Mitophagy in cardiovascular diseases: a literature review

Introduction

Background

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, accounting for an estimated 17.9 million deaths annually (1). The heart is a high-energy-demanding but low-energy-storage organ, requiring nearly 1 mmol/L adenosine triphosphate (ATP) per second to sustain normal contractile activity. Mitochondria, which occupy 30–40% of the myocardial cell volume, serve as the primary source of ATP, and are closely involved in cell proliferation, apoptosis, signal transduction, and calcium homeostasis (2-4). The structural integrity and functional competence of mitochondria are therefore essential for maintaining cardiac physiology.

In patients with heart failure (HF), mitochondrial dysfunction leads to disturbances in myocardial energy metabolism (5). Beyond energy deficits, impaired mitochondrial regulation results in the excessive accumulation of damaged mitochondria, elevated reactive oxygen species (ROS), calcium overload, and cellular stress, ultimately contributing to fibrosis, apoptosis, and the progression of CVDs (3,5-7). Adequate mitochondrial quality control (MQC) is thus critical for sustaining mitochondrial and cardiomyocyte homeostasis (3,4).

Mitophagy is a selective form of autophagy that plays a central role in MQC by removing dysfunctional mitochondria, thereby preventing cellular injury under conditions such as ROS overload, mitochondrial DNA (mtDNA) mutations, and exposure to toxic stimuli (8-10). This process involves four key steps: initiation of mitochondrial damage and depolarization, autophagosome formation, autophagosome-lysosome fusion, and final lysosomal degradation (11). Accumulating evidence shows that mitophagy regulates multiple cardiovascular processes and participates in the pathogenesis of hypertension, atherosclerosis (AS), myocardial ischemia/reperfusion (I/R) injury, and HF (3-5).

Rationale and knowledge gaps

Several reviews have examined the role of mitophagy in cardiovascular biology; however, notable gaps remain. Previous studies, particularly those published between 2020 and 2025, have largely failed to systematically integrate recent advances, including emerging clinical evidence and novel therapeutic approaches. Moreover, most reviews have largely emphasized classical mitophagy pathways, such as PINK1/Parkin, while providing limited insights into alternative, disease-specific signaling mechanisms and their dynamic regulation. Translational perspectives are also insufficient, with inadequate discussion of therapeutic efficacy, tissue specificity, and clinical feasibility. These limitations highlight the need for an updated and comprehensive synthesis of the literature that integrates recent mechanistic discoveries with emerging therapeutic strategies.

Objective

This review aims to address these gaps by providing a comprehensive and updated synthesis of mitophagy in CVDs. It integrates recent mechanistic discoveries in a “core pathway-alternative pathway-crosstalk network” framework across major diseases such as HF and AS, evaluates therapeutic strategies encompassing drugs, exercise interventions, and novel technologies, and incorporates clinical evidence, including phase II data and randomized exercise trials. By summarizing recently identified targets, elucidating key intervention nodes, and proposing a “dynamic balance model of mitophagy”, this review seeks to clarify unresolved mechanistic questions, highlight translational opportunities, and outline future research directions, including microenvironment-responsive nanocarriers and multi-omics-based personalized biomarkers, to guide the continued development of the field. We present this article in accordance with the Narrative Review reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-438/rc).

Methods

A literature search was conducted of PubMed on March 15, 2025 to retrieve studies related to mitophagy and CVDs. The search covered articles published from January 2020 to March 2025 and included both MeSH terms and free-text keywords related to mitophagy and major CVD conditions. The search was restricted to English-language original research articles and review articles; no restrictions were applied in relation to study design unless explicitly stated in individual articles. The literature screening was performed independently by R.Z., J.Z., and S.M. using a three-step process: title screening, abstract screening, and full-text assessment. After independent review, any discrepancies were resolved by group discussion, and if necessary, by consensus voting among the three reviewers. The final included studies were used to summarize the recent mechanistic advances, disease-specific regulatory networks, and emerging therapeutic strategies related to mitophagy in CVDs. The search strategy is summarized in Table 1.

Mitophagy: mechanisms and significance

Molecular mechanisms of mitophagy

Mitophagy, which removes damaged or surplus mitochondria via specialized molecular mechanisms, has attracted significant scientific interest since its initial proposal. Its mechanisms include mitochondrial proteins interacting with microtubule-associated protein 1A/1B-light chain 3 (LC3) through adaptors, direct LC3-mitochondrial receptor interaction, and lipid accumulation in the outer mitochondrial membrane (OMM), with pathways falling into ubiquitin (Ub)-dependent and Ub-independent types. The efficient clearance of damaged/excess mitochondria is vital for maintaining intracellular homeostasis. Dysregulated mitophagy is associated with various diseases, making research into its molecular regulatory mechanisms crucial for understanding pathogenesis, identifying new drug targets, and advancing drug development and clinical treatments (Figure 1).

Figure 1 Key mechanisms in mitophagy. ROS, reactive oxygen species; Ub, ubiquitin.

Ub-dependent pathway

Ub-dependent mitophagy is a major MQC mechanism, among which the PINK1/Parkin pathway has been the most extensively studied (12). Under mitochondrial stress, PINK1 accumulates on the OMM and activates downstream Ub signaling cascades that label damaged mitochondria for autophagic degradation, thereby preserving mitochondrial integrity and cellular homeostasis (13,14). Apart from Parkin, PINK1 can also coordinate mitophagy through alternative E3 Ub ligases, indicating that PINK1-mediated mitochondrial surveillance is not exclusively dependent on Parkin (15-18).

Accumulating evidence suggests that the dysregulation of the PINK1-centered Ub-dependent mitophagy pathway plays a crucial role in the pathogenesis of CVDs. In diabetic cardiomyopathy, the activation of PINK1/Parkin-mediated mitophagy has been shown to improve mitochondrial respiratory function and cardiac performance, exemplified by the cardioprotective effects of canagliflozin (19). In pulmonary arterial hypertension (PAH), PINK1 or Parkin deficiency impairs mitophagy, promotes the abnormal phenotypic switching of pulmonary artery smooth muscle cells (PASMCs), and accelerates vascular remodeling (20). Conversely, the excessive or maladaptive activation of PINK1/Parkin-dependent mitophagy may exacerbate vascular inflammation and mitochondrial dysfunction, as observed in Kawasaki disease associated with mycoplasma pneumoniae infection (21).

