Macrophage efferocytosis in cardiovascular disease: mechanisms and therapeutic implications

Abstract

Cardiovascular diseases (CVDs) account for millions of deaths worldwide each year, underlining their significant impact on global health. An expanding body of evidence identifies atherosclerosis, myocardial infarction, heart failure, and ischemic stroke as major contributors to this burden. Central to the pathogenesis of these conditions is the inflammatory response—a key defense mechanism that, when dysregulated, accelerates disease progression and disrupts cellular homeostasis, ultimately leading to adverse clinical outcomes. Efficient resolution of inflammation is essential not only for halting the inflammatory responses but also for restoring tissue integrity. One critical aspect of resolving inflammation is the efficient clearance of apoptotic cells, a process known as “efferocytosis,” which remains underappreciated. Cardiac macrophages are tasked with removing apoptotic cells, necrotic cells, and cellular debris through efferocytosis. Importantly, recent studies have demonstrated that efficient efferocytosis is associated with improved outcomes in CVDs, whereas impaired efferocytosis perpetuates inflammation and hinders recovery. This tightly regulated mechanism not only resolves inflammation by suppressing proinflammatory cytokines but also stimulates the production of anti-inflammatory cytokines and reprograms macrophages to promote tissue homeostasis. This mini-review consolidates current understanding of macrophage efferocytosis and its molecular mechanisms, providing valuable insights into cardiac health and highlighting its significant potential as a therapeutic avenue for treating CVDs.

Introduction

Cardiovascular diseases (CVDs) encompass a broad spectrum of disorders affecting the heart and blood vessels, including atherosclerosis, myocardial infarction (MI), stroke, and heart failure. Despite significant advances in medical research and treatment, CVDs continue to be the leading cause of death worldwide, imposing a substantial burden on global public health systems and economies.¹ A key driver of CVD development and progression is the inflammatory response, which, when dysregulated, can affect cellular homeostasis and accelerate disease progression, leading to adverse outcomes. Thus, to control inflammation and maintain cellular homeostasis, the human body relies on a highly conserved evolutionary process known as “efferocytosis” for apoptotic cell (AC) clearance.

The term “efferocytosis” is derived from the Latin efferre, meaning “to bury,” and describes a carefully coordinated process that plays an indispensable role in the efficient elimination of ACs and prevents inflammation. Notably, even under physiological conditions, cellular turnover in adult humans is enormous. It is estimated that approximately 0.4% of cells (∼200 to 300 billion) in an adult human undergo apoptosis daily.^2,3 This burden is further amplified in CVDs, where the loss of cardiomyocytes, endothelial cells, and vascular smooth muscle cells occurs on a massive scale. The efficient removal of these ACs is therefore essential to prevent secondary necrosis, restrain sterile inflammation, and promote tissue repair and remodeling. Despite the continuous flux of dying cells, ACs are rarely detected in healthy tissues, highlighting the remarkable efficiency and capacity of endogenous clearance mechanisms.

Central to this process is “efferocytosis,” a highly coordinated process for the clearance of ACs, which is primarily performed by macrophages and, to a lesser extent, by other “professional” phagocytes, such as dendritic cells, and “nonprofessional” phagocytes, such as epithelial cells (Fig. 1).^2,4 In efferocytosis, phagocytes are actively recruited to sites of dead cells, where they recognize ACs via “find-me” and “eat-me” signals, ensuring their efficient removal.^5,6 Most importantly, this process must occur in an immunologically silent manner to avoid inappropriate activation of the immune system.^7–9

Figure 1.

Efferocytosis of apoptotic cells (ACs) by phagocytes. Any impairment in efferocytosis results in the accumulation of ACs, which can contribute to the development of cardiovascular diseases. Image generated by BioRender.

Macrophages are thus recognized as crucial professional phagocytes, primarily involved in the clearance of dead cells across tissues. Historically, in 1882, microbiologist Élie Metchnikoff first described specialized motile immune cells capable of engulfing foreign material, laying the foundation for the modern concept of innate immunity.¹⁰ These cells, later termed macrophages, are a specialized subset of white blood cells that act as key effectors of the innate immune system and play an indispensable role in the body’s defense mechanisms.¹¹ Their primary responsibilities include phagocytosing and degrading pathogens, ACs, and cellular debris, as well as regulating the immune response.¹² In the context of CVDs, macrophages play a dual role: They can trigger harmful inflammation, but also mediate tissue repair and regeneration.¹³ These complex functions suggest that distinct macrophage populations may exist; however, their precise identities remained largely unexplored until the past decade.

Macrophages are long-term residents of nearly all tissues from early developmental stages and are not merely transient responders to injury or infection.^14,15 As long-term resident cells, macrophages acquire tissue-specific gene expression profiles shaped by their local microenvironment.^15,16 Recent advances using mouse models and single-cell or single-nucleus RNA sequencing have demonstrated that cardiac resident macrophage (CRM) populations undergo dynamic changes during disease progression, giving rise to novel macrophage subsets not observed under steady-state conditions.^17,18 In adult human and mouse hearts, macrophages account for approximately 7% of the nonmyocyte population under normal conditions and may represent a larger fraction in developing hearts.¹⁹ Until recently, it was believed that all macrophages originate from circulating monocytes (MoMs).^20,21 However, studies tracing cell lineages have shown that CRMs are heterogeneous, comprising both embryo-derived cells from primitive hematopoiesis (early development) and monocyte-derived cells from definitive hematopoiesis.^22,23

