In typical physiological settings, the stable preservation of mitochondrial morphology in cardiomyocytes relies on a precise equilibrium between fusion and fission processes, which is collaboratively controlled by fusion proteins [mitofusin (Mfn)1/2 and OPA1 mitochondrial dynamin like GTPase (OPA1)] and fission proteins [Drp1 and fission, mitochondrial 1 (Fis1)]. Mfn1 and Mfn2, dynamin-associated GTPases situated on the outer mitochondrial membrane, facilitate the fusing of this membrane, and when they form a trans-complex, they may approximate adjacent mitochondria. OPA1 primarily facilitates mitochondrial inner membrane fusion and cristae restructuring, with its long and short isoforms working in concert to promote efficient inner membrane fusion (16,17). Drp1 plays a central role in mitochondrial division. Typically, Drp1 resides in the cytoplasm, and several post-translational modifications are initiated upon receipt of mitochondrial division signals (18). During mitosis, the B1/cyclin-dependent kinase (Cdk)1 complex of the cell cycle phosphorylates the Ser-585 site of Drp1, inducing its aggregation in the outer mitochondrial membrane. Conversely, under healthy conditions, CDK19/Cdk8 phosphorylates Drp1 at Ser616, facilitating proper mitochondrial division (19). Furthermore, Rho-associated coiled-coil protein kinase 1 can dephosphorylate the Ser637 site of Drp1 by enhancing the activities of protein phosphatase 1 (PP1) and protein phosphatase 2A(PP2A), therefore activating Drp1 and facilitating its translocation to the mitochondria, where it assembles into a helical shape (20). Fis1, an auxiliary protein involved in mitochondrial division, interacts with Drp1 to recruit it to the site of division. Subsequently, GTP hydrolysis by GTP-bound Drp1 induces a conformational change, generating a mechanical force that facilitates mitochondrial membrane constriction and rupture, thereby completing the division process (21).

However, in pathological situations like ischemia and hypoxia, the balance of mitochondrial dynamics is disturbed in the case of Drp1, ischemia and hypoxia can augment the activity of calcium-modulated phosphatase (Calcineurin), which dephosphorylates the Ser637 site of Drp1, thereby increasing its affinity for the mitochondrial membrane and expediting its translocation to the mitochondria (22). Du et al (23) found that in the cardiac ischemia-reperfusion model, Drp1-Ser616 phosphorylation was markedly increased, accompanied by extensive Drp1 translocation to the mitochondrial surface, resulting in excessive mitochondrial division and fragmentation. In Sirt3-knockout mice, Sirt3 deficiency impaired deacetylation, thereby reducing activation of downstream proteins, including kinases that regulate Drp1 phosphorylation. This resulted in reduced Drp1 phosphorylation levels and heightened mitochondrial hypersegmentation, ultimately causing a marked deterioration in cardiac function. The absence of Mfn2 directly impaired mitochondrial fusion and disrupted calcium signaling coupling between mitochondria and the endoplasmic reticulum, owing to the role of Mfn2 in their linkage. Under physiological conditions, calcium ions released from the endoplasmic reticulum can be transported to mitochondria via Mfn2-mediated channels, and moderate calcium signaling can activate dehydrogenases and ATP synthase in the TCA cycle, thereby enhancing ATP production (24) (Fig. 1).