Recent studies further suggest that endogenous metabolic cues critically modulate Ub-dependent mitophagy. For example, mitochondrial metabolites such as fumarate can suppress Parkin E3 ligase activity and mitochondrial translocation via post-translational modification, highlighting the tight coupling between mitochondrial metabolism and mitophagic flux (22). In addition, physiological conditions, including cellular energy status and oxidative stress, may influence the balance between Parkin-dependent and Parkin-independent Ub signaling pathways, particularly in cardiac tissues under pathological stress (23).

However, research on the Parkin-independent pathway is limited, suggesting that the PINK1/Parkin pathway predominates under various pathological conditions. By analyzing the components of mitophagy one by one, such as the damage-sensing function of PINK1 and the effector function of Parkin, an integrated perspective can be established—mitophagy is a dynamic process, the regulation of which depends on the interactions among mitochondrial metabolism, cellular stress, and disease context, and it plays a central role in maintaining cardiovascular health.

Ub-independent pathways

Mitophagy mechanisms and pathways are diverse. The Ub-independent (receptor-mediated) mitophagy pathway, where mitochondrial autophagy receptors directly mediate the process without ubiquitination, is essential. Unlike the PINK1/Parkin pathway, which is dependent on prior PINK1 activation, the Ub-independent mitophagy pathway uses specific protein interactions and signal transduction to deliver dysfunctional mitochondria to autophagosomes for direct selective degradation. For example, OMM proteins, such as FUNDC1, BNIP3, and NIX/BNIP3L, which harbor a conserved LIR motif, directly interact with LC3 and the gamma-aminobutyric acid type A receptor-associated protein (GABARAP), enabling recognition by phagocytic vesicles and initiating mitophagy (17). Studies have identified additional mitophagy receptors that play essential roles in the mitophagy process (Table 2).

Mitophagy in CVDs

HF

HF represents the terminal stage of multiple CVDs, and is associated with high morbidity and mortality (24). A central hallmark of the pathogenesis of HF is mitochondrial dysfunction, leading to impaired myocardial energy production and contractile failure. Recent studies have identified diverse molecular regulators and signaling cascades governing mitophagy during cardiac stress, providing novel insights into the pathophysiological mechanisms of HF and potential therapeutic avenues for mitochondrial-targeted interventions (Table 3 and Figure 2).

Figure 2 Factors and mechanisms related to mitophagy in HF. ACC2, acetyl-CoA carboxylase 2; AKG, α-ketoglutarate; ANP, atrial natriuretic peptide; FAO, fatty acid oxidation; HF, heart failure; NAD⁺, nicotinamide adenine dinucleotide; NNMT, nicotinamide N-methyltransferase.

STX17-CDK1-Drp1 axis: Syntaxin 17 (STX17), a SNARE scaffold protein located at mitochondria-associated membranes (MAMs), serves as a molecular platform for the recruitment of Drp1 during mitochondrial fission. Both human HF and transverse aortic constriction–induced mouse models exhibit significantly reduced STX17 expression, accompanied by impaired mitophagy and mitochondrial fragmentation. Mechanistically, STX17 recruits CDK1 to MAMs, facilitating Drp1 phosphorylation at Ser616, thereby promoting mitophagy and MQC. STX17 overexpression rescues cardiac dysfunction, indicating its essential role in mitochondrial homeostasis (25).

Epigenetic regulation: DNMT1/miR-152-3p/ETS1/RhoH axis: DNA methyltransferase 1 (DNMT1) expression is elevated in doxorubicin-induced HF models, leading to the hypermethylation of the miR-152-3p promoter and the suppression of its transcription. The downregulation of miR-152-3p enhances ETS1 and RhoH expression, thereby inhibiting mitophagy and exacerbating HF pathology. Conversely, DNMT1 knockout or miR-152-3p restoration reactivates mitophagy and mitigates cardiac dysfunction, revealing a critical epigenetic mechanism linking DNA methylation to mitochondrial quality decline (26).

Adrenergic signaling and the PDE4D-cyclic adenosine monophosphate (cAMP)-SIRT1 pathway: chronic β-adrenergic stimulation upregulates phosphodiesterase 4D (PDE4D), the principal cAMP-degrading enzyme in the heart. Elevated PDE4D suppresses cAMP-PKA-CREB-SIRT1 signaling, leading to impaired mitophagy, mitochondrial damage, and cardiomyocyte hypertrophy. Thus, maladaptive adrenergic activation inhibits mitophagy via metabolic stress signaling and contributes to progressive HF remodeling (27).

NPLOC4 and redox imbalance: nuclear protein localization protein 4 homolog (NPLOC4) exacerbates cardiac hypertrophy and fibrosis by promoting ROS accumulation through ERO1α and β-catenin/GSK3β signaling. The genetic silencing of NPLOC4 attenuates oxidative stress, restores mitochondrial function, and improves cardiac remodeling, indicating that NPLOC4-mediated redox imbalance impairs mitophagy and mitochondrial homeostasis (28).

AMPK-dependent mitophagy regulation: AMP-activated protein kinase (AMPK), particularly the α2 subunit (AMPKα2), functions as a master regulator of cardiac mitophagy. HF hearts display reduced AMPKα2 but increased AMPKα1 expression, reflecting an isoform shift during disease progression. AMPKα2 phosphorylates PINK1 at Ser495, enhancing PINK1-Parkin-SQSTM1 signaling and mitochondrial clearance (29). Moreover, AMPKα2 phosphorylates BCL2L13 at Ser272, an essential step in BCL2L13-mediated mitophagy activation during pressure overload (30,31). The loss of AMPKα2 or disruption of this phosphorylation leads to mitochondrial dysfunction and aggravated HF, confirming that AMPK-dependent phosphorylation is central to stress-induced mitophagy.

ULK1-dependent alternative mitophagy: under chronic pressure overload, canonical ATG7/ATG5/LC3-dependent mitophagy becomes transient and insufficient, while ULK1/Rab9-mediated alternative mitophagy persists as a compensatory mechanism. ULK1-deficient mice exhibit accelerated cardiac hypertrophy, fibrosis, and contractile failure, underscoring the critical role of ULK1 in maintaining mitochondrial turnover during sustained stress (32).

Protective regulators, including Omentin1, RNF7, and FUNDC1, play crucial roles in preserving cardiac function by activating mitophagy. Specifically, Omentin1 promotes SIRT3/FOXO3a-mediated PINK1/Parkin mitophagy, thereby reducing ischemia-induced mitochondrial injury (33). RNF7, a mitochondrial E3 Ub ligase, stabilizes PINK1 and mediates Parkin-independent mitophagy, preventing mitochondrial dysfunction and HF (34). FUNDC1, a hypoxia-responsive mitophagy receptor, enhances mitochondrial clearance during hypoxia acclimation, improving post-myocardial infarction (MI) outcomes (35).