In CVDs, CRMs play a central role in maintaining cardiac homeostasis and are considered more specialized and efficient efferocytes than MoMs, which predominantly contribute to disease progression.²⁴ CRMs constitutively express high levels of AC recognition and engulfment receptors, such as MerTK and TIM4 family members, enabling rapid and persistent clearance of dying cells in an immunologically silent manner that maintains tissue integrity. In contrast, MoMs recruited during injury or inflammation in CVDs and metabolic diseases often exhibit reduced expression of efferocytic mediators and impaired apoptotic cell uptake, thereby contributing to defective inflammation resolution. This functional divergence highlights a division of labor in cardiovascular tissues: CRMs maintain physiological conditions, while MoMs dominate injury responses and may exacerbate pathology when efferocytosis is defective.^17,24 For example, CRMs monitor the myocardium for damage, while recruited monocyte-derived macrophages clear debris after MI. Defective efferocytosis leads to the accumulation of apoptotic and necrotic cells, resulting in the formation of a necrotic core within atherosclerotic plaques and an increased risk of acute cardiovascular events.^25–27 Additionally, recent studies have identified the receptor tyrosine kinase MerTK (c-Mer tyrosine kinase) as a key signaling regulator that links efferocytosis to cardiovascular repair.^28,29 These findings have prompted us to better appreciate the diversity of macrophages and sparked interest in understanding macrophage efferocytosis under normal and disease conditions. This review outlines the molecular mechanisms governing efferocytosis of ACs and summarizes recent findings as well as the unresolved challenges associated with macrophage efferocytosis in CVDs. Exploiting macrophage reprogramming pathways to eliminate necrotic plaque accumulation further highlights the emerging potential of macrophage-targeted therapies in CVDs.

Mechanistic overview of efferocytosis

Despite daily massive cellular turnover, ACs are less detectable under physiological conditions, highlighting the remarkable efficiency of phagocytes and the capacity of the efferocytic machinery. Efferocytosis is a tightly regulated, highly coordinated process that ensures the continuous clearance of cellular corpses. This immunologically silent process maintains tissue homeostasis and prevents an inflammatory response by controlling the off-target engulfment of healthy cells and by maintaining clearance rates.³⁰ The mechanism of efferocytosis occurs through these sequential stages: ACs first release (i) “find-me” signals, a set of chemoattractant and other molecules that recruit phagocytes to dying cells; (ii) the “eat-me signal,” receptor-mediated recognition of ACs; (iii) the engulfment of the dying cells; and (iv) subsequent activation of the digestion mechanism, postengulfment processing of cellular components via phagolysosomal degradation. These steps in processing ACs are highly coordinated, and disturbances at any stage compromise efferocytosis, thereby triggering inflammatory responses.^31,32 The following sections will explore the molecular mechanisms underlying each stage of efferocytosis and discuss emerging therapeutic strategies that target these processes.

Recognition of dying cells

“Find-me” signal

During programmed cell death, dying cells actively release chemokines as “find me” signals that attract phagocytes and initiate their own elimination.³³ Following injury or apoptosis, rupture of the cellular membrane leads to the release of soluble factors that both recruit phagocytes and ACs and prime phagocytes by modulating cytoskeletal dynamics, thereby enhancing the expression of engulfment receptors required for efficient uptake and subsequent digestion of the dying cells. These “find-me” signals include nucleotides (eg ATP/UTP), lipids (eg lysophosphatidylcholine [LPC]), and chemokines (eg CX3CL1, also known as fractalkine) (Fig. 2).^34–36

Figure 2.

(a) Efferocytosis is a multistep process involving the recognition, binding, internalization, and degradation of apoptotic cells (ACs) to maintain tissue homeostasis. (b) When impaired, ACs accumulate, driving inflammation, necrotic core formation (atherosclerosis), defective cardiac repair, and fibrotic remodeling that exacerbate cardiovascular disease progression (myocardial infarction and heart failure). Image generated by BioRender.

1. Nucleotides, such as ATP, are released in a caspase-dependent manner via activation of Pannexin-1 (Panx-1) channels, which are detected by purinergic receptor P2Y, G-protein coupled, 2 (P2Y2) receptors on phagocytes.³⁴ ATP is one of the most well-characterized “find-me” signals. P2Y2 disruption leads to the accumulation of dying cells in vivo.^33,37

2. Fractalkine/CX3CL1 was first identified as a “find-me” signal by Truman et al., and it recruits macrophages.³⁶ CX3CL1 is cleaved by caspase-3 and released as a recruitment factor for phagocyte chemotaxis, interacting via CX3CR1.^36,38 Here, it is essential to highlight that Fas/CD95-induced chemokines and cytokines, including IL-8 and MCP1/CCL2, promote chemotaxis and can also serve as “find-me” signals.³⁹

