Adenosine triphosphate homeostasis in cardiovascular cell-fate transitions: Adenosine triphosphate-induced cellular senescence and adenosine triphosphate-induced cell death

Abstract

This narrative review examines adenosine triphosphate (ATP) homeostasis as a context-dependent framework linking cellular energy metabolism, stress responses, and cell-fate regulation in the cardiovascular system. Intracellular ATP is closely related to mitochondrial oxidative phosphorylation, glycolysis, and cellular energy demand, whereas extracellular ATP serves as an important signal in purinergic communication. Changes in ATP production, utilization, release, and clearance may therefore influence how cardiovascular cells respond to metabolic and pathological stress. When these changes persist, they may be associated with senescence-related alterations or, under more severe conditions, with irreversible cell injury and death. In this review, ATP-induced cellular senescence and ATP-induced cell death are used to describe these ATP-associated cell-fate changes. They are not intended to replace established mechanisms of cellular senescence or regulated cell death. Current evidence is predominantly preclinical and heterogeneous across experimental models, cell types, ATP compartments, and disease contexts, and a defined ATP threshold separating adaptation, senescence, and cell death has not been established. The biological consequences of ATP disturbance are likely to depend on ATP compartment, cell type, disease stage, and the intensity and duration of stress. Further studies that directly measure ATP together with mitochondrial function and cell-fate changes will be important for determining the role of ATP homeostasis in cardiovascular disease.

Key Words: Adenosine triphosphate homeostasis; Cardiovascular disease; Cellular senescence; Regulated cell death; Purinergic signaling

Core Tip: Adenosine triphosphate (ATP) homeostasis provides an integrative framework for understanding cardiovascular cell-fate transitions by linking energy metabolism, mitochondrial function, and purinergic signaling. By distinguishing intracellular bioenergetic ATP from extracellular purinergic ATP, this review examines how ATP production, utilization, release, and clearance may shape cellular responses from reversible adaptation to senescence-associated phenotypes and regulated cell death. ATP-induced cellular senescence and ATP-induced cell death are used to describe ATP-associated cell-fate changes rather than distinct biological categories. This perspective highlights compartment-specific ATP regulation as an important area for clarifying cardiovascular disease mechanisms and for evaluating the potential translational relevance of ATP-associated metabolic regulation.

INTRODUCTION

The progression of cardiovascular disease involves complex interactions among energy metabolism, mitochondrial function, stress signaling, and cell-fate regulation rather than disruption of a single pathway. Adenosine triphosphate (ATP) is therefore more than an intracellular energy currency; changes in ATP homeostasis are closely associated with cardiovascular cell adaptation, senescence, and death[1-3]. Intracellular and extracellular ATP represent distinct but interconnected regulatory pools. Intracellular ATP reflects cellular bioenergetic status and is mainly maintained by mitochondrial oxidative phosphorylation and glycolysis, whereas extracellular ATP functions as a signaling molecule that regulates cellular responses through purinergic receptors[4-6]. These two ATP pools should be considered separately when interpreting changes in ATP production, utilization, release, and clearance. In particular, extracellular ATP released within injured tissues may differ substantially from circulating ATP and should be interpreted according to its spatial and pathological context. Extracellular ATP-P2X7R signaling has been implicated in several cell-death-related processes, although its contribution varies across cell types and experimental settings[7]. In myocardial ischemia–reperfusion injury, RBM15-mediated upregulation of CD39 enhances extracellular ATP hydrolysis and is associated with reduced myocardial injury[8]. By contrast, LETM1 dysregulation in cardiomyocytes impairs oxidative phosphorylation and ATP generation and is accompanied by mitochondrial dysfunction and cellular injury[9]. These observations illustrate two distinct aspects of ATP homeostasis—extracellular ATP turnover and intracellular bioenergetics—rather than a single linear mechanism. Together, they indicate that ATP production, utilization, release, and clearance need to be considered collectively when examining ATP-associated changes in cardiovascular cells. Under physiological or transient stress conditions, ATP homeostasis supports cellular adaptation and recovery. Persistent ATP disturbance, however, may accompany the development of senescence-associated phenotypes or regulated cell death[10-12]. In this review, ATP-induced cellular senescence (AICS) and ATP-induced cell death (AICD) are used to describe these ATP-associated cell-fate states. From this perspective, ATP homeostasis provides a context-dependent framework for examining cardiovascular cell-fate transitions. The outcome is likely to depend on the ATP compartment involved, cell type, disease context, and the intensity and duration of stress, rather than on a single ATP concentration or universal threshold.