Autophagic flux and NAD⁺ metabolism: impaired autophagic flux leads to nicotinamide adenine dinucleotide (NAD⁺) deficiency due to the activation of nicotinamide N-methyltransferase (NNMT), which converts nicotinamide (NAM) into N-methyl nicotinamide. This process is driven by SQSTM1-NF-κB-NNMT signaling. Restoring NAD⁺ via nicotinamide mononucleotide (NMN) supplementation or NNMT inhibition restores mitophagy, mitochondrial function, and cardiac performance, establishing a direct link between autophagy and the regulation of energy metabolism (36).

α-ketoglutarate (AKG) and metabolic homeostasis: AKG, a tricarboxylic acid cycle intermediate, promotes mitophagy by upregulating NAD⁺ and activating SIRT1, thereby reducing oxidative stress, ferroptosis, and myocardial remodeling. AKG supplementation has been identified as a potential metabolic modulator for enhancing MQC in HF (37).

Mitophagy in heart failure with preserved ejection fraction (HFpEF): in HFpEF, defective fatty acid oxidation (FAO) suppresses mitophagy, leading to mitochondrial dysfunction and energetic insufficiency. Enhancing FAO by deleting acetyl-CoA carboxylase 2 (ACC2) restores mitophagy and improves cardiac energetics (38). Further, atrial natriuretic peptide (ANP) promotes autophagy and mitophagy, mitigates mitochondrial oxidative stress, and improves cardiac function. Angiotensin receptor-neprilysin inhibitor treatment increases ANP levels and exerts cytoprotective effects in both heart failure with reduced ejection fraction (HFrEF) and HFpEF (39).

AS

AS is a chronic, progressive vascular disorder characterized by lipid accumulation, inflammation, and plaque formation in major arteries, which can culminate in MI. Mitochondrial dysfunction and oxidative stress are central contributors to the pathogenesis of AS. Recent evidence indicates that mitophagy is a crucial regulator of vascular homeostasis (40). Impaired mitophagy in endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages leads to excessive ROS generation, inflammasome activation, and cell death, thereby promoting plaque formation and instability (40) (Table 4 and Figure 3). Understanding the molecular mechanisms linking mitophagy dysregulation to atherogenesis offers new diagnostic and therapeutic opportunities.

Figure 3 Factors and mechanisms related to mitophagy in AS. AIBP, apolipoprotein A-I binding protein; AS, atherosclerosis; LDL, low-density lipoprotein; LPEAT, lysophosphatidylethanolamine acyltransferase; mmLDL, multiply modified low-density lipoprotein; TMAO, trimethylamine N-oxide; Ub, ubiquitin.

Differential effects of LDL and multiply modified low-density lipoprotein (mmLDL) on mitophagy: low-density lipoprotein (LDL) is a key initiator of AS, but its modified forms exert distinct effects on mitophagy. Bezsonov et al. (41) demonstrated that native LDL enhances mitophagy in both THP-1 and TCN521 cells, whereas mmLDL inhibits mitophagy in THP-1 macrophages but enhances it in TCN521 cells. This inhibition may occur through the activation of the mTOR pathway, suggesting that mmLDL suppresses mitophagy and contributes to mitochondrial dysfunction and plaque development. Additionally, variations in mtDNA genotypes may modulate this response, indicating a genetic basis for mitophagy heterogeneity in AS.

AIBP-Mfn1/2-PARK2 signaling in macrophage mitophagy: apolipoprotein A-I binding protein (AIBP) is highly expressed in human and murine atherosclerotic plaques. AIBP loss reduces oxidized density lipoprotein (ox-LDL)-induced autophagy and mitophagy, leading to mitochondrial ROS accumulation and cell death. Mechanistically, AIBP interacts with mitochondrial proteins PARK2, Mfn1, and Mfn2, promoting Mfn1/2 ubiquitination and mitophagic clearance (42). Enhancing intracellular AIBP expression rescues mitochondrial homeostasis and limits macrophage apoptosis, positioning AIBP as a mitophagy-promoting and anti-atherogenic factor.

AIBP-mediated macrophage polarization and PINK1-dependent mitophagy: AIBP deficiency polarizes macrophages toward the pro-inflammatory M1 phenotype by inhibiting PINK1-dependent mitophagy through phosphatase and tensin homolog (PTEN)-induced PINK1 cleavage (43). Bone marrow transplantation experiments have shown that AIBP-deficient macrophages exacerbate lesion formation, while mitochondrial AIBP maintains the M1/M2 balance. Thus, AIBP is a critical metabolic switch linking MQC to macrophage phenotype regulation.

The PTEN-AMPK-CREB-Mfn2 Axis in endothelial mitophagy: Ox-LDL triggers endothelial apoptosis via mitochondrial dysfunction, including reduced membrane potential and calcium overload. Li et al. (44) revealed that PTEN inhibition protects endothelial cells by activating the AMPK-CREB-Mfn2 pathway, which promotes mitophagy and mitochondrial recovery. Conversely, PTEN overexpression exacerbates mitochondrial damage, underscoring the dual role of PTEN in regulating both metabolism and mitophagy.

Mitophagy defects drive macrophage hyperinflammation: mitophagy is essential for maintaining macrophage immune tolerance. Defective mitophagy increases basal cytokine secretion [chemokine ligand 2, interleukin 8 (IL-8), and tumor necrosis factor] and triggers uncontrolled inflammation on secondary stimulation. Cells lacking mitophagy fail to establish endotoxin tolerance, displaying exaggerated IL-1β, IL-6, and IL-8 responses (45). These findings suggest that mitophagy deficiency sustains chronic macrophage activation, perpetuating vascular inflammation and plaque progression.

Shear stress and the Cav-1/miR-7-5p/SQSTM1 pathway: hemodynamic forces profoundly affect endothelial function. Low shear stress reduces endothelial mitophagy, leading to oxidative stress and dysfunction. Mechanistically, Caveolin-1 (Cav-1) acts as a mechanosensitive regulator that modulates miR-7-5p, which suppresses mitophagy by targeting SQSTM1/p62, forming the Cav-1/miR-7-5p/SQSTM1 axis (46). This pathway connects vascular biomechanics to MQC.

MtDNA mutation-induced mitophagy impairment: Sukhorukove et al. (47) identified a mitochondrial nonsense mutation (m.15059G>A) that disrupts mitophagy and immune homeostasis, promoting chronic vascular inflammation. The removal of the mutant allele restores immune tolerance and reactivates mitophagy. This mutation upregulates fatty acid synthase, linking mitochondrial genomic instability to lipid metabolism and immune dysfunction in AS.

