long-term outcomes, underscoring the need for novel mechanistic targets and therapeutic strategies. A major contributor to poor outcomes is maladaptive inflammation that fails to resolve appropriately, promoting infarct expansion, fibrosis, and progressive ventricular dysfunction.

Among the cellular mediators involved in post-MI remodeling, macrophages constitute the most abundant immune population within the cardiac injury microenvironment and play central roles in coordinating inflammatory and reparative responses [5]. As key components of the mononuclear phagocyte system—comprising monocytes, macrophages, and dendritic cells—circulating monocytes infiltrate injured myocardium and differentiate into functionally distinct macrophage subsets. These cells orchestrate early inflammatory clearance of necrotic debris and subsequently promote wound healing and tissue repair. While controlled inflammation is essential for initiating myocardial repair, excessive or prolonged inflammatory signaling can exacerbate cardiomyocyte injury, impair reparative processes, and accelerate adverse ventricular remodeling [6].

The progression of MI can be broadly divided into sequential yet overlapping phases, including an initial inflammatory phase dominated by leukocyte recruitment, a resolution phase characterized by anti-inflammatory and reparative macrophage polarization, and a final repair/remodeling phase involving extracellular matrix deposition, fibrosis, and scar maturation. Macrophages are critically involved at each stage, dynamically shifting phenotypes to balance inflammation and repair. Disruption of this balance contributes directly to infarct size determination, ventricular remodeling, and the eventual development of heart failure.

Thus, metabolic regulation of macrophage polarization represents a promising therapeutic axis for limiting myocardial injury, optimizing cardiac repair, and improving long-term outcomes. Defining these mechanisms may enable interventions that modulate post-infarction immunity with greater specificity than broad anti-inflammatory approaches.

In this review, we summarize current evidence on the metabolic regulation of macrophage polarization during MI, integrating insights from immunology, cardiovascular biology, and cellular metabolism. We discuss how distinct metabolic programs shape inflammatory and reparative macrophage phenotypes across the stages of post-infarction remodeling, and we highlight emerging metabolism-targeted strategies and delivery platforms aimed at improving cardiac repair and clinical outcomes.

Spatiotemporal programs of macrophages after MI dynamic

Following MI, ischemic necrosis initiates a robust immune response characterized by an early inflammatory phase and a later phase of tissue repair, fibrosis, and ventricular remodeling. Macrophages—key effector cells of the innate immune system—participate throughout this entire process and critically determine the balance between injury resolution and pathological remodeling. Traditionally, macrophages have been categorized into pro-inflammatory M1 and anti-inflammatory/reparative M2 phenotypes. However, recent single-cell transcriptomic analyses reveal far greater phenotypic diversity and pronounced temporal and spatial heterogeneity. Therefore, systematic characterization of the dynamic evolution and spatial distribution of macrophage subsets is essential for identifying therapeutic targets to prevent adverse cardiac remodeling after MI (Fig. 1).

Fig. 1.

Central illustration. This figure illustrates how macrophage metabolic shifts regulate the cardiac repair process at different stages after myocardial infarction, integrating four core elements: timeline, cell lineage, metabolic switches, and functionl outcomes

Temporal dynamics

Macrophage phenotypes and functions exhibit marked plasticity in response to the evolving post-infarction microenvironment. Survival signals, cytokines, and epigenetic regulation critically shape the transition from circulating monocytes to differentiated macrophage subsets. Resting macrophages (M0) represent an unpolarized intermediate state that remains highly responsive to environmental cues. Microbial products, chemokines, and inflammatory mediators can polarize M0 macrophages toward M1 or M2 phenotypes, which exert distinct effects after MI [7]. In the context of MI, these polarized subsets produce markedly divergent pathophysiological effects. Sheng and colleagues identified resident cardiac macrophages populating the interstitial spaces between fibroblasts, cardiomyocytes, and endothelial cells. These tissue-resident populations can be categorized into three distinct subsets based on differential expression of CCR2 and MHC-II: CCR2-MHC-II^low, CCR2-MHC-II^high, and CCR2⁺-MHC-II^high. Ly6C serves as a critical marker for discriminating monocyte subpopulations, with varying expression levels correlating with distinct functional properties. Monitoring Ly6C expression enables investigators to trace the cellular dynamics underlying post-infarction pathogenesis [8]. Following MI, cardiac macrophages exhibit striking temporal plasticity, transitioning sequentially through distinct inflammatory, reparative, and remodeling phases [9].

Inflammatory phase (Days 1–3)

During the early inflammatory phase, Ly6C^hi CCR2⁺ inflammatory macrophages predominate. These cells express high levels of IL-1β, TNF-α, and MMP-9, cooperate with neutrophils to clear necrotic debris, and degrade extracellular matrix [10, 11]. At the transcriptional level, NF-κB, STAT1, STAT5, and IRF3 drive the M1 inflammatory program. M1 macrophages express markers such as CD68, iNOS, and IL-6 and are essential for debris clearance. However, persistent M1 activation enlarges infarct size and delays inflammation resolution, thereby impairing scar formation and cardiac repair [12].

Repair phase (Days 4–7)

Subsequently, macrophages shift toward Ly6C^lowCCR2⁻ reparative phenotypes, secreting TGF-β, IL-10, and VEGF-A to promote angiogenesis, fibroblast activation, and inflammation resolution.M2 macrophages expand rapidly during this stage [13], and include multiple functional subtypes. M2a (IL-4-induced): anti-inflammatory and wound healing [14]; M2b (immune-complex-induced): immunomodulatory and fibroblast-activating effects [15]. M2 macrophages express CD206, Arg-1, IL-10, TGF-β, and VEGF, suppress inflammation, limit fibrosis, and support vascular regeneration [9, 16].

Remodeling phase (>7days)

During late remodeling, macrophages regulate fibrosis, collagen maturation, and electrical conduction, thereby shaping ventricular structure and function. Balanced macrophage activity promotes adaptive fibrosis, characterized by a dense collagen scar that preserves structural integrity and prevents rupture. M2a and M2c subsets are key drivers of this reparative process [17]. Conversely, prolonged or dysregulated macrophage activation leads to excessive collagen deposition, ventricular stiffening, diastolic dysfunction, and progression toward heart failure [18]. Thus, precise temporal control of macrophage polarization is essential to balance adaptive repair and pathological remodeling [19].

Spatial distribution

Macrophage function after MI is also governed by regional microenvironmental heterogeneity. The myocardium can be divided into: infarct core, border (peri-infarct) zone, and remote myocardium [20].

Infarction core

The central infarct territory constitutes the region of most profound ischemic insult, where sustained coronary occlusion precipitates widespread cardiomyocyte necrosis, structural disintegration, and the development of a profoundly hypoxic milieu [11]. Within this necrotic landscape, macrophages achieve their highest cellular density, driven by robust chemotactic signals released from dying cells [21]. Their primary mission involves the efficient clearance of cellular debris and necrotic material. This phagocytic activity serves a critical protective function, preventing the release of damage-associated molecular patterns that would otherwise propagate uncontrolled inflammation and exacerbate secondary tissue injury [22]. Early post-infarction, these cells predominantly execute tissue debridement functions; subsequently, the core undergoes progressive collagenous replacement, ultimately forming a fibrotic scar [23]. Although this avascular scar tissue lacks contractile capability, it preserves cardiac structural integrity, protects against catastrophic ventricular rupture, and provides essential mechanical support. The therapeutic objective within this region centers on promoting rapid necrotic material clearance while facilitating timely macrophage transition toward reparative phenotypes [24].