Extracellular ATP-P2X7R-NLRP3 signaling is one well-described route linking purinergic stimulation to inflammasome activation and inflammatory cell injury, although much of the supporting evidence extends beyond cardiovascular models[13]. Cardiovascular ATP biology is broader and also includes mitochondrial ATP production, energetic demand, ATP release, and extracellular ATP degradation[8,14,15]. The specific question addressed in this minireview is therefore whether evidence from cardiovascular models can be organized into a compartment-specific framework that relates ATP-associated metabolic states to adaptation, persistent senescence-associated phenotypes, and regulated cell death. The proposed framework differs from an ATP-P2X7R-NLRP3-centered model by separating intracellular bioenergetic failure from extracellular purinergic signaling and by treating their apparent convergence as a hypothesis to be tested rather than an established linear sequence[16,17]. Accordingly, the framework does not assume a universal ATP threshold or a fixed temporal sequence linking adaptation, senescence-associated phenotypes, and regulated cell death.

LITERATURE SEARCH STRATEGY

A narrative literature search was performed in PubMed, Web of Science, and Scopus and was last updated on August 2026. Representative search combinations included: (“ATP homeostasis” OR “intracellular ATP” OR “extracellular ATP” OR “ATP/ADP”) AND (“cardiovascular disease” OR cardiomyocyte OR myocardium OR endothelium OR “vascular smooth muscle”) AND (senescence OR “regulated cell death” OR apoptosis OR pyroptosis OR ferroptosis OR mitochondria OR P2X7). The final evidence set predominantly comprised English-language, peer-reviewed articles. Primary cell and animal studies were prioritized for mechanistic interpretation whenever available, whereas human studies were included primarily to provide measurement or translational context. For mechanistic interpretation, studies that directly measured or experimentally manipulated ATP were given greater evidential weight than studies reporting only indirect mitochondrial, metabolic, oxidative, or purinergic correlates. Reviews were used mainly to frame background concepts and to identify primary literature. Conference abstracts and preprints were not used as primary mechanistic support, corrections/corrigenda and commentaries were replaced by the corresponding original studies where possible, and retracted articles were excluded. Reference lists of key reviews and relevant primary studies were also screened. The literature search and selection process was independently checked by two authors to verify the relevance of the selected studies and the consistency of key mechanistic interpretations with the reported findings. Because this was a narrative rather than systematic review, study selection was purposive and no formal risk-of-bias instrument or exhaustive screening flow was applied; selective-citation bias therefore remains possible. Accordingly, the review is intended to provide a structured conceptual synthesis rather than an exhaustive or quantitatively weighted evidence assessment. Table 1 is a selective, representative evidence matrix rather than a comprehensive evidence map[8,9,18-25]. Evidence was interpreted according to whether ATP was directly measured or manipulated, whether the reported link was pathway-associated or causal, and whether the model was cellular, animal, or human.

Table 1 Experimental evidence linking ATP regulation to cardiovascular cell-fate transitions.