Gut microbiota metabolite trimethylamine N-oxide (TMAO) and the lysophosphatidylethanolamine acyltransferase (LPEAT)-mitophagy-pyroptosis pathway: TMAO, a pro-atherogenic gut microbial metabolite, induces mitochondrial damage and pyroptosis in endothelial cells by upregulating LPEAT (48). LPEAT overexpression enhances mitophagy and triggers pyroptosis, while LPEAT silencing or mitophagy inhibition via 3-methyladenine (3-MA) mitigates these effects. These findings reveal a LPEAT-mitophagy-pyroptosis axis, illustrating how gut-derived metabolites contribute to vascular inflammation and plaque instability.

Myocardial I/R injury

I/R injury refers to the damage caused by excessive free radicals attacking cells in ischemic tissues after the restoration of blood supply in ischemic diseases such as MI and stroke (49). Although reperfusion is essential for tissue survival, it paradoxically induces oxidative stress, calcium overload, inflammation, and endothelial barrier disruption, collectively impairing microcirculation and exacerbating cardiomyocyte injury. Mitochondrial dysfunction and excessive ROS generation play central roles in this process. Mitophagy plays a dual role in myocardial I/R injury. Moderate mitophagy activation during early ischemia preserves mitochondrial integrity and reduces oxidative stress, while excessive or dysregulated mitophagy during reperfusion may cause mitochondrial depletion and an energy crisis, aggravating myocardial damage (50-52). Recent research has elucidated the signaling networks balancing these opposing effects, offering novel therapeutic insights for cardioprotection (Table 5 and Figure 4).

Figure 4 Factors and mechanisms related to mitophagy in myocardial I/R injury. I/R, ischemia/reperfusion; Mff, mitochondrial fission factor; PKD, protein kinase D.

Human cardiac 3D modelling revealing ULK1-dependent mitophagy flux: using human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues, researchers simulated I/R conditions and observed increased mitochondrial-lysosome proximity and enhanced autophagic flux dependent on ULK1 activity. This human three-dimensional (3D) model provided the first demonstration of dynamic changes in mitophagy following I/R, representing an advanced platform for mechanistic and therapeutic studies (53).

PINK1-Parkin pathway and RhoA-PKD signaling: the canonical PINK1/Parkin pathway remains central to I/R-related mitophagy. RhoA activation promotes PINK1 accumulation on mitochondria, enhances Parkin recruitment, and facilitates mitochondrial protein ubiquitination, thereby reducing infarct size in vivo (54). Protein kinase D (PKD) regulates RhoA localization to mitochondria, highlighting a PKD-RhoA-PINK1 axis that protects the heart by stabilizing PINK1 independent of mitochondrial depolarization.

ZIP7-mitochondrial zinc efflux modulation: zinc transporter 7 (ZIP7) negatively regulates mitophagy. Its expression increases during reperfusion, and its knockdown promotes mitophagy by inducing mitochondrial zinc efflux and membrane hyperpolarization. ZIP7 suppresses PINK1/Parkin accumulation, while its deletion reduces mitochondrial ROS and infarct size. Elevated ZIP7 levels in HF patients suggest that ZIP7 inhibition may enhance mitophagy-mediated protection against I/R injury (55).

The Notch1-PTEN-PINK1 axis: the Notch1 intracellular domain (N1ICD) mitigates hypoxia/reoxygenation (H/R) injury by transcriptionally repressing PTEN via Hes1. Reduced PTEN activity enhances PINK1 stability and MQC, improving post-I/R cardiac function. The overexpression of PTEN or PINK1 abolishes these effects, confirming a Notch1-PTEN-PINK1 regulatory cascade crucial for cardioprotection (56).

SUMOylation-HOXB5-PIAS3 signaling: SUMO modification plays a regulatory role in mitophagy. PIAS3-mediated SUMOylation of CARD9 inhibits HOXB5 O-GlcNAcylation and nuclear translocation, suppressing mitophagy. PIAS3 knockdown restores HOXB5 translocation, activates PINK1/Parkin signaling, and alleviates myocardial injury. This reveals a novel PIAS3-CARD9-HOXB5-PINK1/Parkin pathway regulating SUMO-dependent mitophagy during I/R (57).

NR4A1-mediated mitochondrial dysfunction and FUNDC1 inhibition: nuclear receptor subfamily 4 group A member 1 (NR4A1) expression increases after I/R, promoting mitochondrial fission and suppressing Parkin- and FUNDC1-mediated mitophagy. NR4A1 knockout preserves mitochondrial integrity and reduces inflammation and apoptosis, indicating that NR4A1 disrupts mitochondrial homeostasis via mitochondrial fission factor (Mff)-mediated fission and FUNDC1 inhibition (58,59).

FUNDC1-related pathways: AMPK, PLK1, and adenosine receptor regulation: A2B receptor (A2BR) activation inhibits mitophagy by promoting FUNDC1 phosphorylation through Src kinase, reducing its binding to the OMM (60). Polo-like kinase 1 (PLK1) enhances p-AMPK/FUNDC1 signaling, inducing protective mitophagy and reducing infarct size (61). These findings demonstrate that FUNDC1 serves as a pivotal receptor that integrates multiple upstream stress and kinase signals during reperfusion.

BNIP3 and RNA m6A regulation: BNIP3, a hypoxia-inducible mitophagy receptor, plays context-dependent roles. The HIF-1α/BNIP3 axis promotes adaptive mitophagy and reduces apoptosis during I/R (62). However, excessive BNIP3 activation can be detrimental. The N6-methyladenosine (m⁶A) reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) binds to methylated BNIP3 messenger RNA (mRNA) to promote its degradation, thereby attenuating H/R-induced mitophagy and oxidative injury. YTHDF2 overexpression protects cardiomyocytes, revealing a YTHDF2-BNIP3 regulatory mechanism of RNA epitranscriptomic control over mitophagy (63).

MiR-mediated regulation: several microRNAs (miRs) fine-tune mitophagy during I/R injury. Notably, miR-494-3p targets PGC1α to suppress excessive mitophagy and apoptosis, promoting cardiomyocyte survival (64). Post-I/R, miR-23a is upregulated and directly targets CX43, promoting mitophagy and exacerbating injury via the NF-κB/miR-23a/CX43 axis (65). MiR-130a, which is elevated in acute MI and I/R hearts, represses GJA1 and inhibits FUNDC1-mediated mitophagy, exacerbating mitochondrial dysfunction (66). Together, these studies establish miR-mitophagy networks as potential therapeutic modulators.