Following Mfn2 loss, mitochondrial calcium uptake becomes disordered and susceptible to calcium excess. Excessive calcium ions can activate calcium-dependent proteases and phospholipases within the mitochondria, compromising mitochondrial membrane integrity and inducing substantial ROS production, which further impairs mitochondrial function. Mitochondrial morphological impairment is closely associated with aberrant mPTP opening (25). In compromised cardiomyocytes, disrupted energy metabolism and diminished ATP synthesis lead to impaired ion pump activity, which is essential for maintaining intracellular ionic homeostasis. This leads to excessive Ca²⁺ influx and intracellular accumulation, while the mitochondrial respiratory chain is concurrently dysregulated, hindering electron transfer and causing a significant rise in ROS production (26). Elevated Ca²⁺ and ROS levels can serve as cues to initiate mPTP opening. mPTP is a protein complex situated between the inner and outer mitochondrial membranes, which is typically in a closed state. Upon opening of the mPTP, the mitochondrial membrane potential rapidly dissipates; the proton electrochemical gradient across the inner membrane is reduced; OXPHOS coupling is disrupted; and ATP production decreases significantly. Concurrently, mPTP opening facilitates the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, where it associates with apoptotic protease-activating factor 1, thereby recruiting and activating caspase-9, which subsequently initiates the downstream caspase cascade and induces apoptosis (27). Drp1 activation has been shown to promote excessive mitochondrial fission and to enhance mPTP opening via interactions with mPTP-associated proteins, thereby exacerbating mitochondrial injury. Conversely, the small molecule mitochondrial division inhibitor 1 (Mdivi-1), functioning as a Drp1 inhibitor, selectively binds to Drp1, impedes its GTPase activity and obstructs Drp1 from forming a helical shape with fission activity on the mitochondrial membrane, hence postponing mPTP opening (28). In the MI-reperfusion injury model, Mdivi-1 treatment reduced mitochondrial fragmentation, delayed mPTP opening and markedly decreased the myocardial infarct area, suggesting that modulating mitochondrial dynamics-related proteins may be an effective intervention for myocardial ischemic injury (29).

The onset of MI involves the disruption of essential mitochondrial energy metabolism pathways, significantly impairing cardiomyocyte function, with the dysregulation of the SIRT3-AMPK-PGC-1α axis being pivotal (30). SIRT3, a mitochondrial deacetylase, is primarily localized in the mitochondrial matrix and modulates the acetylation status of several mitochondrial proteins. Under physiological conditions, SIRT3 preserves the proper function of mitochondrial proteins through deacetylating action (31). Superoxide dismutase 2 (SOD2) is a crucial mitochondrial antioxidant enzyme and its activity is modulated by acetylation. Physiological expression of SIRT3 deacetylates Lys-68 and other residues of SOD2, thereby activating SOD2, augmenting mitochondrial ROS scavenging capacity and preserving mitochondrial redox homeostasis (32). Additionally, SIRT3 deacetylates α-ketoglutarate dehydrogenase (OGDH), a pivotal enzyme in the TCA cycle that catalyzes the conversion of α-ketoglutarate to succinyl coenzyme A. Following deacetylation by SIRT3, OGDH activity is increased to facilitate the uninterrupted progression of the TCA cycle, allowing for the continuous supply of reducing equivalents (NADH, FADH₂) for OXPHOS (33). In MI, SIRT3 expression is markedly downregulated by stressors such as ischemia and hypoxia. Research indicates that in a mouse model of myocardial ischemia-reperfusion, SIRT3 protein levels in cardiac tissues decreased by ~50% following 20 min of ischemia and 24 h of reperfusion. The absence of SIRT3 reduced mitochondrial protein deacetylation, resulting in hyperacetylation (34). Excessive acetylation of SOD2 markedly diminished its activity and impaired its ability to scavenge ROS, leading to substantial ROS accumulation within the cell. Excessive ROS not only directly impaired the structural integrity of the mitochondrial membrane but also altered critical enzymes in the TCA cycle, thereby inhibiting their function (35). Simultaneously, the catalytic activity of OGDH was significantly diminished following hyperacetylation, thereby disrupting the TCA cycle. Obstruction of the TCA cycle reduced NADH and FADH₂ generation, thereby impairing OXPHOS and significantly reducing ATP synthesis efficiency, and resulting in a failure to meet the energy requirements of cardiomyocytes (36).