Cell type	Disease model/stress context	ATP compartment measured	Direction of ATP alteration	Representative mechanism	Cell-fate outcome	Evidence of causality	Level of evidence	Ref.
Cardiomyocytes	Myocardial ischemia/reperfusion injury	Extracellular ATP	↑ Extracellular ATP accumulation due to impaired degradation	RBM15-mediated m6A modification increases Entpd1/CD39 expression and enhances extracellular ATP hydrolysis	Reduced myocardial injury and improved cardiac protection	CD39 upregulation decreases extracellular ATP accumulation and alleviates ischemia–reperfusion injury	Animal experimental evidence with molecular intervention	[8]
Cardiomyocytes	Mitochondrial dysfunction and oxidative stress	Intracellular ATP	↓ Intracellular ATP generation	LETM1 dysregulation impairs oxidative phosphorylation and mitochondrial function	Cardiomyocyte stress, apoptosis, and impaired mitochondrial homeostasis	Restoration of mitochondrial function improves cellular survival	Cellular experimental evidence	[9]
Cardiomyocytes	Myocardial injury and ischemic stress	Extracellular ATP	↑ Extracellular ATP release	PANX1-mediated ATP release activates purinergic signaling involving P2X7-related pathways	Cardiomyocyte injury, apoptosis, and inflammatory remodeling	PANX1/P2X7 pathway interference attenuates injury-associated responses	Cellular and animal mechanistic evidence	[18]
Cardiac macrophages and cardiomyocytes	Hepatic ischemia–reperfusion-induced remote cardiac injury	Circulating extracellular ATP	↑ Circulating ATP	Extracellular ATP activates macrophage P2X7 receptor, inducing NLRP3 inflammasome assembly and GSDMD-dependent pyroptosis	Cardiomyocyte pyroptosis and cardiac dysfunction	P2X7 inhibition, macrophage depletion, and pathway interference reduce cardiac injury	Animal model with mechanistic validation	[19]
Cardiomyocytes	Hypoxia/reoxygenation injury	Intracellular ATP-associated mitochondrial metabolism	↓ ATP availability associated with mitochondrial dysfunction	Mitochondrial stress causes ROS accumulation, antioxidant defense impairment, and lipid peroxidation	Ferroptotic cell death	Mitochondrial protective intervention restores metabolic function and reduces ferroptosis markers	Cellular experimental evidence	[20]
Cardiomyocytes	5-Fluorouracil-induced myocardial injury	Intracellular ATP	↓ Mitochondrial ATP production	Mitochondrial injury and impaired autophagic quality control reduce bioenergetic capacity	Cardiomyocyte apoptosis and myocardial fibrosis	Mitochondrial protection reduces myocardial injury phenotype	Animal experimental evidence	[21]
Cardiomyocytes	Cardiac aging and senescence	Intracellular ATP	↓ ATP availability associated with energetic dysfunction	Disruption of ATP synthase organization and impaired Ca²+ handling impair cellular energetics	Senescence-associated phenotype and contractile dysfunction	ATP synthase disruption correlates with senescence-associated dysfunction	Experimental cellular and animal evidence	[22]
Vascular smooth muscle cells	Aging-related vascular calcification	Intracellular ATP and mitochondrial homeostasis	↓ Mitochondrial ATP generation	SIRT1/PGC-1α/Mfn2-associated mitochondrial dysfunction affects energy metabolism	Cellular aging and vascular remodeling	Pathway modulation improves mitochondrial homeostasis	Animal and molecular experimental evidence	[23]
Cardiomyocytes	Myocardial infarction and cardiovascular remodeling	Extracellular ATP signaling	↑ Extracellular ATP-dependent signaling	ATP-P2X7 receptor activation promotes inflammatory signaling and NLRP3-related responses	Pyroptosis, fibrosis, and cardiac dysfunction	P2X7 inhibition or pathway blockade improves cardiac phenotype	Experimental animal and molecular evidence	[24]
Cardiovascular tissues/endothelium	Hypertension, atherosclerosis, and vascular inflammation	Extracellular ATP signaling	↑ Extracellular ATP signaling activity	P2X7 activation promotes inflammatory cytokine production, oxidative stress, and vascular remodeling	Endothelial dysfunction and vascular remodeling	P2X7 inhibition reduces inflammatory cardiovascular injury	Experimental and translational evidence	[25]

ATP: Adenosine triphosphate; ROS: Reactive oxygen species; NLRP3: NOD-like receptor family pyrin domain-containing 3.

AICS AS A DYNAMIC STRESS-ASSOCIATED STATE IN CARDIOVASCULAR INJURY

In this review, AICS is used as a descriptive term for a persistent senescence-associated phenotype occurring in the setting of demonstrable disturbance of ATP metabolism or ATP-related signaling. For the purposes of this review, an AICS-like state is considered to involve an ATP-related alteration together with persistent senescence features, such as stable cell-cycle arrest and established senescence-associated markers; stronger mechanistic evidence would require direct manipulation of ATP availability or ATP-regulatory machinery accompanied by corresponding changes in the senescence phenotype. AICD is used analogously to describe regulated cell death associated with directly measured or experimentally perturbed ATP dysregulation, including intracellular bioenergetic failure or extracellular ATP-related signaling[10,26]. These terms are proposed as working concepts for organizing ATP-associated cardiovascular cell-fate transitions rather than as new biological entities, and they do not replace established criteria for cellular senescence or regulated cell-death pathways. By contrast, an ATP-associated adaptive state refers here to a reversible metabolic response in which cellular energetic and stress responses remain compensable without persistent senescence-associated features or execution of regulated cell-death programs.