Border zone

Encircling the necrotic core lies the peri-infarct border zone—a region of paramount pathophysiological significance [25]. Here, hemodynamic compromise results in partial perfusion deficits, creating a heterogeneous cellular environment populated by both irreversibly injured and potentially salvageable cardiomyocytes. Macrophages within this transitional territory display exceptional phenotypic plasticity [11]. Conversely, persistent M1-polarized macrophages inflict bystander injury upon endangered but viable myocytes through the release of reactive oxygen species and pro-inflammatory mediators, thereby driving infarct expansion [26]. In contrast, alternatively activated M2 macrophages confer cytoprotection through the secretion of anti-inflammatory IL-10 and pro-survival growth factors [27], thereby stabilizing jeopardized cardiomyocytes, attenuating apoptosis, and limiting infarct expansion. The biological fate of this border zone ultimately determines final infarct size and cardiac prognosis, representing a key therapeutic target where suppressing destructive M1 inflammation while amplifying M2 cardioprotective signals can salvage viable myocardium [11].

Remote myocardium

Although Although spared from direct ischemic injury, remote myocardium undergoes substantial pathological remodeling driven by neurohormonal activation, mechanical stress, and macrophage-mediated fibrosis [11]. Resident macrophages in these distal regions, activated primarily by systemic signals rather than hypoxic cues, typically assume profibrotic M2-like characteristics that promote interstitial fibrosis and compromise global cardiac compliance, contributing significantly to heart failure progression. Consequently, region-specific therapeutic strategies—potentially leveraging nanotherapeutics or targeted biologics for precise macrophage modulation across all myocardial territories [28] —may prove essential for optimizing cardiac outcomes and preventing post-MI heart failure development.

Functional states beyond M1/M2

Contemporary understanding of cardiac macrophage biology has evolved substantially beyond the conventional M1/M2 dichotomy, with single-cell and metabolic profiling revealing specialized subsets actively sculpted by local microenvironmental signals and specific metabolic substrates [29]. Elucidating the functional capabilities, plasticity mechanisms, and regulatory networks governing these discrete populations has become essential for deciphering post-infarction pathophysiology and advancing precision immunotherapeutic strategies [28].

Reparative macrophages

Reparative macrophages represent specialized subsets that predominate during the late phase of MI, with distinct surface marker profiles including Trem2^high (expressing Trem2, Spp1, and Gdf15) [30] and BHLHE41⁺ (characterized by elevated Fabp5 and Cd36) [31] populations. Functionally resembling M2-like macrophages, these cells secrete anti-inflammatory cytokines (IL-10, TGF-β) to suppress excessive inflammation [27], while releasing TGF-β and PDGF to activate myofibroblasts, stimulate collagen deposition, and facilitate scar formation, thereby preventing cardiac rupture. Additionally, they promote neovascularization through VEGF secretion, restoring perfusion and providing metabolic support for tissue regeneration. Importantly, the abundance, functional competence, and temporal emergence of these cells are critical determinants of healing outcomes [32]; premature appearance may impair essential inflammatory clearance, whereas delayed or insufficient activation can result in inadequate repair, ventricular rupture, or maladaptive fibrosis [24]. Thus, precise spatiotemporal control of reparative macrophage dynamics emerges as crucial for optimal post-infarction cardiac recovery [9].

Interferon-regulated macrophages

Interferon-stimulated signaling is a potent immunomodulatory pathway that critically regulates macrophage activation and function following MI [33]. IFN-γ, produced primarily by activated T cells and NK cells, is one of the most powerful inducers of classically activated (M1) macrophages [18]. Through activation of the JAK–STAT1 signaling pathway, IFN-γ drives macrophages to express high levels of pro-inflammatory cytokines and iNOS, thereby enhancing their microbicidal activity and capacity to clear cellular debris. In addition, IFN-α/β can be produced by multiple immune and damaged cell types in response to danger-associated molecular patterns, further shaping macrophage inflammatory programs [34].

Sustained activation of interferon signaling after MI has been associated with adverse left ventricular remodeling and progressive cardiac dysfunction. This detrimental effect is likely mediated by prolonged maintenance of a pro-inflammatory macrophage phenotype, leading to extended myocardial injury and impaired resolution of inflammation [35]. Accordingly, therapeutic modulation of interferon signaling has emerged as a potential strategy to suppress harmful hyperinflammation while promoting the transition of macrophages toward reparative phenotypes, thereby improving cardiac repair and functional recovery [36].

Lipid-associated macrophages (LAMs)

Recently characterized lipid-associated macrophage subsets (LAMs) have emerged as a specialized population playing an increasingly important role in MI pathophysiology [37]. Following cardiomyocyte necrosis, large quantities of intracellular lipids are released into the infarcted tissue and avidly taken up via TREM2 [38], driving macrophages into a distinct activation state that transcends classical M1/M2 polarization. Single-cell transcriptomic studies have defined TREM2^high LAMs as functionally and transcriptionally unique populations reflecting adaptive responses to lipid overload.

LAMs exert biphasic effects during MI progression. TREM2-dependent signaling promotes reparative functions by enhancing lipid phagocytosis, reducing lipotoxicity, and potentially dampening inflammation [39]. However, excessive lipid uptake drives foam-cell transformation, which sustains chronic inflammation through pro-inflammatory mediator secretion and triggers endoplasmic reticulum stress and apoptosis. Myocardial lipid accumulation and foam-cell formation are closely associated with adverse remodeling and subsequent heart failure development, making modulation of TREM2 signaling and macrophage lipid metabolism—specifically strategies enhancing lipid clearance while preventing foam-cell formation—promising therapeutic avenues for improving cardiac repair [40].

These processes are tightly interconnected throughout MI evolution. Early interferon-driven inflammation promotes M1-like differentiation for debris clearance while coinciding with massive lipid release. As repair emerges, reparative macrophages become dominant, with specific subsets transitioning into LAMs through TREM2-dependent lipid internalization. Although initially contributing to repair, persistent lipid overload and foam-cell conversion can impair inflammation resolution and promote fibrosis. Thus, elucidating the functional heterogeneity, lineage transitions, and regulatory mechanisms governing LAMs remains essential for developing next-generation precision immunotherapies to optimize post-MI recovery.

Conceptual integration

Post-MI macrophage biology reflects a highly coordinated interplay among interferon-driven inflammatory signaling, lipid metabolic reprogramming, and reparative differentiation. Early macrophage activation is essential for efficient clearance of necrotic debris and containment of tissue damage, whereas subsequent metabolic and phenotypic reprogramming supports inflammation resolution, tissue repair, and adaptive remodeling. Disruption of these tightly regulated transitions—through sustained interferon signaling, impaired lipid handling, or defective reparative programming—can drive chronic inflammation, maladaptive fibrosis, and progressive ventricular dysfunction. Accordingly, a comprehensive understanding of the spatiotemporal dynamics and metabolic control of macrophage subsets will be critical for the development of next-generation precision immunotherapies aimed at improving structural and functional recovery after MI.

Metabolic circuits governing macrophage polarization

In MI, macrophage immune function is inextricably linked to cellular metabolic state through immunometabolic reprogramming [41]. During polarization, macrophages undergo profound shifts in energy production and substrate utilization that directly shape their inflammatory or reparative phenotypes, representing an adaptive mechanism to dynamic environmental cues. Distinct metabolic signatures characterize these populations: pro-inflammatory M1 macrophages predominantly depend on aerobic glycolysis [42], whereas M2 macrophages rely more heavily on mitochondrial oxidative metabolism, including fatty-acid oxidation [43]. Nevertheless, emerging evidence suggests metabolic regulation of M2 macrophages is more complex than previously appreciated. Transitions between states are strongly influenced by microenvironmental cues—such as lactate accumulation, extracellular adenosine signaling, and TCA cycle intermediates including α-ketoglutarate [44] —which collectively modulate polarization and function.