Under typical circumstances, cardiomyocytes primarily obtain energy by FAO, with ~70% of ATP generated by fatty acid β-oxidation, whereas glucose metabolism contributes considerably less to energy production. The pivotal rate-limiting step in the ingress of fatty acids into mitochondria for β-oxidation is facilitated by carnitine palmitoyltransferase 1 (CPT-1), which is located in the outer mitochondrial membrane, and catalyzes the conversion of lipoacyl-coenzyme A of long-chain fatty acids to lipoacylcarnitine, thereby permitting their entry into the mitochondrial matrix to ensure oxidation (37). At the onset of MI, the intracellular environment undergoes considerable alterations, resulting in inhibition of FAO and a gradual metabolic shift toward glycolysis. During ischemia and hypoxia, intracellular ATP concentrations decrease rapidly, whereas ADP and AMP levels rise, thereby activating AMPK. Activated AMPK phosphorylates and inhibits acetyl coenzyme A carboxylase, a crucial enzyme in fatty acid synthesis, leading to decreased generation of malonyl coenzyme A (38). Malonyl coenzyme A serves as an endogenous inhibitor of CPT-1; thus, reduced malonyl coenzyme A levels increase CPT-1 activity, presumably facilitating FAO. Of note, poor mitochondrial function resulting from ischemia, diminished activity of FAO-related enzymes and malfunction of fatty acid transporters collectively limit FAO, despite elevated CPT-1 activity (39). Concurrently, the cell redirects its metabolic flux toward glycolysis to meet its fundamental energy requirements. On the one hand, HIF-1α expression is upregulated and stabilized under ischemic hypoxic conditions. HIF-1α binds to the promoter regions of key glycolytic genes, such as glucose transporter 1 and hexokinase 2, thereby promoting their transcription and enhancing glucose uptake and glycolytic initiation. On the other hand, the activity of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis, was also increased (40,41). Elevated intracellular AMP concentrations can allosterically activate PFK-1 while concurrently increasing fructose-2,6-bisphosphate levels, the most effective allosteric activator of PFK-1. This interaction further enhances PFK-1 activity and accelerates glycolysis (42). The energy supply efficiency of glycolysis is significantly lower than that of FAO in conjunction with OXPHOS. One molecule of glucose can yield 30–32 molecules of ATP via complete decomposition through aerobic oxidation, while glycolysis results in the production of only 2 molecules of ATP. This substrate utilization conversion serves as an emergency strategy; however, prolonged dependence on glycolysis for energy does not meet the substantial energy requirements of cardiomyocytes. Additionally, the excessive lactate produced by glycolysis further impairs cardiomyocyte function. This results in a reduction of intracellular pH, subsequently compromising cardiomyocyte function (43,44) (Fig. 2).

Impaired mitochondrial energy metabolism affects energy supply and leads to the abnormal release of various metabolites. Notably, overproduction of ROS and mtDNA spillover are significant factors that trigger aseptic inflammation (45). In the standard mitochondrial respiratory chain, electrons are sent to oxygen through complexes I, II, III and IV, while ADP is phosphorylated to generate ATP. In MI, mitochondrial structural damage and respiratory chain dysfunction impede electron transfer, leading to significant electron leakage that reacts with oxygen to generate the superoxide anion (O₂·⁻). This ROS can subsequently generate hydrogen peroxide (H₂O₂), hydroxyl radicals (·OH) and other more reactive ROS (46). Excess ROS are potent oxidants that can directly damage lipids, proteins and mtDNA within the mitochondrial membrane. ROS in the mitochondrial membrane can induce lipid peroxidation, thereby diminishing membrane fluidity, increasing permeability and compromising the structural integrity of the mitochondrial membrane. For example, ROS can oxidize cardiolipin, a phospholipid unique to the inner mitochondrial membrane, crucial for the stability and functionality of the respiratory chain complex. The oxidation of cardiolipin impairs the function of respiratory chain complexes, thereby exacerbating ROS generation (47). Conversely, ROS can affect mitochondrial proteins, hence changing their structure and function. For example, ROS can induce oxidative alterations of Drp1, thereby facilitating excessive mitochondrial division and fragmentation (48). Concurrently, ROS can also cause mtDNA damage, encompassing base mutations, deletions and double-strand breaks (49).

In conclusion, impaired mitochondrial energy metabolism in cardiomyocytes following MI leads to an injury network characterized by kinetic imbalances, disruption of metabolic pathways, alterations in substrate use and the release of inflammatory signals. An imbalance in mitochondrial fusion and fission disturbs energy production, dysregulation of the SIRT3 axis impedes OXPHOS, a metabolic shift to glycolysis intensifies the energy crisis and the activation of inflammation by ROS and mtDNA deteriorates the microenvironment. Therefore, targeting the mitochondrial metabolic network is a potential direction for prevention and treatment; modulation of Drp1/Mfn2, activation of the SIRT3 axis, optimization of substrate utilization and blockade of the inflammatory cascade improve energy supply and promote macrophage polarization toward the M2 phenotype by intervening in the mitochondrial-immune axis, providing a novel direction for clinical translation.