3. Lipids such as LPC and S1P (sphingosine-1-phosphate) act as apoptosis-specific “find-me” signals that attract phagocytes to ACs. During apoptosis, LPC is generated by caspase-3, which activates the calcium-independent phospholipase A2 (iPLA2/PLA2G6), which converts phosphatidylcholine to LPC. LPC is then secreted via the ATP-binding cassette subfamily A member 1 (ABCA1)–mediated transporter, which, along with ATP-binding cassette subfamily G member 1 (ABCG1) and High-density lipoprotein, can ameliorate oxidative stress and protect macrophages against apoptosis during efferocytosis.^35,40,41 Recent findings suggest that LPC exerts anti-inflammatory effects, as G2A (LPC receptor) deficiency enhanced tissue inflammation and autoimmunity.⁴¹ Similarly, S1P is produced through caspase-dependent activation of sphingosine kinases 1 and 2, serving as a potent chemoattractant.^42,43 S1P elevates macrophage recruitment through binding to S1PR1-5 (S1P family of G protein–coupled receptors).⁴² Beyond chemotaxis, S1P promotes both anti-inflammatory and anti-apoptotic responses in macrophages by suppressing IL-12 and TNF-α, while enhancing VEGF, IL-8, and IL-1 via PPARγ activation and NF-κB inhibition.^42,44,45

“Eat-me signal”

After migration to ACs, phagocytes identify them by recognizing specific surface receptors that directly or indirectly bind to the “eat-me” signals displayed on the AC surface, thereby distinguishing them from surrounding healthy cells. Phosphatidylserine (PS) serves as a key ligand (eat-me signal) recognized by macrophage receptors, either directly or through intermediary bridging molecules.^46,47 Brain angiogenesis inhibitor 1 (BAI1),⁴⁸ stabilin receptors 1 and 2,⁴⁹ members of the Tyro3, Axl, and MERTK (TAM) family, integrins such as αVβ3 and αVβ5, and CD36 are engulfment receptors that indirectly recognize PS on ACs by bridging molecules.^50–53 The intermediary bridging molecules include thrombospondin-1 (TSP-1), MFG-E8, and Gas6/protein S, which act as linkers connecting PS to CD36, integrins, and TAM members, respectively^53–55 (Fig. 2). Among these, Gas6 and protein S are well studied. Gas6 binds to TAM family members such as MerTK and Axl, while protein S binds to MerTK and Tyro3.⁵⁶ Other “eat-me” signals identified so far include intercellular adhesion molecule-3 (ICAM-3), calreticulin, oxidized low-density lipoprotein (LDL)–like moieties, and glycosylated surface proteins.^47,57,58 In contrast, SIRPα and Siglec-10 belong to the “don’t-eat-me” signal category, and these ligands engage anti-phagocytic receptors that prevent the engulfment of ACs.^59,60

Engulfment of the dying cells

The process of ACs recognition and uptake begins with ligand-receptor interaction, which activates multiple signaling pathways that primarily induce cytoskeletal rearrangements to enable the engulfment of apoptotic targets. This process is tightly regulated by small GTPases (Rho family)—RhoA, Rac1, and the cell division control protein 42 homolog (CDC42)—whose functions are controlled by guanine nucleotide exchange factors (GEFs).⁶¹ Activation of Rac1 is essential for inducing cytoskeletal rearrangements that form the phagocytic cup, a crucial structure for engulfment. Downstream effectors, such as ELMO1-Dock180 and GULP, further facilitate actin-based polymerization around ACs,^61,62 thereby promoting phagosome formation and internalization. On the contrary, RhoA negatively regulates this process, whereas CDC42 intensifies actin reorganization and aids phagocytosis.^61,63 The engulfed cargo is subsequently internalized into a membrane-bound phagosome, which matures by fusing with endosomes and lysosomes to form a phagolysosome, where enzymatic degradation occurs in the acidified environment. Beyond cell clearance, efferocytosis also reprograms macrophages from a proinflammatory state to a proresolving phenotype by activating signaling cascades such as PI3K/AKT, PPARγ, and ERK1/2, thereby enhancing the anti-inflammatory response.^64,65 The PI3K/AKT signaling pathway is a key regulator of efferocytosis, facilitating cell survival, phagosome formation, and cytoskeletal remodeling and membrane trafficking. Upon activation by receptors such as MerTK, this pathway initiates downstream signals, including the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and the phosphorylation of AKT, which are essential for adequate clearance and the suppression of inflammation.⁶⁶ When MerTK function is impaired, ACs accumulate, promoting inflammation and tissue damage, increasing the risk of cardiovascular events.⁶⁷ Therefore, understanding and potentially restoring MerTK function holds promise as a therapeutic strategy for CVDs.

Degradation of ACs

Although much is known about the recognition and engulfment of ACs, the available literature remains insufficient to understand the mechanism by which phagocytes handle the burden of processing an engulfed dead cell, an area drawing great scientific attention. The process of dead cell clearance must occur in a quiescent manner to avoid unnecessarily alerting the immune system.⁶⁸

After recognition and engulfment of the dying cell, the resulting phagosome and its contents undergo a tightly controlled degradation process. The phagosome fuses with lysosomes, which are rich in acid proteases, nucleases, and lipases that break down the engulfed cargo (Fig. 2). This phagolysosomal fusion depends on specific modifications of the phagosome, which can either facilitate or halt the process. The Rab GTPase family of proteins regulates these processes. The early phagosome is marked by the presence of Rab5-GTPase, which organizes endocytic trafficking and biogenesis of the phagosome during maturation.⁶⁹ The early phagosome undergoes maturation, characterized by the gradual loss of Rab5. Upon Rab5 inactivation, Rab7-GTPase is recruited for late-stage maturation and promotes endosome fusion with the lysosomal membrane proteins LAMP1 and LAMP2.^58,70 The early endosome is less acidic than the late endosome due to enhanced proton translocation into the phagosome lumen, driven by the vacuolar ATPase (V-ATPase) complex.^71,72 In addition, such direct fusion requires intact microtubules and is coordinated by a Ca2+-dependent SNARE complex, composed explicitly of syntaxin 7 and VAMP7. Ultimately, this leads to the fusion and formation of a phagolysosome where engulfed cargoes are hydrolyzed and degraded in an acidic milieu. Still, it is under investigation how Rab5 is initially recruited to the early endosome.⁵⁸