The infarcted myocardium itself exhibits remarkable metabolic flexibility, utilizing diverse substrates—including glucose, fatty acids, amino acids, ketone bodies, and pyruvate—to sustain energy production under ischemic conditions [45]. Cardiomyocytes dynamically adjust substrate preference to maximize ATP generation while minimizing oxygen consumption [46]. Because macrophages operate within this metabolically evolving microenvironment, myocardial substrate availability critically influences polarization and downstream responses. The following sections examine key metabolic pathways governing macrophage polarization after MI, integrating insights from glucose metabolism, lipid utilization, mitochondrial function, and intermediary metabolite signaling (Fig. 2).

Fig. 2.

Roles of M1 and M2 macrophages in different metabolic mechanisms such as glucose metabolism, lipid metabolism, amino acid metabolism, iron metabolism, oxidative stress and matrix remodeling, nucleotide metabolism after myocardial infarction

Glycolysis and the pentose phosphate pathway (PPP)

Macrophage polarization is fundamentally intertwined with glucose metabolism, with extensive metabolic rewiring serving as a hallmark of activation [41]. Upon stimulation, macrophages undergo profound metabolic transition toward aerobic glycolysis, rapidly generating ATP through cytosolic rather than mitochondrial mechanisms [47].Pro-inflammatory M1 macrophages exhibit pronounced dependency on glycolytic flux, utilizing accelerated glucose consumption and lactate accumulation to sustain inflammatory effector functions [48]. Interestingly, this metabolic reprogramming also influences adjacent cardiomyocyte biology: enhanced glucose uptake through GLUT1 upregulation [49] and PKM2 modulation promotes cardiomyocyte proliferation by stimulating glycogen synthesis and nucleotide biosynthesis [50].

Four critical molecular nodes orchestrate this glycolytic phenotype. GLUT1 controls substrate availability, HK2 catalyzes the first committed step while linking metabolism to survival signaling, PFKFB3 accelerates glycolytic flux, and PKM2 functions as a metabolic switch whose low-activity state promotes accumulation of pro-inflammatory intermediates [51]. LPS-induced M1 polarization correlates with enhanced glycolysis and diminished oxygen consumption, establishing a tightly controlled program supplying substrates for inflammatory activation. Given that excessive glycolysis drives pathological inflammation, pharmacological targeting of these nodes represents a compelling strategy: GLUT1 inhibition limits glucose uptake, HK2 or PFKFB3 blockade attenuates flux, and PKM2 activation promotes tetramer formation, redirecting carbon flux away from biosynthetic pathways and facilitating transition toward reparative phenotypes.

Beyond glycolysis, the pentose phosphate pathway (PPP) constitutes a critical alternative route. Following MI, DAMPs released from necrotic cardiomyocytes activate macrophages through TLR signaling, triggering robust upregulation of PPP enzymes [52]. The oxidative phase, catalyzed by G6PD, generates substantial NADPH [53], which fuels production of NO and ROS. While NO possesses antimicrobial properties, elevated concentrations inhibit mitochondrial respiration; when combined with superoxide, these species form peroxynitrite (ONOO⁻)—an extraordinarily potent oxidant that activates NF-κB, drives IL-6 expression, and reinforces M1 polarization [54, 55]. In the infarcted heart, ONOO⁻ accumulation imposes severe nitrative stress upon cardiomyocytes and endothelium, accelerating injury and adverse remodeling.

The PPP-NADPH-NOX2/iNOS axis therefore represents a central driver of inflammatory injury after MI. G6PD inhibition restricts PPP flux at its origin, NOX2 suppression attenuates ROS generation, and selective iNOS inhibition limits NO and downstream ONOO⁻ formation. Targeting this coordinated network may enable precise attenuation of detrimental inflammation while preserving essential reparative functions, providing a promising framework for metabolism-based therapies in myocardial infarction.

TCA cycle rewiring and immunometabolic signaling metabolites

TCA cycle serves as a central immunometabolic signaling platform in macrophages responding to MI, transcending its traditional role as a mere bioenergetic engine. In pro-inflammatory M1 macrophages, TCA cycle reprogramming favors accumulation of specific intermediates—particularly succinate and itaconate—rather than continuous oxidative flux.

Succinate, normally oxidized to fumarate by succinate dehydrogenase (SDH), accumulates abnormally under metabolic stress and hypoxia during MI. Rapid oxidation upon reperfusion generates excessive reactive oxygen species, exacerbating ischemia-reperfusion injury [56]. In M1 macrophages, disruption of TCA flux creates sustained succinate elevation, which inhibits prolyl hydroxylase activity, stabilizes HIF-1α, activates AKT-mTOR signaling, and drives IL-1β transcription [57].

Additionally, extracellular succinate signals through GPR91, triggering NF-κB and MAPK pathways to amplify pro-inflammatory cytokine production [58]. Pharmacological SDH inhibition or GPR91 blockade thus emerges as a strategy to attenuate post-MI inflammation. Conversely, itaconate functions as an endogenous anti-inflammatory metabolite. Inflammatory stimuli induce Irg1, converting cis-aconitate into itaconate, which inhibits SDH, suppresses NLRP3 inflammasome activation, and activates Nrf2 to limit oxidative stress [59]. Cell-permeable derivatives such as 4-octyl itaconate enhance these cytoprotective effects and promote inflammation resolution [60].

α-KG, generated from isocitrate via oxidative decarboxylation or glutamine metabolism [61], serves dual roles as a metabolic intermediate and epigenetic cofactor. Elevated α-KG concentration-dependently enhances fatty-acid oxidation and drives M2 polarization [62], antagonizing succinate-mediated HIF-1α stabilization and suppressing NF-κB signaling in a prolyl-hydroxylase-dependent manner [63]. Exogenous α-KG supplementation in experimental MI reduces early pro-inflammatory cytokine release, increases M2 macrophage proportions, enhances repair, and limits scar formation, improving left ventricular remodeling and survival.

Clinical translation of α-KG-based therapies remains challenging due to limited metabolic stability and bioavailability. Emerging strategies—including nanoparticle-based delivery, sustained-release formulations, and combination approaches—may overcome these barriers, though future development must account for inter-individual metabolic heterogeneity and immune-response variability to enable precision immunometabolic therapy.

Fatty acid metabolism

Disordered lipid metabolism is a hallmark of cardiovascular disease and closely linked to MI pathogenesis. Postnatally, the mammalian heart undergoes progressive metabolic maturation toward FAO as the dominant ATP source, with the adult myocardium relying primarily on this pathway. Circulating fatty acids are transported within lipoproteins, while lipid synthesis substrates originate from glycolysis, TCA cycle, and PPP intermediates. Lipidomic analyses demonstrate tight associations between lipid metabolic states and macrophage activation [64], suggesting lipid-handling macrophage subsets as promising therapeutic targets.

Endogenous oxidized lipids can simultaneously enhance oxidative phosphorylation and aerobic glycolysis in LPS-stimulated phagocytes [65], highlighting metabolic plasticity. In contrast, reparative M2 macrophages depend predominantly on FAO-driven mitochondrial metabolism, catabolizing lipids via lysosomal lipases to replenish TCA cycle intermediates [66]. IL-4 stimulation augments fatty-acid uptake and FAO through STAT6-dependent induction of PGC-1β, which promotes M2 polarization while suppressing inflammatory responses [67].

Energy-sensing pathways integrate FAO with inflammatory regulation. AMPK activation confers cardioprotection during ischemia-reperfusion injury, suppressing inflammation while promoting FAO [68, 69]. Concurrently, PPAR-γ functions as a lipid-sensing nuclear receptor regulating macrophage lipid handling [70]; its activation suppresses NF-κB signaling, reduces pro-inflammatory cytokine secretion, and limits M1 polarization.