MI, resulting in mitochondrial impairment, leads to succinate accumulation and the release of ATP and ROS into the extracellular milieu, which function as DAMPs and can activate NLRP3 inflammatory vesicles. Compromised mtDNA is less stable and may be extruded from the mitochondria into the cytoplasm. mtDNA functions as a DAMP detectable by TLR9 in the cytoplasm. TLR9 is predominantly expressed on the surface of various cell types, including immune cells (for example, macrophages and dendritic cells) and cardiomyocytes. mtDNA binding to TLR9 initiates a downstream signaling cascade dependent on myeloid differentiation factor 88 (MyD88). MyD88 recruits IL-1 receptor-associated kinase (IRAK) family members, which activate tumor necrosis factor receptor-associated factor 6 (TRAF6), thereby activating nuclear factor-κB (NF-κB). Activated NF-κB translocates to the nucleus and associates with the promoter regions of pro-inflammatory cytokine genes (for example, TNF-α, IL-1β and IL-6), thereby enhancing their transcription and expression (52,53). These pro-inflammatory cytokines are secreted extracellularly to attract and activate immune cells, initiating a sterile inflammatory response. While the inflammatory response serves as a defensive mechanism, excessive inflammation can exacerbate cardiomyocyte damage and worsen MI, creating a detrimental cycle (54). The NLRP3 inflammasome is a multiprotein complex that primarily comprises NLRP3, apoptosis-associated speck-like protein (ASC) and caspase-1 (55). The construction and activation of NLRP3 inflammatory vesicles are triggered by ATP binding to the P2X7 receptor on the cell membrane or by ROS stimulating redox-sensitive signaling pathways within the cell (56). Specifically, ATP binding to the P2X7 receptor induces channel opening, resulting in intracellular potassium efflux that activates NLRP3. Conversely, ROS can activate NLRP3 by oxidizing cysteine residues, thereby inducing a conformational change. Activated NLRP3 inflammatory vesicles assemble multimeric complexes by attracting ASC, which then attracts and activates caspase-1 precursors, resulting in their cleavage into active caspase-1. Activated caspase-1 preferentially cleaves pro-IL-1β, converting it into physiologically active IL-1β, thereby facilitating the initiation and progression of inflammatory responses (57). Additionally, caspase-1 cleaves the Gasdermin D protein, releasing its N-terminal domain, which inserts into the plasma membrane to form a pore. This process induces cell death and the rapid release of inflammatory mediators, thereby intensifying the inflammatory cascade. It causes osmotic imbalance in cardiomyocytes, disrupts membrane integrity and impairs organelle function, ultimately exacerbating structural damage and functional loss in myocytes, while facilitating the pathological progression of MI toward a reversible state and eventually intensifying the structural impairment and functional decline of cardiomyocytes, hence advancing the pathological progression of MI irreversibly (58).

In the context of MI, macrophage metabolic reprogramming modulates inflammatory processes and tissue healing through bidirectional polarization patterns (59). Pro-inflammatory M1 polarization is induced by ischemia and a hypoxic milieu, in which increased HIF-1α stability promotes macrophage polarization toward the pro-inflammatory (M1) phenotype (60,61). HIF-1α can modulate the glycolytic pathway by transcriptionally activating pyruvate kinase M2 (PKM2), thereby steering glucose metabolism toward the lactic acid and pentose phosphate pathways, resulting in the accumulation of metabolic intermediates such as succinate. Succinate not only establishes positive feedback by stabilizing HIF-1α but also facilitates the maturation and release of IL-1β via the mitochondrial ROS-NLRP3 inflammatory vesicle pathway. In contrast, the glycolytic byproduct, lactic acid, inhibits histone deacetylase (HDAC) activity, thereby alleviating the transcriptional repression of NF-κB-mediated pro-inflammatory genes, thereby enhancing the ‘metabolism-epigenetic’ cascade. In a murine model of MI, PKM2 inhibition reduced the expression of the M1 macrophage marker inducible nitric oxide synthase, significantly decreased IL-1β levels and reduced infarct size (62).