Currently, ATP homeostasis is considered an important component of energy availability regulation in the cardiovascular injury microenvironment, helping to maintain cellular energetic stability and limit progression toward irreversible stress-associated phenotypes[27-29]. Mechanistically, ATP imbalance may interact with canonical senescence pathways, including DNA damage response activation, p53/p21 signaling, p16/Rb-mediated cell-cycle arrest, mitochondrial dysfunction-associated senescence, and SASP regulation. The precise role of ATP dysregulation as either an upstream trigger or a downstream metabolic consequence of these pathways depends on the cellular and disease context[16,30]. ATP availability is closely linked to mitochondrial membrane potential, Ca²⁺ and proteostatic homeostasis, redox balance, and mitochondrial dynamics. In vascular pathology, Elabela has been reported to attenuate cuproptosis and vascular calcification through PPAR-γ/FDX1 signaling in vitamin D3-overloaded mice[31]. This finding supports an association between mitochondrial stress-related pathways and vascular injury, but it should not be interpreted as direct evidence that Elabela prevents cellular senescence by restoring ATP homeostasis. In senescent cardiomyocytes, ATP synthase disorganization, altered Ca²⁺ dynamics, and impaired contractile function have been reported[22]. Taken together, the available evidence supports an association among mitochondrial dysfunction, ATP-related bioenergetic alterations, and senescence-associated cardiovascular phenotypes, while the direction and causal contribution of ATP dysregulation require direct experimental validation. Combined doxorubicin and ionizing radiation exposure has been associated with persistent p90RSK–ERK5/PARP activation, NAD⁺/ATP depletion, mitochondrial dysfunction, and SASP-related reprogramming in myeloid cells[32]. These findings suggest a potential mechanistic link between therapy-induced metabolic injury and longer-term cardiovascular complications. Overall, ATP homeostasis may represent an important metabolic dimension associated with the balance between reversible adaptation and persistent senescence-associated phenotypes in cardiovascular cells, as illustrated conceptually in Figure 1.

Figure 1 Adenosine triphosphate homeostasis, metabolic adaptation, and senescence-associated changes in cardiovascular injury. Cardiovascular stress alters cellular energetics together with mitochondrial function, Ca²⁺ handling, redox balance, and proteostasis. During sustained stress, impaired adenosine triphosphate (ATP) homeostasis can accompany mitochondrial dysfunction and oxidative and Ca²⁺ disturbances, whereas prolonged metabolic dysfunction is associated with senescence-related changes, including stable cell-cycle arrest and SASP activity. ATP disturbance may occur upstream or downstream of these processes, and the sequence is unlikely to be uniform across cardiovascular cell types. The figure therefore summarizes the proposed relationships among ATP homeostasis, metabolic adaptation, and senescence-associated remodeling rather than defining a fixed pathway or ATP threshold. ATP: Adenosine triphosphate; Ca²⁺: Calcium ion; NAD⁺: Nicotinamide adenine dinucleotide; PARP: Poly(ADP-ribose) polymerase; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype.

ATP DYSREGULATION AND REGULATED CELL DEATH IN CARDIOVASCULAR INJURY

As illustrated in Figure 2, sustained or severe ATP dysregulation may accompany progression from compensatory stress responses toward regulated cell death under specific cardiovascular conditions. Bioenergetic failure, extracellular purinergic signaling, mitochondrial dysfunction, and oxidative stress may contribute to different regulated cell-death pathways, although their relative importance and temporal relationships vary across cell types and experimental models[33,34]. Evidence from post-myocardial-infarction remodeling links PANX1 with P2RX7/amphiregulin signaling and cardiac fibrosis[18]. In a separate experimental context, extracellular ATP can be sensed by cardiac macrophages through P2X7 receptors, leading to NLRP3 inflammasome assembly and GSDMD-dependent pyroptosis and identifying P2X7 as a potential regulatory node for inflammatory cell death[19]. Concurrently, hypoxia-reoxygenation cardiomyocyte studies provide evidence of mitochondrial oxidative injury and ferroptosis-related changes[20], but these endpoints should not be treated as interchangeable with direct ATP measurements. Taken together, these findings suggest that disturbances in intracellular bioenergetics and extracellular ATP signaling may intersect with pyroptotic, apoptotic, or ferroptotic processes under specific cardiovascular conditions; however, the available studies do not establish these pathways as components of a single ATP-driven sequence.