Following cardiomyocyte necrosis, large quantities of intracellular lipids are released into the infarct microenvironment. Macrophages internalize these via scavenger receptors such as SR-A1 and CD36. When uptake exceeds metabolic capacity, intracellular lipid overload develops, causing lipotoxic stress, mitochondrial dysfunction, and inflammatory activation. This transforms macrophages from reparative to pro-inflammatory, pro-fibrotic phenotypes, contributing to sustained inflammation, impaired healing, adverse remodeling, and heart failure progression. Targeting macrophage lipid uptake, FAO capacity, and lipotoxic signaling thus represents a promising strategy to enhance cardiac repair and prevent post-MI heart failure.

Amino acid metabolism

Amino acids are amphoteric organic molecules containing both amino and carboxyl functional groups and participate in diverse metabolic processes, including protein synthesis, cellular signaling, and energy production. Amino-acid metabolism encompasses dietary intake, absorption, transport, catabolism, and reutilization within tissues [71]. Beyond their structural roles, specific amino-acid metabolic pathways critically regulate macrophage activation, inflammatory signaling, and tissue repair following MI.

Arginine metabolism and macrophage polarization

Arginine, a semi-essential amino acid released from injured cardiomyocytes and activated immune cells within the post-MI inflammatory microenvironment, undergoes metabolism through two competing enzymatic pathways that determine macrophage functional polarization. The nitric oxide synthase (NOS) pathway, driven primarily by inducible NOS (iNOS), converts arginine into nitric oxide (NO) and citrulline, characteristic of pro-inflammatory M1 macrophages [72]. Upregulation of iNOS increases NO production via the citrulline-NO cycle; while NO contributes to pathogen clearance and debris removal, excessive levels reversibly inhibit mitochondrial complex IV, disrupting myocardial energy metabolism and amplifying tissue injury. Conversely, the arginase (ARG) pathway, particularly the cytoplasmic isoform ARG1 induced by Th2 cytokines such as IL-4 and IL-13, serves as a hallmark of M2 macrophages, facilitating inflammation resolution, collagen synthesis, and scar formation. Because both pathways compete for the same substrate, activation of one suppresses the other. Thus, temporal regulation of the iNOS-ARG1 axis represents a key therapeutic opportunity: early iNOS-mediated clearance followed by timely ARG1-driven repair.

Glutamine metabolism in inflammatory and reparative responses

Glutamine, the most abundant circulating amino acid, plays a central role in macrophage activation and metabolic reprogramming [73]. Elevated glutamine utilization reflects heightened cellular activation and supports biosynthesis, redox balance, and energy production in post-MI macrophages [74]. Inflammatory signaling—particularly via TLR4 activation by lipopolysaccharide or damage-associated molecular patterns—upregulates glutamine transporters and glutaminase (GLS), thereby promoting M1-associated pro-inflammatory functions. Conversely, glutamine-derived intermediates entering the TCA cycle can enhance IL-4–mediated signaling and support M2 polarization and reparative activity [75]. These dual roles indicate that glutamine metabolism acts as a context-dependent regulator of macrophage function. Dysregulated glutamine flux may therefore contribute to persistent inflammation after MI, highlighting glutamine metabolic pathways as emerging therapeutic targets.

Tryptophan metabolism and immune regulation

Tryptophan (Trp), an essential amino acid metabolized primarily through the kynurenine pathway, plays a critical immunoregulatory role after MI. Indoleamine 2,3-dioxygenase 1 (IDO1), highly expressed in immune cells—particularly M2 macrophages—catalyzes Trp conversion to kynurenine [76]. Genetic or pharmacologic IDO1 inhibition impairs cardiac regeneration, whereas elevated kynurenine levels promote cardiomyocyte proliferation and angiogenesis, supporting tissue repair. During early MI, M1 macrophages dominate inflammatory clearance, while subsequent IDO1 activation limits excessive inflammation and facilitates transition toward reparative M2 phenotypes. Downstream kynurenine signaling via the aryl hydrocarbon receptor (AHR) further regulates extracellular matrix remodeling and vascular repair. Collectively, these findings position Trp-kynurenine-AHR signaling as a critical immunometabolic axis [77]; modulation of IDO1 activity or AHR signaling may enable reprogramming of macrophage functional orientation to achieve optimal balance between inflammatory containment and tissue repair, offering synergistic potential when integrated with conventional therapies.

Branched-chain amino acids and cardiovascular risk

Branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—are essential nutrients obtained exclusively from dietary sources [78]. Beyond their anabolic roles, BCAAs function as metabolic signaling molecules influencing energy homeostasis and intracellular pathways [79]. Large-scale epidemiological studies consistently associate elevated circulating BCAA levels with cardiovascular diseases, including hypertension, atherosclerosis, and heart failure [80, 81], with complementary bioinformatic analyses further implicating BCAA metabolic dysregulation in atherosclerosis progression [82]. These observations suggest that plasma BCAA elevation may serve as a prognostic biomarker for adverse cardiovascular outcomes following MI and may reflect maladaptive metabolic remodeling.

Integrated perspective

Taken together, amino-acid metabolic pathways—including arginine–NO/ARG balance, glutamine utilization, tryptophan–kynurenine signaling, and BCAA metabolism—form a tightly interconnected regulatory network that shapes macrophage polarization and cardiac repair after MI. Targeting these immunometabolic circuits offers promising opportunities for precision modulation of inflammation, fibrosis, and ventricular remodeling, thereby improving long-term cardiovascular outcomes.

Iron metabolism and ferroptosis

Iron is an essential trace element required for maintaining cellular homeostasis, mitochondrial respiration, and enzymatic activity. Macrophages serve as central regulators of systemic iron homeostasis and key responders to dynamic changes in iron metabolism, with emerging evidence indicating that iron handling—including uptake, storage, export, and ferroptotic signaling—critically governs phenotypic polarization and post-MI remodeling [83, 84]. Physiological iron metabolism involves three coordinated processes: heme iron is internalized through CD163-mediated endocytosis of hemoglobin-haptoglobin complexes and degraded by heme oxygenase-1 (HO-1), whereas non-heme iron enters via transferrin receptor-1 (TfR1); excess iron is sequestered within ferritin to prevent oxidative injury; and ferroportin (FPN1) mediates iron efflux, negatively regulated by hepcidin. These metabolic circuits shape macrophage phenotype by modulating oxidative stress, metabolic activity, and inflammatory signaling. In M1 macrophages, upregulated TfR1 and ferritin expression coupled with suppressed FPN1 result in intracellular iron retention, stimulating NADPH oxidase activity and amplifying pro-inflammatory responses [85]. Conversely, M2 macrophages exhibit reduced TfR1 and enhanced FPN1-mediated iron export, limiting ROS accumulation, suppressing pro-inflammatory JAK-STAT1 signaling, and directly inducing M2-associated genes including Arg1 and IL-10, thereby reinforcing the anti-inflammatory phenotype [86].

Ferroptosis and macrophage–cardiomyocyte crosstalk

Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxide accumulation, glutathione depletion, and GPX4 inactivation [87]. Cardiomyocytes are particularly susceptible due to their high oxygen consumption, abundant mitochondria, and enrichment in polyunsaturated fatty acids. Following MI, erythrocyte rupture releases hemoglobin-derived iron, which is phagocytosed by macrophages through erythrophagocytosis. Inflammatory signaling suppresses macrophage FPN1 expression, leading to intracellular iron trapping or unstable extracellular iron release [88]. Excess free iron promotes ROS generation via the Fenton reaction, catalyzes lipid peroxidation, and directly induces ferroptosis in neighboring cardiomyocytes. Ferroptotic cardiomyocytes subsequently release DAMPs and lipid peroxides that activate TLR4/MyD88 signaling and reinforce M1-type inflammatory polarization, thereby amplifying myocardial injury. In contrast, M2 macrophages display relative resistance to ferroptosis, characterized by elevated GPX4 expression, enhanced glutathione synthesis, and activation of the Nrf2/HO-1 antioxidant pathway, with IL-4 signaling further protecting against lipid peroxidation and supporting reparative functions.