Conversely, reparative M2 polarization is induced by IL-4/IL-13 activation of the JAK1-STAT6 signaling pathway through the IL-4Rα/IL-13Rα1 receptor (63). The phosphorylation of STAT6 within the nucleus promotes the expression of PPAR-γ, which assembles a transcriptional complex with retinoic acid X receptor (RXR) and coactivator PGC-1α to collaboratively modulate mitochondrial biosynthesis (for example, transcription factor A, mitochondrial and nuclear respiratory factor 1 and essential enzymes of FAO (e.g., CPT-1A and acyl-coa oxidase 1). PGC-1α facilitates repair via two metabolic mechanisms: i) Promoting FAO of long-chain fatty acids into β-oxidation, supplying acetyl coenzyme A for the TCA cycle; and ii) upregulation of electron transport chain complex expression to enhance OXPHOS efficiency. ATP generated by OXPHOS facilitates the ubiquitin-mediated clearance of HIF-1α via the AMPK/mTORC1 signaling pathway, thereby suppressing the glycolysis-dependent pro-inflammatory response. Significantly, the PPAR-γ agonist rosiglitazone augmented the percentage of CD206+ M2-type macrophages by 35% in the MI model and expedited neovascularization by enhancing vascular endothelial growth factor (VEGF) secretion. Conversely, PGC-1α knockdown led to a 40% reduction in macrophage FAO, accompanied by a decrease in the secretion of the anti-inflammatory factor IL-10, thereby supporting the role of mitochondrial metabolism in promoting M2-type polarization (64). This confirms that mitochondrial metabolism facilitates M2-type polarization (Fig. 3).

In summary, compromised mitochondrial metabolism during MI initiates a proinflammatory response through the release of metabolites such as succinate and ATP/ROS, which activate the HIF-1α/NF-κB and NLRP3 inflammatory vesicle pathways, thereby promoting macrophage polarization toward the glycolysis-dominant M1 phenotype. Simultaneously, IL-4/IL-13 modifies mitochondrial OXPHOS/FAO metabolism through the STAT6-PPARγ-PGC-1α pathway, facilitating M2-type polarization to promote repair. Therefore, focusing on the metabolism-immunity-linked interaction axis (for example, modulating the SIRT3-AMPK pathway or targeting the HIF-1α-PDK1 axis) may reshape macrophage polarization phenotype and offer a novel approach for anti-inflammatory-restorative combination therapy in MI. Future research should focus on the spatial and temporal dynamics of transcellular metabolic signaling.

The immediate pathological response to MI is characterized by a temporal sequence of metabolic homeostasis disruption and inflammatory activation, which underlies early damage (65). Within minutes to hours following MI, the ischemia and hypoxic milieu swiftly induce an imbalance in mitochondrial dynamics and metabolic signaling, establishing a ‘metabolic-inflammatory’ positive feedback loop (52). Specifically, enhanced calcium-modulated phosphatase (Calcineurin) activity facilitates dephosphorylation of Ser637 on Drp1, markedly increasing its affinity for the mitochondrial membrane and leading to excessive mitochondrial fragmentation. When the damaged inner mitochondrial membrane ruptures during mitochondrial fission, mtDNA is released into the cytoplasm. Macrophage TLR9 recognizes these molecules as DAMPs. Through MyD88, TLR9 recruits IRAK, which, in turn, activates TRAF6, thereby inducing NF-κB nuclear translocation and increasing levels of pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6 (66,67). These proinflammatory factors worsen secondary myocardial injury through two mechanisms: TNF-α causes cardiomyocytes to undergo apoptosis via the death receptor pathway, increases vascular permeability and encourages neutrophil infiltration; and IL-1β binds to IL-1R1 on cardiomyocytes, activates the MAPK/p38 pathway, inhibits mitochondrial complex II activity and further encourages succinate accumulation and ROS generation. The key involvement of the mtDNA-TLR9 axis in early inflammatory storms was confirmed by TLR9 silencing, which reduced infarct size by 35% and IL-1β levels by 40% in a mouse model of myocardial ischemia-reperfusion (68).