Emerging mitophagy-related targets: multiple new regulators have been identified. CD137, a tumor necrosis factor (TNF) receptor superfamily member, suppresses mitophagy and promotes NLRP3 inflammasome activation, aggravating myocardial injury; however, the inhibition of CD137 or the activation of mitophagy mitigates damage (67). TRAF3IP3 knockdown enhances mitophagy by promoting NEDD4 degradation, improving mitochondrial function, and cardiac outcomes (68). PRRX1, a stress-induced transcription factor, exacerbates excessive mitophagy and ferroptosis via FKBP5/p38 MAPK signaling, while the silencing of PRRX1 provides cardioprotection (69). DUSP12, which is downregulated in I/R, induces HSPB8-dependent mitophagy on overexpression, reducing infarct size and oxidative stress (70). These findings reveal a broad landscape of mitophagy modulators that act to maintain mitochondrial integrity and regulate inflammation.

Cumulative evidence underscores the biphasic nature of mitophagy in myocardial I/R injury. The PINK1/Parkin and FUNDC1 axes have emerged as central pathways integrating multiple upstream signals, including RhoA-PKD, ZIP7, Notch1-PTEN, and SUMO/PIAS3 modifications. Regulatory inputs from miRs, RNA methylation (YTHDF2), and transcription factors (NR4A1 and PRRX1) further refine mitophagic responses.

Cardiomyopathies

Cardiac hypertrophy and dilated cardiomyopathy (DCM) are two critical pathological adaptations to sustained cardiac stress. Cardiac hypertrophy initially serves as a compensatory response to mechanical or metabolic overload, but chronic or excessive hypertrophy leads to maladaptive remodeling, fibrosis, and ultimately HF or sudden cardiac death. Conversely, DCM, is characterized by ventricular dilation and contractile dysfunction, with multifactorial etiologies involving ischemia, stress, and mitochondrial defects. In both conditions, mitophagy plays a central role in preserving cardiomyocyte survival and function. The dysregulation of mitophagy leads to mitochondrial fragmentation, defective bioenergetics, and maladaptive remodeling. Recent studies have shown that mitochondrial dynamics regulators, metabolic enzymes, and transcriptional circuits converge on mitophagy to modulate hypertrophy and DCM progression (71) (Table 6 and Figure 5).

Figure 5 Factors and mechanisms related to mitophagy in cardiomyopathy. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy.

Opa1-mediated mitochondrial dynamics and hypertrophic remodeling: Opa1, a dynamin-related GTPase located on the inner mitochondrial membrane, orchestrates mitochondrial fusion and cristae organization. Experimental evidence shows that Opa1 processing is not required under normal metabolic or thermal stress but becomes crucial under pathological mitochondrial dysfunction. In a mitochondrial cardiomyopathy model with oxidative phosphorylation (OXPHOS) deficiency, Opa1 processing was shown to extend lifespan and confer cardioprotection by maintaining mitochondrial biogenesis and autophagic balance (72). Conversely, impaired Opa1 processing was shown to disrupt MQC, suppress compensatory hypertrophic growth, and accelerate cardiac deterioration. These findings highlight the dual role of Opa1 in metabolic adaptation and mitochondrial homeostasis, positioning it as a molecular switch balancing protective and pathological hypertrophy.

The FOXO3a-PARKIN regulatory axis: Sun et al. (73) demonstrated that mitophagy is suppressed under hypertrophic stress, primarily due to the downregulation of Parkin, an E3 MQC ligase central to the PINK1-Parkin mitophagy pathway. Using cardiac-specific Parkin transgenic mice and Ang II-induced hypertrophy models, the authors found that Parkin overexpression restores mitophagy, inhibits cardiomyocyte enlargement, and improves cardiac function. Mechanistically, FOXO3a transcriptionally activates Parkin, establishing the FOXO3a-PARKIN axis that limits pathological hypertrophy by activating mitophagy. This underscores the role of transcriptional regulation of mitophagy as a key determinant of hypertrophic remodeling.

SDHAF4 and mitochondrial complex II assembly: succinate dehydrogenase (SDH, mitochondrial complex II) is a central component of the tricarboxylic acid cycle and electron transport chain. Succinate dehydrogenase assembly factor 4 (SDHAF4) ensures the proper assembly and stability of the complex. SDHAF4 expression is markedly downregulated in human and murine models of MI and DCM. Cardiac-specific Sdhaf4 knockout in mice resulted in mitochondrial disorganization, the loss of respiratory supercomplexes, reduced oxygen consumption, and severe cardiac dilation. Mechanistically, SDHAF4 deficiency activates Drp1-mediated mitochondrial fission through ERK1/2 signaling, leading to excessive mitophagy and metabolic stress. Notably, fumaric acid supplementation or Drp1 inhibition restores mitochondrial integrity and improves survival, revealing that SDH assembly is a key mitochondrial determinant in DCM pathogenesis (74).

The BMAL1-BNIP3 axis and circadian control of mitophagy: the circadian transcription factor BMAL1 regulates cardiac metabolism and mitochondrial homeostasis. Using Bmal1 knockout mice and human embryonic stem cell-derived cardiomyocytes, researchers observed DCM-like phenotypes, including mitochondrial dysfunction, impaired OXPHOS, and contractile defects (75). BMAL1 binds directly to the E-box motif in the BNIP3 promoter, activating BNIP3 transcription and sustaining basal mitophagy. The loss of BMAL1 downregulates BNIP3, disrupts mitophagy, and triggers mitochondrial accumulation and cardiomyocyte injury. These findings reveal a BMAL1-BNIP3 mitophagy circuit that links circadian rhythm to MQC and cardiac integrity.

Metabolic cardiomyopathy (MC)

MC represents a spectrum of cardiac abnormalities arising from systemic metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). MC is characterized by diastolic dysfunction, hypertrophy, fibrosis, and inflammation, often progressing to HF (76). The hallmark of MC is excessive lipid accumulation in cardiomyocytes, leading to altered substrate utilization, favoring FAO over glucose metabolism, resulting in elevated oxidative stress, mitochondrial dysfunction, and energetic inefficiency (77). Recent studies have identified mitophagy as a central regulator of MQC in MC (78). The balance between mitophagy activation and suppression determines whether cardiomyocytes adapt to metabolic stress or succumb to injury. This section reviews current advances linking mitophagy to cardiac pathology in obesity and diabetes, emphasizing the molecular pathways and therapeutic implications (Table 7 and Figures 6,7).

Figure 6 Factors and mechanisms related to mitophagy in obesity-related cardiomyopathy. ACC2, acetyl-CoA carboxylase 2; ER, endoplasmic reticulum; FAO, fatty acid oxidation; MAMs, mitochondria-associated membranes.