Pathophysiological feedback and therapeutic implications

Extensive cardiomyocyte ferroptosis generates a microenvironment dominated by oxidative stress and inflammation, which impairs reparative M2 polarization and stabilizes the destructive M1 phenotype [89]. This establishes a self-reinforcing pathological loop between macrophage iron dysregulation and ferroptotic myocardial injury, ultimately contributing to delayed healing, adverse ventricular remodeling, and heart failure progression [90].

Therapeutic strategies that simultaneously inhibit cardiomyocyte ferroptosis and reprogram macrophage iron handling may therefore represent a promising avenue for post-MI cardioprotection [91]. Breaking this cycle could shift macrophages from inflammatory “destroyers” toward reparative “healers” while preserving cardiomyocyte viability. To systematically integrate these concepts, the relationships between metabolic reprogramming pathways and macrophage functional phenotypes are summarized in Fig. 3.

Fig. 3.

Metabolic circuitry of macrophage polarization. The picture illustrates how major metabolic pathways within macrophages detetermine their inflammatory (M1) and reparative (M2) phenotypes, highlighting the“broken cycle”phenomenon of the TCA cycle and its impact on polarization states

Nucleotide metabolism and purinergic signaling

Macrophages contribute to host defense and tissue homeostasis through phagocytosis, antigen presentation, and cytokine secretion, functions tightly coupled to metabolic reprogramming. Nucleotide metabolism plays a central role in cellular energy balance, intracellular signaling, and epigenetic regulation, with both purine and pyrimidine pathways critically regulating macrophage activation, polarization, and immune responses [92].

Nucleotide metabolism encompasses deoxynucleotide synthesis, ribonucleotide synthesis—including de novo and salvage pathways—and nucleotide catabolism [93], such as the degradation of adenosine to hypoxanthine and uric acid. Functionally, pro-inflammatory M1 macrophages preferentially rely on de novo nucleotide synthesis to sustain rapid transcriptional activity and inflammatory mediator production, whereas reparative M2 macrophages more frequently utilize salvage pathways consistent with lower biosynthetic demand.

Following MI, severe cellular injury releases ATP, ADP, and AMP into the extracellular space, where these nucleotides function as DAMPs [94]. ATP activates P2 purinergic receptors (P2X and P2Y subtypes) on macrophages, promoting recruitment to the infarct zone. P2 × 7 receptor activation induces NLRP3 inflammasome assembly, leading to IL-1β maturation and robust M1-type inflammatory responses. M1 macrophages exhibit low CD39 and CD73 expression, resulting in inefficient ATP degradation and sustained pro-inflammatory signaling. Conversely, M2 macrophages highly express these ectonucleotidases, efficiently converting ATP to anti-inflammatory adenosine [95, 96]. Post-MI healing thus depends on the spatiotemporal transition from ATP-dominant to adenosine-dominant signaling. Pharmacological P2 × 7 antagonists administered during the early inflammatory phase demonstrate cardioprotective effects.

NAD⁺ functions as a pivotal metabolic coenzyme in glycolysis, oxidative phosphorylation, and redox reactions, while also serving as an essential signaling substrate [97]. NAD⁺ availability regulates Sirtuin family deacetylases, which sense cellular energy states and modulate gene expression, DNA repair, mitochondrial function, antioxidant defenses, and inflammatory signaling [98]. Following MI, NAD⁺ depletion contributes to impaired Sirtuin activity, increased cardiomyocyte death, and adverse remodeling. Restoration of NAD⁺ signaling through precursors—including niacin, nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN)—effectively elevates tissue NAD⁺ levels and demonstrates cardioprotective effects in preclinical and clinical studies. The NAD⁺/Sirtuin axis thus represents a central metabolic surveillance system; therapeutic restoration through nutritional or pharmacological interventions offers a compelling strategy to enhance myocardial repair and improve outcomes after MI.

Oxidative stress and extracellular matrix (ECM) remodeling

Macrophages function as critical orchestrators of tissue homeostasis, immunological regulation, and structural remodeling. Their intracellular metabolic configuration not only dictates phenotypic polarization trajectories but also directly governs ROS generation. Consequently, these cells serve as principal mediators of oxidative stress within the injured myocardium. Contemporary investigations have established that under pathological conditions—such as acute tissue injury and chronic inflammation—macrophages undergo profound metabolic reprogramming that intensifies oxidative stress responses [99]. This metabolic shift significantly influences ECM degradation, architectural remodeling, and pathological deposition, thereby profoundly impacting the progression of cardiac fibrosis.

As previously detailed, necrotic cardiomyocytes liberate substantial quantities of DAMPs following myocardial infarction. These molecular signals drive the robust recruitment and activation of diverse immune cell populations, among which macrophages constitute the predominant effectors. Upon activation, these cells markedly upregulate NOX2 expression, leading to vigorous production of superoxide and other reactive oxygen intermediates [100]. These oxidants inflict direct cytotoxic damage upon adjacent viable cardiomyocytes. Simultaneously, excessive oxidative burden precipitates functional impairment within the macrophages themselves, triggering sustained release of pro-inflammatory mediators [101]. This establishes a self-perpetuating cycle that amplifies tissue inflammation, impedes reparative processes, and ultimately culminates in ventricular decompensation. The underlying molecular mechanisms involve DAMP-mediated activation of pattern recognition receptors—particularly TLRs—driving commitment toward pro-inflammatory M1 phenotypes. These stimuli activate membrane-bound NOX2 complexes, generating superoxide anions that dismutate to hydrogen peroxide (H₂O₂). H₂O₂ diffuses into mitochondria, precipitating organellar dysfunction that reinforces the M1 state through HIF-1α and NF-κB activation while suppressing M2 transition. The ROS and inflammatory cytokines released induce apoptotic death in salvageable cardiomyocytes within the peri-infarct border zone, expanding irreversible injury. Furthermore, persistent inflammatory signaling inhibits fibroblast differentiation into functional myofibroblasts, compromising collagen deposition and scar integrity. These sequelae manifest as ventricular dilation, interstitial fibrosis, contractile dysfunction, and heart failure. Highly specific NOX2 inhibitors suppress macrophage-derived oxidant generation at its source, while strategies promoting mitochondrial quality control through pharmacological activation of mitophagy enable elimination of dysfunctional organelles. Both approaches effectively disrupt the vicious cycle of oxidative damage and inflammation.

Cardiac fibrosis following MI represents dysregulated ECM deposition and aberrant tissue repair. Matrix remodeling is precisely regulated by cytokines, MMPs, and their inhibitors (TIMPs) [102]. Macrophages participate in ECM homeostasis through MMP secretion and pro-fibrotic mediators, coordinating oxidative stress pathways. TGF-β and MMPs function as principal regulatory nodes governing tissue architecture. TGF-β promotes fibrogenesis through canonical Smad-dependent and non-canonical MAPK/PI3K/Akt pathways [103]. MMPs are synthesized as inactive zymogens requiring proteolytic activation. Following injury, inflammatory cells release bioactive TGF-β, stimulating fibroblast proliferation and MMP upregulation. Notably, MMP-2 and MMP-9 proteolytically activate latent TGF-β, establishing a positive feedback loop [104] wherein activated TGF-β further stimulates ECM synthesis and MMP/TIMP expression. Selective targeting of MMP-2-mediated TGF-β activation represents a precision therapeutic strategy, offering a safe and effective antifibrotic approach for post-infarction remodeling.