Figure 2 Adenosine triphosphate dysregulation and regulated cell-death pathways in cardiovascular injury. Cardiovascular stress disrupts cellular energy metabolism, mitochondrial function, and extracellular adenosine triphosphate (ATP) signaling, potentially contributing to distinct regulated cell-death pathways. A: Apoptosis in cardiomyocytes: Hypoxia/reoxygenation-associated stress promotes pannexin 1 (Panx1)-mediated extracellular ATP release and purinergic signaling, accompanied by mitochondrial dysfunction, cytochrome c release, and caspase-3 activation, which are associated with cardiomyocyte apoptosis. B: Pyroptosis in cardiac macrophages: Extracellular ATP activates the P2X7 receptor (P2X7R), promoting NLRP3 inflammasome assembly, caspase-1 activation, maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), and gasdermin D (GSDMD)-mediated pyroptosis. C: Ferroptosis in cardiomyocytes: Sustained oxidative stress and mitochondrial dysfunction are associated with impaired antioxidant defenses, including reduced glutathione peroxidase 4 (GPX4) activity and glutathione (GSH) availability, leading to lipid peroxidation and ferroptotic cell death. Together, these pathways illustrate the potential convergence of bioenergetic impairment, purinergic inflammation, and mitochondrial oxidative stress in cardiovascular injury and pathological remodeling. These pathways are presented as distinct, context-dependent mechanisms rather than consecutive stages of a single ATP-driven process. ASC: Apoptosis-associated speck-like protein containing a caspase recruitment domain; ATP: Adenosine triphosphate; GPX4: Glutathione peroxidase 4; GSDMD: Gasdermin D; GSH: Glutathione; I/R: Ischemia/reperfusion; IL-1β: Interleukin-1 beta; IL-18: Interleukin-18; NLRP3: NOD-like receptor family pyrin domain-containing 3; Panx1: Pannexin 1; P2X7R: Purinergic receptor P2X7; ROS: Reactive oxygen species; ΔΨm: Mitochondrial membrane potential.

Other regulated cell-death modalities may intersect with cellular energetics. For example, mitochondrial ATP synthesis impairment has been associated with RIPK3-dependent necroptosis in non-cardiovascular experimental systems[35]. However, such observations should not be extrapolated directly to cardiovascular AICD without cardiovascular-specific evidence.

ATP HOMEOSTASIS AND CARDIOVASCULAR CELL-FATE TRANSITIONS: A PROPOSED INTEGRATIVE FRAMEWORK

ATP homeostasis not only reflects cellular energy metabolism but may also be associated with context-dependent metabolic states that influence cellular adaptation, senescence, or death responses. These metabolic states integrate functional processes into an adaptive-maladaptive network underlying chronic cardiovascular dysfunction rather than isolated acute injury[1,36]. Importantly, intracellular ATP depletion and extracellular ATP accumulation represent distinct but interconnected processes. Intracellular ATP mainly reflects mitochondrial oxidative phosphorylation, glycolytic metabolism, and cellular energy availability; conversely, extracellular ATP functions as a signaling molecule involved in purinergic receptor activation, including P2X7-mediated inflammatory responses[37,38]. Therefore, their integration within the ATP homeostasis framework represents functional convergence rather than biological equivalence.

The biological consequences of ATP perturbation are highly dependent on cardiovascular cell identity[16,39,40]. Cardiomyocytes rely predominantly on mitochondrial oxidative phosphorylation and are particularly vulnerable to ATP depletion during acute stress, whereas vascular smooth muscle cells and endothelial cells display additional metabolic adaptations involving mitochondrial dynamics, glycolysis, and inflammatory signaling. Fibroblasts and immune cells may exhibit prominent responses to extracellular ATP through purinergic sensing and inflammatory signaling pathways[37,41]. Hence, the ATP homeostasis framework proposed here should be interpreted as a cell-type-dependent model rather than a universal mechanism across all cardiovascular populations. Acute cardiovascular injury and chronic remodeling represent distinct metabolic contexts. Rapid ATP depletion and mitochondrial dysfunction are prominent features associated with acute cardiomyocyte injury and death during ischemia-reperfusion injury or chemotherapy-induced cardiotoxicity[28,42]. In comparison, sustained metabolic adaptation coupled to prolonged inflammatory activation and senescence-associated changes in chronic heart failure and vascular remodeling may contribute to sustained ATP dysregulation and progressive tissue remodeling. Recent therapeutic studies targeting mitochondrial dysfunction and metabolic remodeling have highlighted the potential of restoring bioenergetic homeostasis in cardiovascular disease, although the precise relationship between these approaches and ATP homeostasis remains to be further clarified[15,43].