On the other hand, phagosomes can undergo modifications that regulate their maturation and degradation capacity via LC3-associated phagocytosis (LAP) and other pathways. LAP is a process distinct from canonical autophagy. This process is initiated by the recruitment of the PI3KC3 complex, which contains Rubicon, UV radiation resistance-associated gene (UVRAG), VPS34, Beclin-1, and VPS15,⁷³ enabling the stabilization of lipid phosphatidylinositol 3-phosphate (PI3P) on the phagosome membrane to produce reactive oxygen species (ROS), leading to the recruitment of LC3 to AC-containing phagosomes.⁷⁴ These phagosomes are known as laposomes; eventually, these laposomes fuse with lysosomes, leading to the rapid degradation of the engulfed material.

Furthermore, after the postdegradation of engulfed ACs, the metabolites released from it reprogram macrophages and promote the secretion of proresolving factors.⁷⁴ The activation of signaling pathways by these metabolites supports macrophage proliferation, epigenetic remodeling, sustained efferocytosis, cholesterol efflux, and the production of specialized proresolving mediators (SPMs), collectively driving macrophage reprogramming.^75,76 This involves a shift from the synthesis of proinflammatory factors (eg IL-1β, IL-12, TNF) to increased production of anti-inflammatory mediators (eg TGF-β, PGE₂).^77,78

In addition, efferocytosis is generally considered a host-‐protective mechanism that eliminates dying cells and promotes the resolution of inflammation. However, much evidence indicates that certain pathogens can hijack this pathway by infecting ACs and exploiting their immunologically silent clearance as a “Trojan horse” to gain entry into phagocytes. In this setting, engulfment of pathogen-‐infected corpses can disseminate microbes to previously uninfected macrophages, extend their intracellular niche, and attenuate antimicrobial immune responses.⁷⁹ Thus, efferocytosis represents a double-‑edged sword—essential for tissue homeostasis, yet potentially exploitable by microbes to facilitate persistence and spread. In contrast, CVDs are sterile inflammatory conditions in which efficient efferocytosis is crucial for resolving inflammation and maintaining tissue integrity. Any impairment in this process constitutes the dominant pathological consequence, linking defective AC clearance to chronic inflammation and adverse tissue remodeling. In this review, we elaborate further on the role of efferocytosis in CVDs.

Macrophage efferocytosis in CVD

Macrophage efferocytosis is crucial for maintaining tissue homeostasis and resolving inflammation in the cardiovascular system. In CVDs, the balance between cell death and clearance determines whether injury resolves or progresses to chronic inflammation.² Impaired efferocytosis has been reported across primary CVD settings. In atherosclerosis, the defective removal of apoptotic foam cells promotes the formation of a necrotic core and plaque instability. During MI, timely clearance of dying cardiomyocytes limits postischemic inflammation. It supports repair, whereas persistent efferocytosis sustains inflammation in the case of heart failure (Fig. 2).⁸⁰

Macrophage efferocytosis in atherosclerosis

Atherosclerosis is a lipid-driven chronic inflammatory condition characterized by the buildup of lipid-rich plaques within the arterial walls.⁸¹ Retained lipoproteins trigger macrophage foam-cell formation and repeated cycles of cell death. When efferocytosis fails, apoptotic debris accumulates, releasing inflammatory mediators that expand the necrotic core. Multiple mechanisms converge to suppress efferocytosis, including MerTK cleavage, CD47 upregulation, metabolic exhaustion, and cytokine-driven macrophage polarization.^67,82,83 Together, these result in defective resolution signaling, reduced production of SPMs, and progressive plaque instability.

The receptor tyrosine kinase MerTK is a key AC recognition surface receptor expressed on macrophages.⁸⁴ Under inflammatory stress, the metalloprotease ADAM metallopeptidase domain 17 (ADAM17) cleaves the ectodomain of MerTK, generating soluble Mer (sMer), which acts as a decoy and depletes functional receptors from the cell surface.⁸⁵ Human carotid endarterectomy specimens demonstrate that MerTK cleavage correlates with enlarged necrotic cores and ischemic symptoms, while mouse lesions with enhanced MerTK shedding display defective efferocytosis and impaired resolution signaling.⁶⁷ Functionally restoring MerTK can rescue this defect. For instance, in diabetic Apoe^-/- mice, membrane-engineered nanoparticles that deliver MerTK significantly enhance efferocytosis and reduce plaque burden, validating receptor replacement as a therapeutic concept.⁸⁶

The immune checkpoint protein CD47 functions as a canonical “don’t-eat-me” signal that binds SIRPα on macrophages, activating inhibitory phosphatases and blocking engulfment. Elevated CD47 expression is observed in both human and murine plaques, and its inhibition enhances efferocytosis and reduces necrosis in experimental models. However, systemic blockade carries a risk of anemia and other immune effects.⁸³ Macrophage LDL receptor–related protein-1 (LRP1) limits lesion cellularity and necrosis and is required for the full proefferocytic effect of anti-CD47 therapy.^87,88 These findings position CD47–SIRPα signaling as a key suppressor of efferocytosis and a promising but challenging therapeutic target in advanced atherosclerosis.