Metabolic targets and translational opportunities

Representative metabolic targets

Metabolic reprogramming is adapted to inflammatory immune function of macrophages. In recent years, targeted metabolites, as important molecules regulating macrophage function, are considered to have potential to treat cardiac injury after MI, and the number of articles published in related fields increases year by year. As glycolysis increases, the reprogrammed TCA cycle enables macrophages to acquire a pro-inflammatory phenotype. Metabolites produced during metabolism also regulate macrophage activation. Metabolic enzymes such as PKM2 and PDK are also involved in cardiomyocyte proliferation and heart regeneration. We focused on the characteristics of metabolic reprogramming of macrophages after MI, focusing on how key metabolites such as PKM2, SDH, α-KG, itaconate, FAO/PPAR γ, P2 × 7/NLRP3, NPM1, DMF, ACSL4/iron death regulate macrophage polarization and functional status through metabolism-inflammation axis, and it is necessary to explore the application prospect of metabolite intervention strategies in improving cardiac prognosis. According to the level of evidence (A/B/C) to highlight robustness. Table 1 summarizes:

Table 1.

Key metabolic targets, interventions, and translational relevance in post-MI macrophage polarization

Target / Pathway	Cell type	Intervention (Drug/Genetic)	MI Model (Species)	Phase / Timing	Macrophage Effect	Cardiac Outcome	Evidence Level	Translational Notes	Representative Reference
PKM2 (glycolysis)	Macrophage	PKM2 deficiency / inhibitor (e.g., TEPP-46)	LAD ligation (Mouse)	Early, D1–3	↓IL-1β, ↓TNF-α; shift from M1 bias	↓Infarct size; ↑LVEF	B	Potential target for acute MI inflammation; no clinical trials yet	Palsson-McDermott 2015 [105]; Zeng 2024 [50]
Succinate / SDH (TCA)	Macrophage	Dimethyl malonate (SDH inhibitor)	I/R (Mouse)	At reperfusion, D1–3	↓HIF-1α, ↓IL-1β	↓Infarct size	B	Concept proposed for STEMI patients undergoing PCI	Tannahill 2013 [63]; Kula-Alwar 2019 [56]
α-Ketoglutarate (epigenetic cofactor)	Macrophage	α-KG supplementation / nanoparticles	LAD ligation (Mouse)	Reparative, D4–7	↑M2 phenotype, ↑efferocytosis	↑Repair; ↓Fibrosis; ↑Survival	A	Candidate for metabolic supplementation in repair phase	Liu 2017 (Nat Immunol) [62]
Itaconate / IRG1	Macrophage	4-Octyl-itaconate, DMI; nanofiber delivery	LAD ligation (Mouse)	Reparative, D4–7	↑M2-like, ↑NRF2 signaling	↓Fibrosis; ↑Healing	B	Derivatives (e.g., 4-OI) under preclinical evaluation	Nakkala 2021 (Small) [106]
FAO / PPARγ–CPT1	Macrophage	AMPK activators, CPT1 agonists	I/R (Mouse)	Reparative, D4–7	↑FAO, ↑M2 polarization	↑Angiogenesis; ↓Fibrosis	C	Conceptual link; indirect MI data, repurposing (metformin) possible	Bates 2021 [68]
NPM1 (epigenetic/metabolic switch)	Macrophage	NPM1 inhibitor	LAD ligation (Mouse)	Early, D1–3	Shift from glycolysis → OXPHOS	↑Recovery, ↓Damage	B	Novel concept; small-molecule inhibitors preclinical only	Zhang 2024 (Circulation) [107]
Dimethyl fumarate (DMF, NRF2 activator)	Macrophage / Fibroblast	Oral DMF	LAD ligation (Mouse)	Reparative, D4–7	↑Macrophage OXPHOS; ↓Fibroblast OXPHOS	Improved remodeling	B	Repurposing MS drug; potential remodeling therapy	Mouton 2021 (J Mol Cell Cardiol) [108]
ACSL4 / Ferroptosis	CM ↔ Macrophage crosstalk	Ferrostatin-1, FIN02 (concept)	I/R (Mouse)	Early & remodeling (D1–3, > D7)	↓Pro-inflammatory signals from ferroptotic CM	↓Infarct; ↓Adverse remodeling	C	Conceptual; combination with lactate proposed	Gao 2024 [109]

Representative metabolic targets implicated in macrophage polarization after MI. Shown are the primary cell type, interventions, models, macrophage phenotypic effects, cardiac outcomes, and translational relevance. Evidence levels: A, multiple in vivo MI models/species with replication; B, single robust MI model with mechanistic support; C, indirect or limited MI evidence

Key immunometabolic metabolites

Following MI, a spectrum of immunomodulatory metabolites—including lactic acid, succinic acid,α-KG, itaconic acid, and tryptophan-derived kynurenine—serve as pivotal orchestrators of macrophage immunometabolism throughout the inflammatory, reparative, and ventricular remodeling phases. These metabolic intermediates exert phase-specific influences that dynamically shape the functional trajectory of the infarcted heart.

Lactic acid

Lactate, historically regarded as a metabolic by-product of glycolysis, is now recognized as a multifunctional signaling metabolite. Myocardial ischemia and hypoxia enhance LDHA-mediated anaerobic glycolysis, leading to substantial lactate accumulation. Beyond its association with lactic acidosis, lactate exerts immunomodulatory, anti-inflammatory, and wound-healing effects through microbiome-related mechanisms [110]. Mechanistically, lactate regulates macrophage phenotype via histone lactylation, enabling M1-to-M2 transition in LPS/IFN-stimulated macrophages [111]. It also activates ERK-STAT3 signaling, promotes angiogenesis, suppresses M1 polarization through GPR81-dependent signaling, and modulates epigenetic regulation via HDAC inhibition [112]. These findings position lactate as a key immune-metabolic regulator of post-MI remodeling, suggesting therapeutic potential for MCT inhibitors, GPR81 agonists, or modulators of lactylation.

In addition to L-lactate, the stereoisomer D-lactate has recently emerged as a potential modulator of immune and neuroimmune signaling. Although traditionally considered a minor metabolic by-product derived largely from microbial metabolism, accumulating evidence suggests that D-lactate may exert distinct biological effects on immune cell activation, redox balance, and inflammatory signaling. Notably, recent experimental findings indicate that D-lactate can influence stress-related neuroimmune interactions and behavioral outcomes, supporting a broader role for lactate enantiomers in immune–metabolic communication along the gut–brain–immune axis. Mechanistically, D-lactate may regulate macrophage function through modulation of mitochondrial metabolism, oxidative stress responses, and receptor-mediated signaling pathways that only partially overlap with those triggered by L-lactate [113]. These observations raise the possibility that stereospecific lactate signaling contributes to the fine-tuning of inflammatory resolution and tissue repair after MI. Future studies clarifying the cellular sources, transport mechanisms, and receptor targets of D-lactate in cardiac injury will be essential to determine whether enantioselective metabolic interventions could represent a novel strategy for immunometabolic therapy.

Succinate, α-KG, and itaconate

Accumulation of succinate in hypoxic myocardium and infiltrating immune cells amplifies inflammation, whereas α-KG and itaconate exert context-dependent anti-inflammatory and cytoprotective effects. Together, these metabolites function as metabolic checkpoints that coordinate the transition from inflammation to repair. Similarly, tryptophan–kynurenine metabolism links immune-cell metabolic state to functional output, restraining excessive inflammation while promoting reparative processes. The integrated effects of these metabolites are summarized in Table 2.