Mitochondrial ATP generation failure may occur early during drug- or toxin-induced cardiovascular injury. Beyond absolute ATP deficiency, cardiovascular cell fate may depend on whether ATP availability remains within an adaptive range or exceeds cellular compensatory capacity. Indeed, 5-fluorouracil decreases mitochondrial ATP levels and membrane potential in myocardial tissue and enhances fibrosis and cardiomyocyte apoptosis[21]. Chronic derangement of mitochondrial dynamics can aggravate ATP deficiency and increase reactive oxygen species (ROS), which in turn leads to accelerated cardiomyocyte senescence and the development of heart failure[44]. Concurrently, aberrant IGF1R signaling in post-maturity is associated with impaired autophagic flux and oxidative phosphorylation, limiting the degradation of dysfunctional organelles (e.g., mitochondria)[45]. Together, these observations provide evidence to support a unifying model wherein defective autophagy promotes the accumulation of dysfunctional mitochondria and oxidative stress, contributing to progressive bioenergetic dysfunction and maladaptive cardiac remodeling[46]. Under conditions of sustained or severe ATP dysregulation, cardiovascular cells may shift from compensatory responses toward persistent senescence-associated phenotypes or regulated cell-death programs, depending on cell type and pathological context, as shown in Figure 3. Nonetheless, whether ATP imbalance serves as an initiating determinant or a consequence of cellular stress remains context dependent and requires further experimental validation.

Figure 3 A conceptual framework linking adenosine triphosphate homeostasis disruption to cardiovascular cell-fate transitions and pathological remodeling. The potential importance of adenosine triphosphate (ATP) homeostasis is proposed as an integrative metabolic framework influencing the cell-fate trajectories in cardiovascular cells. Under physiological conditions, adequate ATP availability supports mitochondrial function, organelle quality control and cellular compensatory capacity. Different pathological insults, including drug/toxin treatment, mitochondrial dynamics imbalance, and autophagy dysfunction, may be associated with ATP homeostasis disruption together with mitochondrial damage, oxidative stress, and impaired organelle clearance. Persistent ATP dysregulation accompanying failure of metabolic adaptation is proposed to be associated with persistent senescence-associated phenotypes, maladaptive remodeling, and regulated cell-death programs. In this framework, ATP homeostasis is positioned as an integrative metabolic framework that links metabolic derangements with cardiovascular remodeling across disease progression. ATP: Adenosine triphosphate; DRP1: Dynamin-related protein 1; IGF1R: Insulin-like growth factor 1 receptor; OXPHOS: Oxidative phosphorylation; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype; ΔΨm: Mitochondrial membrane potential.

THERAPEUTIC IMPLICATIONS AND FUTURE DIRECTIONS

Building on the proposed framework, ATP homeostasis may provide a useful metabolic perspective for evaluating therapeutic interventions that influence cardiovascular bioenergetics and cell-fate responses, rather than serving simply as a target for energy replenishment. Restoration of ATP homeostasis may therefore contribute to preserving mitochondrial bioenergetic capacity during drug- or toxin-induced injury[47]. In doxorubicin-treated H9c2 cardiomyoblasts, gypenosides maintained mitochondrial membrane potential and enhanced cell viability, ATP production, and basal oxygen consumption[48]. These findings suggest that future approaches to ischemia–reperfusion injury may benefit from jointly considering mitochondrial structural preservation and bioenergetic recovery. Hyperoside induces mitochondrial fusion through the Tom70-OPA1 axis, while GJA1 activates ATP production and oxidative phosphorylation, stabilizes mitochondrial membrane potential and initiates mitophagy[49,50]. Accordingly, these compounds may be viewed as indirect modulators of ATP-associated bioenergetic processes rather than as direct ATP-targeting agents[51]. ATP homeostasis may therefore provide a conceptual framework for evaluating how metabolic interventions influence senescence-associated, cytoprotective, and myocardial injury-related processes. Nevertheless, therapeutic restoration of ATP homeostasis should not be interpreted as simply increasing ATP abundance. In particular, extracellular ATP-P2X7 signaling may contribute to maladaptive purinergic responses and cellular injury under specific pathological conditions[41]. Future studies should therefore determine whether restoring the balance among ATP production, utilization, release, and clearance is more beneficial than simply increasing ATP availability.