Figure 7 Factors and mechanisms related to mitophagy in diabetes-related cardiomyopathy.

Drp1 as a dual regulator of conventional and alternative mitophagy: Drp1, a key mediator of mitochondrial fission, plays a multifaceted role in mitophagy regulation. The ULK1-Rab9-Ripk1-Drp1 complex coordinates alternative mitophagy by phosphorylating Rab9 (Ser179) and Drp1 (Ser616), recruiting trans-Golgi membranes to damaged mitochondria and initiating autophagic degradation (79). In cardiac-specific Drp1 knockout and heterozygous mice exposed to a high-fat diet (HFD), Drp1 was found to regulate mitophagy via distinct temporal mechanisms. In the acute phase, Drp1 promotes conventional LC3-dependent mitophagy through the Beclin 1-Bcl-2/Bcl-xL interaction. In the chronic phase, Drp1 translocates to endoplasmic reticulum-MAMs, engaging the Rab9/Fis1 axis to drive ULK1-Rab9-dependent alternative mitophagy. Hearts from obese patients exhibit increased Drp1 Ser616 phosphorylation, supporting its role as a protective mediator of mitochondrial quality in obesity-related cardiomyopathy (79). However, further research needs to be conducted to determine how Drp1 senses acute versus chronic stress, and to identify the molecular switch controlling the transition between classical and alternative mitophagy.

ULK1-Rab9-TFE3 signaling in chronic obesity: chronic HFD feeding induces a sustained activation of ULK1-Rab9-dependent alternative mitophagy, independent of the LC3 and Parkin pathways. Cardiac mitophagy increases within 3 weeks of HFD exposure and persists for up to 24 weeks, and is correlated with improved mitochondrial integrity and diastolic function (80). Mechanistically, HFD upregulates ULK1 phosphorylation and Rab9 expression, both of which are driven by the transcription factor E3 (TFE3), which binds to the Rab9 promoter. The loss of ULK1 or Rab9 (via knockout or S179A mutation) suppresses mitophagy and exacerbates cardiac dysfunction, while the overexpression of Rab9 restores mitochondrial function and alleviates hypertrophy. Interestingly, Atg7 knockout, which impairs conventional autophagy, triggers a compensatory increase in alternative mitophagy, ensuring MQC is maintained. Thus, promoting ULK1-Rab9 signaling could be a viable therapeutic strategy for obesity-induced cardiomyopathy. However, the paradox of early HFD-induced autophagy inhibition, but preserved late-phase mitophagy, remains unresolved, possibly reflecting differential transcriptional control. Transcription factor EB (TFEB) governs autophagy, while TFE3 regulates mitophagy.

Enhanced FAO and Parkin-mediated mitophagy: obesity and excessive FAO are traditionally linked to lipotoxicity. However, balanced FAO can maintain mitochondrial function. In Acc2 knockout mice with elevated cardiac FAO, HFD-induced cardiomyopathy was prevented despite similar obesity levels. Mechanistically, Parkin-mediated mitophagy remained active, counteracting HFD-induced mitochondrial damage (81). These findings highlight FAO-Parkin coupling as a metabolic defense mechanism that prevents lipid-induced mitochondrial dysfunction.

BRD4 and PINK1/Parkin suppression: in T2DM models, bromodomain-containing protein 4 (BRD4) is upregulated and inhibits PINK1/Parkin-mediated mitophagy by binding to acetylated histones (H3K27ac) at the Pink1 promoter. The BET inhibitor JQ1 disrupts this interaction, restores mitophagy, and improves cardiac function (82). Importantly, the therapeutic effects of JQ1 are abolished in Pink1 knockout mice, confirming that BRD4 impairs MQC through the epigenetic suppression of the PINK1/Parkin axis (82).

ZIP7-mediated mitochondrial Zn²⁺ dysregulation: ZIP7 modulates mitochondrial Zn²⁺ flux and oxidative stress. In diabetic mice, increased ZIP7 inhibits PINK1/Parkin signaling, leading to elevated mitochondrial ROS, membrane hyperpolarization, and fibrosis. Cardiac-specific ZIP7 deletion restores mitophagy, reduces ROS, and improves cardiac performance (83). These findings establish ZIP7 as a crucial mediator linking metal ion homeostasis to mitophagic dysfunction in diabetic cardiomyopathy.

ALDH2 and Parkin-dependent cardioprotection: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity is reduced in diabetic hearts and is correlated with impaired mitophagy and contractile function. ALDH2 overexpression or pharmacologic activation (using Alda-1 or Torezolid) restores mitochondrial integrity through Parkin-dependent mitophagy and the Akt-GSK3β pathway, while ALDH2 deficiency exacerbates myocardial injury and oxidative stress (84). These findings identify ALDH2 as a mitochondrial detoxification enzyme that safeguards diabetic hearts by activating mitophagy.

SFRP2-FZD5-Calcineurin/TFEB signaling: secreted frizzled-related protein 2 (SFRP2), an adipokine downregulated under glucolipotoxic stress, exerts cardioprotective effects by activating mitophagy via the FZD5-calcineurin/TFEB pathway, independent of Wnt/β-catenin signaling (85). In diabetic rats, SFRP2 overexpression reduces fibrosis, apoptosis, and oxidative stress while improving cardiac function. Despite promising results, the precise SFRP2-FZD5 interaction and its regulation in primary cardiomyocytes have yet to be investigated.

Pulmonary hypertension (PH)

PH is a progressive vascular disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, ultimately leading to right ventricular remodeling and HF. A major pathological hallmark of PAH, a subtype of PH, is excessive proliferation and resistance to apoptosis of PASMCs, driving pulmonary vascular remodeling (PVR) (86). Recent research has shown that mitochondrial dysfunction and aberrant mitophagy are central drivers of PASMC metabolic reprogramming and hyperproliferation (87,88). Proper mitophagy maintains mitochondrial integrity under hypoxic stress, while dysregulated activation sustains pseudohypoxia and proliferative signaling. This section summarizes emerging findings on mitophagy-mediated mechanisms in PH and their therapeutic implications (Table 8 and Figure 8).

Figure 8 Factors and mechanisms related to mitophagy in PH. PASMCs, pulmonary artery smooth muscle cells; PKD, protein kinase D; PH, pulmonary hypertension; PVR, pulmonary vascular remodeling; TUFM, mitochondrial translation elongation factor Tu.