Table 2.

Key immunometabolic metabolites, phase-specific roles, and translational relevance in post-MI macrophage polarization

Metabolite	Receptor / Enzyme	Macrophage Effect	Phase-Specific Role	Cardiac Outcome	Evidence Level	Translational Notes	Representative Reference
Lactate	HCAR1 (GPR81); histone lactylation	Promotes M2-like polarization, efferocytosis	Early: ↑Lactate may sustain inflammation; Reparative: lactylation supports resolution	Balanced lactate improves repair; excess may impair healing	C	Concept of lactate + ferroptosis inhibitor for remodeling	Zhang 2019 [112]; Gao 2024 [109]
Succinate	SDH / GPR91	Stabilizes HIF-1α, ↑IL-1β	Early (D1–3): pro-inflammatory driver	↓Infarct size if SDH inhibited; risk of impaired angiogenesis	B	Reperfusion-phase SDH inhibition proposed	Tannahill 2013 [63]; Kula-Alwar 2019 [56]
α-Ketoglutarate	JmjC demethylases, PHDs	Supports M2-like, epigenetic reprogramming	Reparative (D4–7): enhances repair and resolution	↑Repair; ↓Fibrosis	A	α-KG nanoparticles for reparative therapy	Liu 2017 [62]
Itaconate	IRG1 → NRF2/KEAP1	Anti-inflammatory, antioxidant, resolution promoting	Reparative (D4–7): shifts metabolism, promotes repair	↓Fibrosis; ↑Healing	B	4-Octyl-itaconate and derivatives in preclinical MI models	Nakkala 2021 [106]
Tryptophan–Kynurenine	IDO1 → AHR	Immune suppression, tolerance	Reparative (D4–7): may aid resolution; Remodeling (> D7): risk of impaired clearance	Dual role, context dependent	C	Kynurenine–AHR axis proposed in MI repair	Zhang 2022 [76]

Selected metabolites with critical roles in macrophage polarization during distinct phases of MI. Listed are their receptors/enzymes, macrophage effects, phase-specific roles, cardiac outcomes, evidence levels, and translational implications. Evidence levels as in Table 1.

Stage-specific intervention strategies

Metabolic reprogramming runs through the process of macrophage polarization and functional remodeling in myocardial infarction, which not only determines its pro-inflammatory or repair effects, but also profoundly affects the repair quality of cardiac tissue. The regulation of metabolic state and macrophage function after myocardial infarction is heterogeneous in time and space. It is necessary to limit pro-inflammatory injury in acute stage of myocardial infarction, and promote anti-inflammatory function and tissue reconstruction in repair stage. It is difficult to adapt to the dynamic demand of inflammation-repair by single time point or single target intervention. It is necessary to study multi-target combination therapy, which can act on different metabolic pathways simultaneously and present multi-temporal and multi-spatial therapeutic effectiveness.

Early inflammatory phase (Days 1–3)

Macrophages exhibiting the M1 pro-inflammatory phenotype display a metabolic profile dominated by aerobic glycolysis (the Warburg effect). This metabolic adaptation ensures rapid ATP generation to fuel acute cellular activation while supplying intermediates for the synthesis of nucleic acids, proteins, and lipids, thereby supporting cellular proliferation and robust cytokine secretion. Moreover, this pathway generates NADPH to drive ROS production necessary for pathogen clearance and debris elimination. While this hyperglycolytic state provides substrates for rapid energy production and anabolic processes, it simultaneously amplifies local inflammation and tissue injury. Consequently, early inhibition of glycolytic flux can promote macrophage polarization toward the reparative M2 phenotype, fostering sustained tissue repair, attenuating inflammation, and ultimately improving cardiac function. During the acute phase of MI, infiltrating macrophages undergo profound metabolic reprogramming wherein the TCA cycle becomes bottlenecked at SDH, resulting in substantial succinate accumulation. Elevated succinate levels not only stabilize HIF-1α to perpetuate glycolytic metabolism but, more critically, can efflux from mitochondria into the extracellular space. Once outside the cell, succinate transmits potent pro-inflammatory signals through its cognate receptor SUCNR1 (GPR91), thereby amplifying the inflammatory cascade and exacerbating tissue damage. Pharmacological antagonism of SUCNR1 during the critical early window following MI may therefore serve to “brake” excessive inflammatory responses, offering a novel metabolism-based immunotherapeutic strategy for cardioprotection.Concurrently, DAMPs released by early necrotic cardiomyocytes, in concert with metabolic disturbances, co-activate the NLRP3 inflammasome in macrophages. This activation drives the maturation and release of the potent IL-1β and IL-18, triggering intense local and systemic inflammatory responses that directly mediate further cardiomyocyte death and adverse cardiac remodeling. Direct inhibition of NLRP3 using MCC950 [114], or intervention targeting its upstream metabolic drivers, can similarly attenuate these deleterious early inflammatory events.

Repair phase (Days 4–7)

As inflammation resolves, macrophages undergo phenotypic transition from proinflammatory M1 states toward reparatory M2 configurations. Central to this phase is efferocytosis—the specialized process through which macrophages recognize, internalize, and degrade apoptotic cells, including neutrophils and cardiomyocytes undergoing programmed cell death. Timely clearance of these apoptotic bodies prevents secondary necrosis and the subsequent release of proinflammatory intracellular contents, thereby serving as a critical checkpoint for inflammation resolution. Unlike their glycolysis-dependent M1 counterparts, reparatory M2 macrophages executing efferocytosis demonstrate metabolic reprogramming toward FAO and enhanced OXPHOS. Therapeutic strategies during this window may include exogenous administration of fatty acids or upregulation of fatty acid transporter expression to ensure adequate fuel supply for FAO. Additionally, PPARγ agonists can be employed to promote M2 polarization and enhance efferocytic capacity.

Remodeling phase (> Day7)

As the healing response progresses into the reparative phase, macrophage metabolism continues to govern phenotypic transitions, specifically the conversion from pro-inflammatory (M1) to reparative/regulatory (M2) states. This switch is characterized by a metabolic reprogramming from glycolysis toward OXPHOS. M2 macrophages function as pivotal regulators of fibrosis, activating fibroblasts through TGF-β secretion to stimulate collagen production. Simultaneously, the anti-inflammatory and regulatory cytokines they release promote the formation of organized, mature collagenous scars while restricting excessive fibrotic deposition. However, during adverse remodeling, macrophages experience declining GSH synthesis, impaired antioxidant defenses, and intracellular iron overload, rendering them vulnerable to ferroptosis. The demise of these macrophages releases substantial quantities of free radicals and lipid peroxides, perpetuating a vicious cycle that induces ferroptotic death in adjacent cardiomyocytes and fibroblasts, thereby profoundly compromising the repair process. Interventions to counteract this pathology include GSH supplementation to neutralize lipid peroxides, NAC to provide substrate for GSH synthesis, or pharmacological activation of the NRF2 pathway to bolster macrophage antioxidant capacity and confer resistance to ferroptosis. Oxidative stress during the remodeling phase primarily arises from mitochondrial dysfunction and NOX activation. Sustained oxidative burden impairs cellular function and impedes tissue repair. AMPK agonists can improve mitochondrial integrity, minimize electron leakage, and thereby reduce ROS generation at the source. Furthermore, ketone body supplementation—specifically β-hydroxybutyrate (BHB)—induces the expression of antioxidant genes and inhibits NLRP3 inflammasome activation, thereby attenuating oxidative stress and inflammation in macrophages.Conceptually, an ideal therapeutic strategy would combine PPARγ agonism with antioxidant and mild iron-chelating properties, thereby synergistically guiding the heart toward favorable remodeling and optimal repair during this critical window. (Fig. 4).