When the initial inflammatory surge reaches its peak, the body activates a reparative process facilitated by metabolic reprogramming, in which macrophage phenotypic switching is pivotal (69). Between 24 and 72 h post-MI, macrophages commence phagocytosis by identifying phosphatidylserine on the membranes of apoptotic cardiomyocytes, a mechanism that activates metabolic reprogramming in macrophages. Following phagocytosis of apoptotic cells, AMPK activity in macrophages increases markedly, leading to phosphorylation and activation of CPT-1, thereby facilitating FAO. Acetyl coenzyme A generated by FAO enters the TCA cycle and increases OXPHOS capability, supplying the energy required to sustain an anti-inflammatory phenotype (70). Concurrently, FAO intermediates, such as acetylcarnitine, stimulate SIRT1, which deacetylates PPARγ and enhances its capacity to heterodimerize with RXR. The PPARγ-RXR complex, in conjunction with PGC-1α, stimulates transcription of the anti-inflammatory genes IL-10, TGF-β and VEGF. IL-10 inhibits the release of pro-inflammatory factors by binding to IL-10R1/IL-10R2 receptors on macrophages, increasing JAK1/STAT3 signaling and suppressing NF-κB activity (71,72). In a rat model of MI, PPARγ overexpression led to a 2.3-fold increase in IL-10+ macrophages within the infarcted region and a 40% decrease in myocardial fibrosis area. Additionally, TGF-β facilitated organized type I collagen deposition rather than disorganized fibrosis by inducing fibroblast transformation into myofibroblasts, thereby preserving cardiac structural integrity (73). Furthermore, Willenborg et al (74) discovered that the metabolic phenotype of repair-phase macrophages is dynamically influenced by the oxygen partial pressure within the microenvironment: In the initial hypoxic region (oxygen partial pressure <10 mmHg), HIF-1α remained activated at a low level, facilitating energy for phagocytosis by transiently sustaining glycolysis through the induction of PDK1 expression; as neovascularization occurred, the oxygen partial pressure increased to 20–30 mmHg, leading to the dominance of the PPARγ/PGC-1α axis in the metabolic transition. Neovascularization resulted in oxygen partial pressure returning to 20–30 mmHg, leading to the ubiquitination and degradation of HIF-1α, while the PPARγ/PGC-1α axis governed the metabolic transition. This spatiotemporal regulatory mechanism of metabolism-immunity-linked interaction facilitated the timely transition of macrophages to a reparative phenotype following the removal of necrotic tissues, thereby preventing excessive inflammatory damage (74,75).

Based on the aforementioned regulatory mechanisms of metabolism-immunity-linked interaction, targeted intervention in the metabolic signaling axis has emerged as a novel paradigm for enhancing cardiac healing. SIRT3-mediated modification of the mitochondrial-immunological axis has considerable therapeutic promise owing to its dual role in metabolic control and the inhibition of inflammation (76). Overexpression of SIRT3 ameliorated metabolic-immune disorders via a dual mechanism: First, SIRT3 deacetylation activated liver kinase B1, an upstream kinase of Drp1, thereby enhancing AMPK Thr172 phosphorylation, inhibiting Drp1 Ser637 dephosphorylation and reducing mitochondrial fragmentation. In SIRT3 transgenic mice, MI led to increased production of the mitochondrial fusion protein Mfn2 and increased the recovery of the mitochondrial membrane potential (77). Second, SIRT3 activated SOD2 via deacetylation, diminishing mitochondrial ROS levels, mitigating mtDNA damage and release, and inhibiting the TLR9/NF-κB inflammatory pathway (76,78). Following the restoration of mitochondrial function, ATP synthesis in cardiomyocytes increases, thereby influencing macrophage phenotype via paracrine signaling. ATP is released by the Connexin 43 hemichannel, activating macrophage P2Y purinoceptor 12, inhibiting adenylate cyclase via Gi proteins, reducing cyclic AMP levels and facilitating PPARγ phosphorylation. Lactate dehydrogenase A produced by cardiomyocytes can be taken up by macrophages, facilitating PPARγ binding to DNA and augmenting M2-type gene transcription via HDAC inhibition (79,80) (Fig. 4).

Therefore, metabolic-immune interactions during MI play a bidirectional regulatory function in both damage and healing. During the initial injury phase, mitochondrial dysfunction releases mtDNA, which activates the TLR9/NF-κB pathway, thereby triggering a positive inflammatory feedback loop and exacerbating myocardial injury. During the repair phase, macrophages initiate the AMPK-CPT1-FAO axis via phagocytosis of apoptotic cells, activate the PPARγ/PGC-1α pathway, shift to an anti-inflammatory M2 phenotype, and suppress inflammation and promote myocardial repair through factors such as IL-10 and TGF-β. SIRT3 functions as a metabolic-immune nexus that activates AMPK and SOD2, diminishes ROS and mtDNA release and mitigates inflammation, while further promoting macrophage reprogramming via ATP- and lactate-mediated paracrine signaling. This mechanism reflects the coupled regulation of metabolism and immunity across spatial and temporal scales, providing theoretical support and potential targets for interventions in myocardial injury.