Hypoxia-driven mitophagy and PASMC proliferation via the PINK1/Parkin pathway: under hypoxic conditions, the PINK1/Parkin pathway is activated in PASMCs, promoting mitochondrial clearance, but paradoxically facilitating cell proliferation and conferring apoptosis resistance. This imbalance drives vascular remodeling and contributes to PH pathogenesis (89-91). Chen et al. (87) further revealed that the PI3K p85α-HIF-1α axis regulates fatty acid uptake and mitophagy in PAH. The serum levels of HIF-1α, CD36, Parkin, and PINK1 are significantly elevated in PAH patients. Knocking down HIF-1α or PI3K p85α suppresses mitophagy and PASMC proliferation, reduces ROS accumulation, and alleviates vascular pathology, whereas knocking down CD36 produces the opposite effect. In vivo, HIF-1α inhibition improves hemodynamics and remodeling—effects that are reversed by recombinant CD36—whereas PINK1/Parkin activation ameliorates PAH symptoms. These results establish a HIF-1α-CD36-PINK1/Parkin regulatory loop that links lipid metabolism to mitophagy-driven PASMC proliferation.

Dual roles of FUNDC1 in endothelial versus PASMC mitophagy: controversy continues as to the role of FUNDC1 in PH. In human and experimental PH, FUNDC1 expression is reduced in the pulmonary vasculature. Global or endothelial-specific Fundc1 deletion aggravates PH, while its overexpression is protective (92). Mechanistically, FUNDC1 deficiency suppresses endothelial basal mitophagy, leading to mitochondrial dysfunction, metabolic reprogramming toward glycolysis, pseudohypoxia, and cellular senescence via the ROS-HIF2α pathway. This impairment also increases the endothelial secretion of insulin-like growth factor-binding protein 2 (IGFBP2), which promotes smooth muscle proliferation and PVR. Restoring FUNDC1 expression or targeting IGFBP2 ameliorates PH, suggesting that endothelial FUNDC1-dependent mitophagy maintains vascular homeostasis (92). Conversely, Liu et al. (88) demonstrated that in hypoxia-induced PH, the binding affinity between FUNDC1 and LC3B is enhanced in PASMCs, thereby increasing mitophagy activity. Elevated FUNDC1 stabilizes HIF-1α by increasing mitochondrial ROS and preventing its ubiquitination, thereby promoting PASMC proliferation. In vivo, FUNDC1 transgenic mice display exacerbated hemodynamic deterioration and vascular remodeling, while Fundc1 knockout mice are resistant to hypoxia-induced PH. Treatment with a specific FUNDC1 peptide inhibitor was shown to suppress mitophagy and improve PH. These divergent findings suggest that cell-type-specific mitophagy regulation—protective in endothelial cells but pathogenic in PASMCs—determines the dual role of FUNDC1 in PH.

Other mitophagy regulators in PH: the SMYD2-PPARγ-mitophagy axis, mitochondrial translation elongation factor Tu (TUFM), and the AMPK/mTOR pathway: SET and MYND domain-containing protein 2 (SMYD2) is upregulated in PASMCs from PH patients and hypoxic animal models (93). Cytoplasmic SMYD2 interacts with and monomethylates PPARγ, inhibiting its nuclear translocation and transcriptional activity. This repression activates mitophagy and drives PASMC proliferation by dysregulating the cell cycle checkpoint at the S/G2 transition. The pharmacologic activation of PPARγ with rosiglitazone reverses these effects, identifying the SMYD2-PPARγ-mitophagy axis as a novel epigenetic driver of PASMC proliferation and PH progression.

TUFM, which is associated with mitophagy and apoptosis, is markedly increased in PASMCs from monocrotaline-induced and hypoxia-induced PAH models (94). Silencing Tufm alleviates PH in vivo and inhibits mitophagy in vitro by suppressing the AMPK/mTOR signaling pathway, restoring the balance between PASMC proliferation and apoptosis. Thus, TUFM is a pro-proliferative mitophagy regulator, linking mitochondrial translation machinery to vascular remodeling.

Therapeutic modulation of mitophagy in CVDs

Given the central role of mitophagy in maintaining mitochondrial quality and cardiac homeostasis, the pharmacological and lifestyle-based modulation of this process represents a promising frontier for cardiovascular therapeutics. Dysregulated mitophagy contributes to HF, I/R injury, MC, and hypertrophic remodeling. In the past five years, a growing number of mitophagy-targeted interventions, including small molecules, natural compounds, hypoglycemic drugs, and physical exercise, have shown preclinical and early clinical benefits. This section summarizes recent advances and mechanistic insights into these strategies.

Pharmacological activation of mitophagy

Urolithin A (UA): a natural mitophagy inducer

UA, a gut microbiota-derived metabolite of ellagitannins, has been shown to activate mitophagy, improve mitochondrial respiration, and exert cardioprotective effects. In a pilot two-period, four-week crossover trial involving 10 HFrEF patients, UA (500 mg twice daily) was shown to improve left ventricular ejection fraction and reduce myocardial apoptosis and fibrosis, with the effects reversing after washout (95). Preclinically, UA has been shown to prevent MC in obese mice by restoring autophagic flux, improving diastolic function, and alleviating lipotoxic remodeling via mitophagy activation (77). Thus, UA could serve as a promising mitochondria-targeted nutraceutical for CVD management.

Hypoglycemic agents: SGLT2 inhibitors, GLP1-RAs, and DPP-4 inhibitors

SGLT2 inhibitors, such as canagliflozin and empagliflozin, not only improve glycemic control but also restore mitochondrial function in the heart. Canagliflozin has been shown to enhance PINK1/Parkin-dependent mitophagy, correct metabolic derangements, and improve cardiac performance in diabetic mice, with PINK1 knockdown abolishing its benefits (19). Empagliflozin mitigates I/R-induced endothelial swelling and lumen narrowing by activating the AMPKα1-ULK1-FUNDC1 axis, maintaining endothelial junction integrity, and attenuating mitochondrial fragmentation (96). GLP1 receptor agonists (GLP1-RAs), such as 6,7-Dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB), prevent post-MI remodeling by enhancing Parkin-mediated mitophagy. In wild-type but not Parkin-knockout mice, DMB improves cardiac function and reduces fibrosis, highlighting a Parkin-dependent mechanism (97). DPP-4 inhibitors also exhibit cardioprotective potential. Sitagliptin suppresses oxidative stress, restores mitochondrial function, and normalizes mitophagy by upregulating SIRT3. The knockdown of SIRT3 abolishes these effects, confirming its key role in H/R-induced injury protection (98). Together, these antidiabetic agents suggest that metabolic correction and mitophagy activation are intertwined therapeutic mechanisms in diabetic and ischemic cardiomyopathies.