Fig. 4.

Stage-guided therapeutic framework

Delivery platforms and combinatorial approaches

While pharmacological modulation of macrophage immunometabolism through conventional inhibitors and agonists demonstrates considerable therapeutic promise following myocardial infarction, systemic administration of these agents presents significant pharmacological constraints. Traditional pharmaceutical approaches invariably perturb metabolic homeostasis in off-target organs, precipitating dose-limiting toxicities that restrict clinical utility [115]. Furthermore, small-molecule therapeutics frequently suffer from rapid renal clearance, hepatic metabolism, or proteolytic degradation, thereby precluding the achievement of therapeutically relevant concentrations within the hostile cardiac microenvironment [116]. These pharmacokinetic limitations necessitate the urgent development of precision delivery modalities capable of spatially constrained drug deployment.

Nanoparticle-based targeting

Engineered nanoparticles (NPs) or exosome-based carriers enable cardiac macrophage-specific delivery of metabolic regulators—including small-molecule inhibitors, agonists, siRNAs, and miRNAs [117]—with surface modification using targeting ligands enhancing uptake within infarcted myocardium while minimizing systemic exposure. Notable metabolic interventions include suppression of pro-inflammatory glycolysis through PKM2 inhibition and enhancement of oxidative metabolic capacity via PPARδ activation [118, 119].

Exosome-mediated therapy

Exosomes (30–150 nm) possess natural cardiac tropism, low immunogenicity, and high biocompatibility, making them attractive bioinspired delivery vehicles [120]. Engineered exosomes can be loaded with therapeutic miRNAs to suppress pro-inflammatory signaling and reprogram macrophage bioenergetics toward M2 polarization, or harvested directly from M2 macrophages to propagate anti-inflammatory phenotypes within the infarct milieu. Active targeting strategies leverage high-affinity ligand-receptor interactions to enhance cellular specificity, enabling selective modulation of cardiac macrophages while sparing protective populations in distant tissues, thereby attenuating infarct inflammation without systemic immunosuppression [121]. Given that macrophage functionality and metabolic profiles undergo continuous transformation throughout the healing continuum, mono-target, single-time-point interventions frequently demonstrate limited efficacy. The contemporary paradigm centers upon temporally orchestrated combinatorial immunometabolic therapy tailored to distinct phase-specific signatures, requiring simultaneous or sequential modulation of complementary pathways while maintaining exquisite cellular and spatial specificity [122].

Spatiotemporally coordinated combination therapy

Because MI pathology evolves dynamically, precision immunometabolic therapy should incorporate: (1) Stage-specific drug release (anti-inflammatory → conversion → repair). (2) Microenvironment-responsive carriers sensing pH, ROS, or enzymatic activity. (3) Organ, cell, and subcellular-level targeting. During the acute inflammatory phase, therapeutic objectives center on attenuating excessive inflammation; co-encapsulation of glycolytic inhibitors with inflammasome antagonists within ROS-responsive nanoparticles enables context-specific activation exclusively within high-oxidative-stress environments, ensuring preferential uptake by inflammatory monocytes and macrophages while remaining inert in healthy tissues. During the transitional repair phase, priorities shift toward facilitating M1-to-M2 conversion; nanoparticles coated with M2 macrophage-derived membrane fragments exploit natural homing properties to selectively target regions undergoing active phenotypic transition. In the mature reparative phase, goals encompass enhancement of sustained repair functionality and prevention of pathological remodeling. The future landscape is evolving toward unprecedented spatiotemporal precision and multi-target synergism, deploying sophisticated sequentially released pharmaceutical arsenals with intelligent navigation systems capable of sensing local microenvironmental perturbations and responding with context-appropriate drug release. These next-generation systems will ultimately possess hierarchical targeting capabilities spanning organ, cellular, and subcellular levels, thereby revolutionizing the precision medicine approach to myocardial repair and regeneration.

Conclusion, clinical translation, and future perspective

Macrophage polarization after MI is governed by tightly coordinated immunometabolic programs that evolve across inflammatory, reparative, and remodeling phases. Rather than representing static M1/M2 states, macrophages undergo dynamic metabolic rewiring involving glycolysis, tricarboxylic acid cycle intermediates, lipid utilization, amino-acid metabolism, iron handling, nucleotide signaling, oxidative stress responses, and vitamin-dependent regulation. Disruption of these transitions promotes persistent inflammation, maladaptive fibrosis, and ventricular dysfunction, whereas precise metabolic control enables effective debris clearance, tissue repair, and structural stabilization. Collectively, current evidence positions macrophage immunometabolism as a central determinant of cardiac recovery after MI.

From a therapeutic standpoint, multiple metabolic nodes—including lactate signaling, succinate–SUCNR1 pathways, α-ketoglutarate balance, itaconate-mediated anti-inflammatory feedback, fatty-acid oxidation/PPAR signaling, ferroptosis regulation, purinergic signaling, and NAD⁺–Sirtuin activity—represent promising drug-targetable mechanisms. Importantly, effective intervention is likely to require stage-specific modulation, suppressing excessive glycolysis and inflammasome activation early after MI while promoting oxidative metabolism, efferocytosis, antioxidant defense, and controlled fibrosis during later repair. This temporal precision underscores a shift from conventional anti-inflammatory therapy toward metabolism-guided immune reprogramming.

Advances in targeted delivery technologies further enhance translational potential. Nanoparticles, engineered exosomes, and ligand-directed carriers enable cardiac macrophage–specific drug delivery, improving local efficacy while minimizing systemic toxicity. Integration of microenvironment-responsive release systems and multi-target combinatorial therapies may allow sequential control of inflammation, phenotypic conversion, and tissue regeneration. Such strategies move the field toward spatiotemporally precise immunometabolic therapeutics, representing a major conceptual evolution in post-MI treatment.

Despite rapid progress, several challenges remain. Most mechanistic insights derive from preclinical models, and human macrophage heterogeneity, metabolic diversity, and comorbidity-related influences are incompletely understood. Standardized biomarkers to monitor macrophage metabolic states in vivo are lacking, and long-term safety of metabolic manipulation—particularly regarding fibrosis, arrhythmia risk, and systemic metabolism—requires careful evaluation. Bridging these gaps will demand integrated multi-omics profiling, longitudinal clinical studies, and rigorously designed translational trials.

Looking forward, the convergence of immunology, metabolism, bioengineering, and precision medicine is poised to redefine cardiovascular therapeutics. Future strategies will likely incorporate stage-adapted metabolic modulation, smart delivery platforms, and patient-specific risk stratification to optimize cardiac repair and prevent heart failure. By transforming macrophages from drivers of injury into orchestrators of regeneration, immunometabolic therapy holds substantial promise for improving outcomes after myocardial infarction and may ultimately establish a new paradigm in cardiovascular medicine.

Author Contribution

Lihuimei Zhou: Investigation and Writing—Original Draft. Yi Jiang: Methodology and Validation. Jing Luo: Data curation and Visualization. Jiafu Li: Conceptualization, Supervision, Writing—Review & Editing and Funding acquisition. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by Luzhou Municipal People’s Government-Southwest Medical University Science and Technology Strategic Cooperation Project (00140256, 2024LZXNYDJ115); Sichuan Provincial Collaborative Innovation Center for Cardiovascular Disease Prevention and Treatment Fund Project(00160082,No.XTCX2019-14).

Data availability

Not applicable.

Declarations

Institutional review board statement

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Informed consent

Not applicable.

Conflict of interest

The authors declare no conflicts of interest.