Macrophage metabolic stress further restricts efferocytic capacity. Continuous engulfment, digestion, and recycling of ACs demand high ATP levels, intact cytoskeletal dynamics, and efficient lipid metabolism. In advanced plaques, oxidative, endoplasmic reticulum, and mitochondrial stress compromise macrophage bioenergetics, negatively impacting cytoskeletal remodeling and lysosomal processing.⁸⁹ Recent studies have highlighted mitochondrial dysfunction and altered substrate utilization as significant causes of efferocytosis failure in advanced lesions, identifying metabolic reprogramming as a potential strategy to restore clearance and resolution signaling.⁹⁰

The inflammatory microenvironment of late-stage plaques imposes additional barriers to efficient clearance. Accumulation of apoptotic and necrotic foam cells saturates local efferocytic capacity. At the same time, oxidized LDL, cholesterol crystals, and proinflammatory cytokines disrupt bridging molecules such as Gas6 and MFG-E8, thereby impairing TAM-receptor signaling. This milieu skews macrophages toward an IRF5-high, proinflammatory M1 state. A recent study identified CD147 as a myeloid driver of IRF5-mediated polarization that aggravates atherosclerosis and suppresses efferocytic competence. In contrast, the deletion of myeloid CD147 reduces inflammation and necrosis, while improving macrophage clearance.⁹¹ In advanced human plaques, the ratio of the proresolving mediator resolvin D1 (RvD1) to the proinflammatory leukotriene B4 (LTB4) decreases as efferocytosis is impaired and necrosis extends. Supplementation with RvD1 restored the ratio, improved efferocytosis, and stabilized plaques.⁹² This loss of resolution signaling also suppresses macrophage production of anti-inflammatory cytokines, such as IL-10 and TGF-β, locking plaques into a nonresolving inflammatory state.⁹³

Finally, aging further reduces macrophage efferocytosis through several interrelated pathways. Increased oxidative stress, heightened ADAM17 activity leading to MerTK cleavage, defective autophagy, and altered lipid metabolism collectively impair clearance efficiency.⁹⁴ Together, these findings highlight that impaired efferocytosis in atherosclerosis arises from an intricate interplay of receptor cleavage, inhibitory checkpoint signaling, metabolic dysfunction, inflammatory overload, and age-related decline.

In addition to macrophages, smooth muscle cells (SMCs) and SMC-derived cells constitute a major cellular component of advanced atherosclerotic plaques, as demonstrated by genetic lineage-tracing studies showing that SMC-lineage cells represent a substantial proportion of lesion cellularity.^95,96 Although SMCs are not professional phagocytes, experimental studies indicate that vascular cells, including SMCs, can mediate limited apoptotic cell uptake, particularly under early or homeostatic conditions.^31,97 However, compared with macrophages, SMC-mediated efferocytosis is markedly less efficient and lacks the robust coupling to anti-inflammatory and proresolving signaling pathways that characterize professional efferocytes.^95,98 Phenotypic modulation of SMCs into macrophage-like states is further associated with altered transcriptional programs and impaired clearance capacity.^95,99 As atherosclerosis progresses, defective efferocytosis by both macrophages and SMC-derived cells synergistically contributes to apoptotic cell accumulation, necrotic core expansion, and plaque instability, reinforcing the dominant role of professional phagocytes in advanced disease. The convergence of these processes drives necrotic-core expansion and plaque instability, making restoration of macrophage efferocytosis a key therapeutic goal for stabilizing vulnerable lesions and promoting vascular healing.

Efferocytosis in myocardial infarction and heart failure

Efferocytosis is indispensable for resolving postischemic inflammation and orchestrating the reparative remodeling that follows MI. During acute MI, ischemic cardiomyocytes, endothelial cells, and infiltrating neutrophils undergo programmed cell death, releasing damage-associated molecular patterns (DAMPs) that amplify local inflammation. The rapid removal of this cellular debris by cardiac macrophages is therefore crucial in limiting secondary injury and preventing scar maturation. Recent studies have identified macrophage subsets and signaling pathways that couple efferocytosis to metabolic competence and regenerative outcomes. Macrophages enriched for TREM2 exhibit superior efferocytic capacity, enhanced mitochondrial metabolism, and improved post-MI recovery. In contrast, Trem2 deficiency leads to defective clearance of ACs, heightened inflammation, and worsened ventricular remodeling.¹⁰⁰

Furthermore, the macrophage-enriched transmembrane protein Sectm1a has been shown to activate a signaling pathway involving GITR and LXRα, leading to increased expression of genes related to efferocytosis and lysosomal function. Deletion of Sectm1a reduces the clearance of apoptotic cardiomyocytes after ischemia–reperfusion (I/R) injury, leading to greater inflammation and fibrosis. In contrast, treatment with recombinant Sectm1a restores efferocytosis and improves cardiac function.¹⁰¹