Calcium channel blocker: diltiazem

Diltiazem hydrochloride (DIL) attenuates myocardial I/R injury by inhibiting excessive mitophagy. Mechanistically, it activates DUSP1 and suppresses JNK and NIX, thereby restraining overactivated mitophagic flux, improving cell survival, and reducing infarct size (99). This highlights the necessity of balanced mitophagy, where both its deficiency and excess are detrimental to cardiac recovery.

Vitamin D3 and melatonin

Vitamin D3 pretreatment protects against I/R-induced mitochondrial dysfunction by suppressing Drp1/Mff-mediated fission and BNIP3/LC3B-associated mitophagy, thereby preserving ATP production and mitochondrial morphology (100). Melatonin, administered either pre- or post-ischemia, activates melatonin receptor 2 to stabilize mitochondrial dynamics and prevent excessive mitophagy, improving post-I/R recovery independent of membrane receptor signaling (101). These findings suggest that antioxidant hormones may fine-tune mitophagy to protect mitochondrial integrity during reperfusion stress.

Traditional Chinese medicines (TCMs)

Several TCM formulations and natural compounds regulate mitophagy mainly via classical signaling axes (Table 9). Danqi Pill (DQP) enhances FUNDC1-mediated mitophagy through ULK1/PGAM5 to improve energy metabolism and cardiac function (102). Huangqi-Danshen Decoction (HDD) suppresses miR-27a-3p to activate AMPK/PINK1/Parkin signaling, improving myocardial remodeling (103). Nuanxinkang (NXK) promotes PINK1/Parkin-dependent mitophagy, ameliorating cardiac dysfunction (104). Yi Mai Granules (YMGs) induce miR-125a-5p/PINK1-Mfn2-Parkin signaling to restore endothelial function and mitigate AS (105). Xinmaikang (XMK) activates PINK1/Parkin to reduce oxidative stress and plaque formation (106). Ginsenosides (Rg1 and Rg3) activate SIRT1/PINK1/Parkin or ULK1/FUNDC1 signaling to relieve HF and PH (107-109). Mesaconine, rhein, irisin, and gastrodin promote mitophagy via the PINK1/Parkin or Drp1-PINK1 pathways, reducing fibrosis and myocardial injury (110-113). Collectively, these natural compounds offer multi-target, mitochondria-centered approaches for cardiovascular protection, but standardized pharmacokinetic and mechanistic validation is required.

Other mitophagy activators

Several synthetic and bioactive molecules, including GSK3β inhibitors, Dl-3-n-butylphthalide, dexpramipexole, L-carnitine, pitavastatin, sphingosylphosphorylcholine-containing exosomes, and corosolic acid, have been shown to activate PINK1/Parkin-mediated mitophagy across different models of cardiac injury, diabetic cardiomyopathy, and AS (114-120). These agents share a unifying mechanism—restoring mitochondrial clearance and function to improve cellular energy homeostasis.

Exercise-induced mitophagy: a non-pharmacological modality

Resistance training (RT) is considered an indispensable exercise mode in the rehabilitation of patients with HF. The European Society of Cardiology and the 2020 Journal of the American College of Cardiology guidelines recommend personalized RT as a part of cardiac rehabilitation for patients with HF. Studies have shown that regular physical exercise can enhance mitophagy and mitochondrial function (121). Exercise-induced mitophagy helps to maintain mitochondrial quality and to improve the heart’s resistance to stress, making regular exercise a non-pharmacological strategy for CVD management (122).

In chronic HF mice, RT and moderate-intensity continuous training was shown to improve contractility, morphology, and fibrosis more effectively than high-intensity interval training, by regulating HIF1α-Parkin-mediated mitophagy (123). Another study demonstrated that RT-induced irisin (FNDC5) activates the PINK1/Parkin-LC3/P62 axis, increases Opa1 expression, and mitigates oxidative stress in MI models (124). These results underscore the role of exercise as a physiological activator of mitophagy, offering safe, non-pharmacological cardioprotection.

Nanotherapeutics

Selenium-loaded porous silica nanospheres (Se@PSNs) represent a novel approach to MI therapy. By scavenging ROS and preserving mitochondrial integrity, Se@PSNs activate HIF-1α-dependent mitophagy, reduce infarct size, and improve post-MI cardiac function (125). This nanoplatform highlights the future potential of cardiac-targeted modulation of mitophagy via smart nanomaterials.

Future prospects

Although mitophagy-based therapeutic strategies for CVDs have shown encouraging progress, they remain largely exploratory. Further experimental validation is required, particularly regarding tissue-specific delivery, off-target effects, and long-term safety, while well-designed clinical trials are needed to establish their myocardial protective efficacy and translational value (126,127). Over the past five years, research has expanded beyond the canonical PINK1/Parkin pathway to uncover critical noncanonical mechanisms, including ULK1-Rab9-dependent alternative mitophagy (128), FUNDC1-mediated receptor pathways (129), and their context-dependent crosstalk, providing a more integrated framework linking mitophagy to metabolic, inflammatory, and hemodynamic cues in CVDs.

Future research should focus on several key directions. First, defining the dose–effect relationship and spatiotemporal dynamics of mitophagy activation is essential, as optimal thresholds vary across disease stages and CVD subtypes. Second, tissue- and cell-type specificity must be addressed, given the distinct roles of mitophagy in cardiomyocytes, endothelial cells, and VSMCs, to minimize off-target effects (130,131). Third, the development of cardiac-targeted nanocarriers and non-invasive quantitative tools, including multi-omics-based biomarkers such as circulating miRNAs and metabolites, will facilitate the real-time monitoring of mitophagy and therapeutic responses. Fourth, combinatorial strategies, such as integrating mitophagy modulation with FAO regulation or microenvironment-responsive delivery systems, may enhance efficacy while reducing systemic toxicity. Harnessing the plasticity of mitophagy could transform the treatment of CVDs characterized by mitochondrial dysfunction, including HF, myocardial I/R injury, and MC.

Conclusions

Mitophagy regulation in CVDs should shift from a simple enhancement–inhibition paradigm to a dynamic, context-dependent equilibrium tailored to disease subtype, cell type, and stage. With precise modulation strategies and personalized monitoring, mitophagy-based therapies have the potential to improve the prevention and treatment of mitochondrial dysfunction-driven CVDs, translating these mechanistic insights into clinical applications.

Acknowledgments

We would like to thank Dr. Bo Zhang for his help in polishing this manuscript.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-438/rc

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-438/prf

Funding: This study was funded by a grant from the National Science Foundation of China (No. 82100282).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-438/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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