DISCUSSION

ATP homeostasis may provide a useful framework for interpreting context-dependent metabolic states associated with cardiovascular senescence-related phenotypes and regulated cell death, but current evidence does not establish ATP dysregulation as a sufficient or universal determinant of these outcomes. Rh2 has been reported to enhance mitochondrial membrane potential and ATP production while reducing ROS accumulation, excessive mitochondrial fission, and cardiomyocyte apoptosis in myocardial infarction models[52]. These findings suggest that preservation of mitochondrial bioenergetic function may be associated with reduced cardiomyocyte injury, although they do not establish restoration of ATP as the causal driver of the observed cell-fate effects. Conversely, adipocyte-derived extracellular vesicles released under lipotoxic conditions reduce mitochondrial respiration and ATP production and activate intrinsic apoptotic signaling in cardiomyocytes[53]. However, these findings do not establish reduced ATP production as the causal mediator of the observed apoptotic response. In addition, the SIRT1-PGC-1α axis regulates both ATP release and ROS-induced apoptosis in vascular smooth muscle cells, highlighting the need to distinguish between intracellular bioenergetic status and extracellular purinergic signaling[23]. Establishing whether distinct ATP-associated metabolic states or quantitative boundaries exist will require approaches integrating ATP/ADP ratio measurements, mitochondrial oxygen consumption analysis, extracellular flux assays, ROS profiling and temporal metabolic tracing[54,55]. Such approaches may provide clarity on whether specific ATP-associated states constitute adaptive responses, senescence-associated phenotypes, or irreversible cell death. Future studies should determine how ATP-associated metabolic states influence, or are influenced by, senescence-associated and cell-death signaling pathways through temporal and cell-type-specific profiling as well as interventions targeting ATP dysregulation-associated stress responses.

Direct human evidence linking quantitative ATP disturbance to defined cardiovascular cell-fate transitions remains limited. No clinically validated intracellular or extracellular ATP threshold currently distinguishes reversible adaptation, persistent senescence-associated phenotypes, and regulated cell death in cardiovascular disease. In addition, ATP measurements are highly compartment- and method-dependent. Intracellular ATP measurements generally reflect cellular or tissue bioenergetic status, whereas extracellular ATP concentrations are influenced by local release, ectonucleotidase activity, sample handling, platelet activation, and cell disruption. Circulating ATP concentrations therefore cannot be assumed to represent ATP levels within injured cardiovascular tissues. Future translational studies should combine compartment-specific ATP or ATP/ADP measurements with mitochondrial functional indices, validated cell-fate markers, temporal sampling, and clinically relevant cardiovascular phenotyping before ATP-associated metabolic states can be considered for biomarker development or therapeutic stratification.

CONCLUSION

ATP homeostasis links cellular energy metabolism with stress responses and cell-fate regulation in the cardiovascular system. Changes in intracellular ATP availability reflect alterations in mitochondrial and glycolytic function, whereas extracellular ATP participates in purinergic and inflammatory signaling. Disturbance of these interconnected processes may influence whether cardiovascular cells remain within an adaptive state or progress toward persistent senescence-associated phenotypes and irreversible cell death. From this perspective, AICS and AICD provide a useful conceptual framework for describing ATP-associated changes in cardiovascular cell fate, but should not be regarded as substitutes for established mechanisms of cellular senescence or regulated cell death. Current evidence remains predominantly preclinical and heterogeneous across experimental models, cardiovascular cell types, ATP compartments, and pathological contexts. It does not yet establish ATP dysregulation as a universal causal determinant of these transitions, nor is there a defined ATP threshold separating adaptation, senescence, and death. The biological outcome is likely to vary with ATP compartment, cell type, disease stage, and the intensity and duration of stress. Future work should therefore determine the temporal relationship between ATP disturbance and cell-fate signaling and establish whether restoring ATP homeostasis can modify disease progression. Importantly, therapeutic strategies should aim to restore the balance of ATP production, utilization, release, and clearance rather than simply increase ATP levels. This distinction will be important for determining the mechanistic and translational relevance of ATP-associated metabolic regulation in cardiovascular disease.