Importantly, efferocytosis in the heart is not simply a debris-removal mechanism but also a regenerative signal. The uptake of ACs by macrophages induces the production of vascular endothelial growth factor C (VEGFC), which stimulates lymphangiogenesis, facilitates edema resolution, and supports myocardial healing. Loss of myeloid-derived VEGFC blunts these reparative processes, leading to worsened ventricular function, whereas restoring VEGFC improves cardiac repair and reduces inflammation.¹⁰² When clearance mechanisms fail or become dysregulated, ACs undergo secondary necrosis, releasing inflammatory mediators that perpetuate neutrophil infiltration and sustain fibro-inflammatory activation. This maladaptive cascade promotes adverse ventricular remodeling and lays the foundation for progression to heart failure. In chronic heart failure, persistent oxidative stress, aging, and metabolic dysfunction further compromise efferocytic capacity, partly due to proteolytic MerTK shedding, which results in accumulation of apoptotic and mitochondrial debris, fibroblast hyperactivation, and progressive extracellular matrix deposition and capillary rarefaction.¹⁰³

Beyond cardiomyocytes, the macrophage metabolic state, phenotypic diversity, and efferocytic ability govern cardiac homeostasis and postinjury remodeling.¹⁰⁴ Mitochondrial quality control closely intersects with efferocytosis, as the engulfment and processing of apoptotic material are energy-intensive and require intact oxidative metabolism. Disruptions in mitochondrial dynamics and mitophagy have been linked to persistent inflammation and contractile dysfunction, providing another mechanistic axis by which defective efferocytosis accelerates the transition from MI to chronic heart failure.¹⁰⁵

Together, these findings establish macrophage efferocytosis as a central determinant of the inflammatory-to-reparative transition in ischemic heart disease. Preservation of efferocytic signaling through stabilization of MerTK, reinforcement of TREM2 and Sectm1a pathways, and maintenance of mitochondrial health emerges as a promising therapeutic strategy to limit post-MI injury and prevent heart failure progression.

Therapeutic strategies targeting efferocytosis in CVDs

Defective efferocytosis has been observed in atherosclerosis and MI, leading to secondary necrosis that amplifies inflammation and contributes to plaque instability and adverse cardiac remodeling. Therefore, many recent studies have employed targeted efferocytosis therapeutic strategies in models of CVDs.^16,17 Therapeutic strategies aimed at restoring efficient engulfment by augmenting MerTK signaling, enhancing bridging molecule availability, or modulating actin remodeling pathways are thus emerging as promising interventions for CVD management. Some of these therapeutic approaches are highlighted in Table 1.

Table 1.

Selected drugs targeting efferocytosis in cardiovascular diseases.

Drug	Mechanism	Animal model	Therapeutic effect	Level of validation	Limitations	References
Anti-CD47 antibodies	Block CD47–SIRPα “don’t-eat-me” signaling to release the macrophage phagocytosis brake	Multiple mouse atherosclerosis models; human plaque tissue expression analyses	↑ Efferocytosis in lesions, ↓ necrotic core, ameliorated atherosclerosis	Preclinical (mouse); early clinical (human correlative)	On-target anemia/erythrophagocytosis risk; systemic immune effects; no late-stage CVD efficacy trials	83
Resolvin D1	Proresolving GPCR activation (eg ALX/FPR2, GPR32) to enhance efferocytosis and limit inflammation	Atherosclerotic mice; mechanistic macrophage studies	Restored lesional efferocytosis and promoted plaque stability; rescued defective clearance in macrophages	Preclinical (mouse)	Short in vivo half-life; dosing and delivery optimization required; limited human data	111
LXR agonism	Activates LXR to upregulate MerTK and lipid-handling genes supporting continual efferocytosis	Macrophage mechanistic work; in vivo proof-of-concept; CAR-macrophage + LXR-NP in vascular inflammation	↑ MerTK expression and debris clearance; combined CAR-macrophage/LXR-NP reduced inflammation and enhanced efferocytosis	Preclinical (mouse)	Systemic activation causes hypertriglyceridemia and hepatic steatosis	116 ,  117
MerTK protein nanovesicles	Replaces/boosts MerTK on plaque macrophages to restore engulfment	Diabetic Apoe-/-atherosclerosis (mouse)	↑ Efferocytosis, ↓ lesion size/necrosis	Preclinical (mouse)	Delivery efficiency, targeting specificity, and long-term safety remain preclinical	86
ADAM17 inhibition	Limits MerTK ectodomain shedding to preserve efferocytic signaling	Mechanistic atherosclerosis studies; human plaque correlations	Preserved surface MerTK; mechanistically linked to ↓ necrosis	Mechanistic preclinical (mouse); human correlative	Broad substrate specificity raises off-target and safety concerns	67
Caspase 1 inhibitor VX765	Suppresses NLRP3 inflammasome activation; promotes macrophage mitophagy, efferocytosis	Apoe-/- mice (atherosclerosis model)	Reduced lesion size and inflammation; enhanced efferocytosis and plaque stability	Preclinical (mouse)	Potential effects on host defense; chronic safety window unclear	118
Annexin A1 mimetic peptide (Ac2-26)	Proresolving/anti-inflammatory signaling that supports efferocytosis and debridement	Hypercholesterolemic mice	↓ Vascular inflammation; supportive of resolution/efferocytosis	Preclinical (mouse)	Peptide Pharmacokinetics and delivery constraints; no large-animal or clinical validation	119
Legumain	Enhances macrophage efferocytosis via lysosomal activation and apoptotic cardiomyocyte degradation	Lgmn-/- and macrophage-specific knockout mice post-MI	Deficiency worsened inflammation and cardiac injury; restoration improved efferocytosis and repair	Preclinical (mouse)	Pleiotropic protease functions raise off-target safety concerns	120
SHP-1–targeting nanoparticles	Downstream CD47–SIRPα pathway modulation via SHP-1 inhibition in lesional macrophages	Atherosclerosis mice	↑ Macrophage efferocytosis; ↓ atherosclerosis	Preclinical (mouse); preclinical (large animal, porcine)	Biodistribution, scalability, and long-term nanotherapy safety need evaluation	121

Checkpoint modulation and receptor–pathway targeting

The inhibitory “don’t-eat-me” signaling through the CD47–SIRPα axis suppresses macrophage efferocytosis in advanced atherosclerotic lesions. Anti-CD47 antibodies restore AC clearance and reduce necrotic core formation in multiple mouse models of atherosclerosis, establishing this checkpoint as a viable therapeutic target. However, systemic blockade can cause anemia and immune-related side effects.⁸³ More recently, macrophage-targeted nanotherapies have achieved selective CD47–SIRPα inhibition without hematologic toxicity in a porcine model, demonstrating translational potential for checkpoint-based therapy.¹⁰⁶

The receptor tyrosine kinase MerTK is essential for AC uptake but is cleaved by ADAM17 under inflammatory conditions, producing a soluble decoy that interferes with efferocytosis. Both human and murine plaque studies demonstrate that MerTK shedding correlates with the expansion of necrotic cores, whereas preserving surface MerTK improves clearance and plaque stability.⁶⁷ Nanoparticle or mRNA-based delivery of MerTK restores efferocytosis and reduces lesion burden in diabetic Apoe^-/- mice, validating receptor-replacement therapy as a promising approach.⁸⁶

SPMs such as RvD1 signal through G protein–coupled receptors (ALX/FPR2, GPR32) to promote macrophage efferocytosis, limit inflammation, and shorten the resolution interval. Synthetic analogues and nanocarrier-based formulations that stabilize SPMs are now in development for the treatment of vascular inflammation and atherosclerosis.¹⁰⁷

Activation of the liver X receptor (LXR) upregulates efferocytosis-related programs, including MerTK, lysosomal enzymes, and genes involved in lipid handling. Recent work in MI–reperfusion injury models has revealed that SECTM1A–GITR–LXRα signaling enhances macrophage efferocytosis and accelerates cardiac recovery, suggesting an immunometabolic avenue for therapeutic targeting.¹⁰¹

Proresolving reprogramming

Efferocytosis not only clears apoptotic debris but also reprograms macrophages toward a proresolving, tissue-reparative phenotype. Therapies that bias macrophage polarization toward M2-like states can indirectly enhance clearance and improve healing. In MI, administration of IL-4 promotes M2 macrophage differentiation, improves cardiac repair, and supports efferocytosis-coupled resolution.¹⁰⁸ Similarly, the bridging molecule MFG-E8, which mediates AC recognition, has shown beneficial effects in post-MI remodeling. Moreover, MFG-E8 supplementation has improved cardiac function and enhanced clearance of dying cells.¹⁰⁹ Across CVD contexts, macrophage metabolism, polarization, and efferocytosis are closely interlinked. Proresolving programs reinforce engulfment and help limit chronic inflammation, highlighting efferocytosis as both an effector and regulator of immune resolution.¹¹⁰

Resolution and metabolic support

Enhancing endogenous resolution mediators or improving macrophage metabolism can further enhance efferocytic efficiency and plaque stability. Boosting SPMs such as resolvins, protectins, and maresins, or activating their GPCRs (ALX/FPR2, GPR32), restores macrophage clearance, promotes anti-inflammatory reprogramming, and stabilizes atherosclerotic plaques.¹¹¹ Additionally, supporting mitochondrial metabolism through targeted interventions can sustain the energy demands of continuous efferocytosis and limit lesion necrosis.

Novel drug-delivery systems

Effective restoration of efferocytosis in lipid-rich plaques or ischemic myocardium requires delivery systems that target lesional macrophages while minimizing systemic toxicity. Membrane-engineered nanovesicles delivering MerTK protein directly to plaque macrophages in diabetic Apoe^-/- mice successfully restored efferocytosis and reduced atherosclerosis, confirming receptor replacement as a viable in vivo strategy.⁸⁶ Proefferocytic nanoparticles carrying checkpoint-modulating agents have now advanced from murine studies to porcine models of atherosclerosis. Nanoparticles have effectively reduced apoptotic debris and vascular inflammation without inducing anemia, marking a significant step toward clinical translation for CD47-targeted approaches.¹⁰⁶ Drug-delivery platforms have also been used to stabilize labile SPMs, extending their half-life and enhancing local concentration in inflamed tissues. Recent reviews summarize SPM-based nanotherapies for atherosclerosis and post-MI repair.^107,112 In cardiac repair, apoptotic body–mimicking nanoparticles and other biomimetic carriers have been demonstrated to enhance macrophage efferocytosis and accelerate the resolution of inflammation following myocardial injury.¹¹³

Other treatment strategies

Inhibition of miR-155 promotes macrophage efferocytosis, reduces the expansion of necrotic cores, and attenuates atherosclerotic progression, supporting microRNA-targeted approaches to restore resolution capacity.¹¹⁴ Unexpectedly, the antipsychotic thiothixene has been identified as an enhancer of macrophage efferocytosis, suggesting opportunities for drug repurposing in CVD.¹¹⁵ Next-generation chimeric antigen receptor (CAR) macrophages are designed to overcome inhibitory cues such as CD47 upregulation. When combined with ROS-responsive, LXR-activating nanoparticles, these cells exhibit superior AC clearance, enhanced lipid efflux, and anti-inflammatory activity, representing a modular platform for boosting efferocytosis.¹¹⁶ Given that efferocytosis failure in advanced plaques results from multiple convergent barriers, synergistic strategies such as checkpoint inhibition combined with MerTK preservation or LXR priming are particularly promising. Early large-animal studies using macrophage-targeted, proefferocytic nanoparticles demonstrated significant plaque regression without hematologic toxicity, addressing a key limitation of systemic checkpoint blockade.¹⁰⁶ Emerging bioengineered systems, including surface-modified macrophages and lesion-directed nanocarriers, also offer the potential to bypass the inhibitory microenvironment and restore AC clearance in complex plaques.

Conclusion and future perspectives

In this review, we have highlighted the importance of macrophage efferocytosis in CVDs. Inflammation plays a critical role in CVDs, and efferocytosis serves as a potent mechanism to resolve inflammation and maintain homeostasis. Since dysregulated efferocytosis is directly linked to CVDs, contributing to necrotic core formation, persistent inflammation, and plaque instability, further in-depth research is required to understand the underlying mechanisms and identify novel therapeutic targets. Though our understanding of macrophage efferocytosis has advanced considerably over the past few decades, it remains an emerging field with unique challenges. First, in vitro models of macrophage efferocytosis may include only a few cell types, whereas the heart contains a diverse array of cells that interact dynamically and could influence macrophage behavior and efferocytosis. Second, studying the entire process of efferocytosis, from the initial recognition of ACs to their clearance in vivo, remains challenging.

Beyond the challenges, recent technological advances have been significantly applied to therapeutics. Prominent examples include the development of CD47-SIRPα as a crucial checkpoint inhibitor, the use of proresolving mediators, and the engineering of macrophages. These approaches collectively show promising restoration of efferocytic capacity and improvements in both cardiac and vascular outcomes. As single-cell technologies and other techniques evolve, the goal of macrophage reprogramming for therapeutic purposes, including sustaining resolution and cardiovascular protection, is not far off. Moreover, efferocytosis shares similar cellular steps with receptor-mediated endocytosis, both of which involve cargo internalization and degradation. Therefore, attention is required for exploring pathways linking endocytosis to efferocytosis. Future research integrating genomics and CRISPR approaches will elucidate how retromer and other vital endocytic proteins coordinate LAP-specific proteins to enhance efferocytic capacity, advancing therapeutic insights into inflammatory diseases such as atherosclerosis. Additionally, there remains an unmet need to identify more precise macrophage-targeted therapies and reliable biomarkers of efferocytosis in patients that can predict disease progression or treatment response. Nevertheless, efferocytosis and its mechanisms remain a critical focus for future research, with the potential for innovative therapeutics to significantly improve outcomes for patients with CVDs.

Glossary

Abbreviations

AC

apoptotic cell

ADAM17

ADAM metallopeptidase domain 17

ApoE

apolipoprotein E

CDC42

cell division control protein 42 homolog

CRMs

cardiac resident macrophages

CX3CL1

C-X3-C motif chemokine ligand 1

CVD

cardiovascular disease

Gas6

growth arrest–specific protein 6

GPR32

G protein–coupled receptor 32

IRF5

interferon regulatory factor 5

LAP

LC3-associated phagocytosis

LPC

lysophosphatidylcholine

LXR

liver X receptor

MCP1

monocyte chemoattractant protein-1

MerTK

MER proto-oncogene, tyrosine kinase

MFG-E8

milk fat globule–epidermal growth factor 8

MoMs

macrophages originate from circulating monocytes

MI

myocardial infarction

P2Y2

purinergic receptor P2Y, G protein coupled, 2

PGE₂

prostaglandin E₂

; PI3K

phosphatidylinositol 3-kinase

PPARγ

peroxisome proliferator–activated receptor gamma

PS/PtdSer

phosphatidylserine

Rab5

Ras-related protein Rab-5

Rac1

Ras-related C3 botulinum toxin substrate 1

ROS

reactive oxygen species

RvD1

resolvin D1

S1P

sphingosine-1-phosphate

Sectm1a

secreted and transmembrane 1A

Siglec-10

sialic acid-binding Ig-like lectin 10

SIRPα

signal regulatory protein α

; SPM

specialized proresolving mediator

TAM

Tyro3, Axl, and MerTK

TGF-β

transforming growth factor beta

TNF-α

tumor necrosis factor alpha

TREM2

triggering receptor expressed on myeloid cells 2

VEGFC

vascular endothelial growth factor C

Author contributions

Neha Gupta (Conceptualization [Equal], Investigation [Equal], Writing—original draft [Equal], Writing—review & editing [Equal]), Yu Liu (Conceptualization [Equal], Investigation [Equal], Writing—original draft [Equal], Writing—review & editing [Equal]), and Bishuang Cai (Conceptualization [Lead], Investigation [Lead], Supervision [Lead], Writing—review & editing [Lead])

Funding

This work was in part supported by National Institutes of Health grants R35GM147269, R01DK134610, and R01HL167107.

Conflicts of interest

None declared.

Data availability

Data sharing is not applicable to this review article, as no datasets were generated or analyzed.