mTORC1 is the more extensively studied of the two complexes and is a key regulator of cell growth and metabolism (Figure 1) (20, 21). It promotes protein synthesis by activating key effectors such as S6K1 (ribosomal protein S6 kinase 1) and 4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1), which control translation initiation and protein synthesis. mTORC1 also regulates lipid biosynthesis and autophagy, coordinating these processes with nutrient availability (21–25). One of the key mechanisms by which mTORC1 exerts its effects is through the regulation of the AMPK (AMP-activated protein kinase) pathway, which responds to cellular energy levels (26, 27). In states of nutrient deficiency or stress, AMPK is activated and inhibits mTORC1, promoting energy conservation through autophagy (28, 29).

A study demonstrated the role of mTORC1 in muscle growth and metabolism, showing that mTORC1 activity is a critical determinant of protein synthesis in muscle cells (30). Furthermore, mTORC1 activity has been shown to be regulated by the availability of amino acids, particularly leucine, which acts as a signal for mTORC1 activation to promote cell growth and proliferation (31, 32). This has significant implications in contexts like cancer, where excessive mTORC1 activation contributes to uncontrolled cell proliferation (Figure 1) (33, 34).

mTORC2, in contrast to mTORC1, primarily regulates cell survival, cytoskeletal organization, and metabolism, and its role is less well understood (35, 36). One of the key functions of mTORC2 is the phosphorylation of Akt, a central regulator of cell survival and metabolism (37). Akt activation promotes glucose uptake, inhibits apoptosis, and supports cell proliferation. mTORC2 also regulates the actin cytoskeleton, influencing cell shape and motility, which is particularly important in cancer metastasis and tissue regeneration (38, 39).

A recent study emphasized the role of mTORC2 in endothelial cell function, showing that mTORC2 inhibition leads to a reduction in vascular remodeling, indicating its critical involvement in endothelial cell survival and function in vascular diseases (40).Additionally, mTORC2-mediated phosphorylation of Akt has been implicated in the development of atherosclerosis, where it contributes to endothelial dysfunction and vascular inflammation (41, 42).

The mechanistic target of rapamycin (mTOR) plays a multifaceted role in the pathogenesis of CVDs, influencing cellular processes such as growth, metabolism, proliferation, and survival (43). mTOR is involved in regulating oxidative stress, inflammation, cell death, and vascular remodeling, all of which are crucial in the development and progression of CVDs (44, 45). Its activity, however, varies between different cardiovascular conditions, and dysregulation of mTOR signaling is associated with several pathological processes, including atherosclerosis, myocardial infarction, heart failure, and coronary artery disease (46).

In atherosclerosis, mTOR activation drives several processes contributing to plaque formation and instability (47). It promotes the proliferation and migration of vascular smooth muscle cells (VSMCs), facilitating the formation of the fibrous cap and contributing to plaque expansion (48). mTOR also influences endothelial cell function, increasing endothelial permeability and inducing oxidative stress, which exacerbates vascular inflammation and promotes foam cell formation (44, 49). Inflammatory cytokines, such as TNF-α, and factors like advanced glycation end products (AGEs) also contribute to mTOR activation, further enhancing the inflammatory environment within plaques (50, 51). This persistent activation of mTOR accelerates the development of atherosclerosis, increases plaque vulnerability, and contributes to plaque rupture, a key event in the pathogenesis of acute coronary events (52).

mTOR's role in myocardial infarction (MI) and heart failure is similarly complex (53, 54). After MI, mTOR signaling is involved in myocardial hypertrophy, fibrosis, and tissue remodeling (55). It promotes the production of extracellular matrix proteins, such as collagen, and inhibits autophagy, a process critical for clearing damaged cellular components (56). This results in increased fibrosis and scarring, impairing the heart's ability to regenerate and repair itself (56). While mTOR activation can initially promote hypertrophic responses in the myocardium as an adaptive mechanism to stress, prolonged activation contributes to pathological remodeling, including ventricular dilation and heart failure (57, 58). Moreover, excessive mTOR signaling can exacerbate ischemic injury by promoting oxidative stress and inflammation, which leads to further tissue damage (59).

In coronary artery disease (CAD), mTOR signaling is integral to the regulation of endothelial function, vascular tone, and smooth muscle cell behavior (Table 1) (60). mTOR modulates the response to oxidative stress in endothelial cells, contributing to endothelial dysfunction, a key early event in CAD (61). mTOR also plays a role in VSMC proliferation and migration, which are important in the development of neointimal hyperplasia following vascular injury (62). In this regard, mTOR regulates the expression of matrix metalloproteinases (MMPs) and other enzymes involved in extracellular matrix remodeling, leading to changes in vascular wall structure and increased susceptibility to rupture in atherosclerotic lesions (63, 64). Furthermore, the activation of mTOR in the context of CAD is associated with an imbalance in the vascular response to stress and injury, ultimately promoting the progression of the disease (65).

In heart failure, mTOR signaling also plays a pivotal role in the transition from compensatory hypertrophy to decompensated heart failure (Table 1) (80). Dysregulated mTOR activity has been implicated in the pathogenesis of heart failure with both reduced and preserved ejection fraction (HFrEF and HFpEF) (Table 1) (81, 82). In the failing heart, mTOR activation may increase oxidative stress, leading to mitochondrial dysfunction and contractile dysfunction (83, 84). mTOR's role in fibrosis, inflammation, and autophagy inhibition in the heart further accelerates cardiac remodeling, fibrosis, and loss of myocardial function (85).

Given mTOR's central role in the pathogenesis of these cardiovascular conditions, targeting this pathway holds significant therapeutic promise (Table 1) (86). However, mTOR functions as a complex hub that regulates multiple cellular processes, and its effects in CVDs are context-dependent (Table 1). While mTOR inhibition with rapamycin or other mTOR inhibitors has shown promise in preclinical models, clinical translation remains challenging due to the broad effects of mTOR on various cell types and tissues (87). Furthermore, as mTOR signaling has both protective and deleterious roles in different stages of CVDs, a more nuanced approach is required (88). Selective modulation of mTOR complexes (such as mTORC1 or mTORC2) or targeting downstream effectors may provide a more refined therapeutic strategy, potentially improving clinical outcomes by mitigating the adverse effects of excessive mTOR activation without compromising its beneficial roles in tissue repair and regeneration (Table 1).

In conclusion, mTOR is a pivotal regulator in the pathogenesis of CVDs, influencing numerous aspects of cardiovascular function (Table 1). A better understanding of the intricate mechanisms by which mTOR regulates oxidative stress, inflammation, and cell death will be critical for the development of targeted therapies (89). Tailoring mTOR inhibition or modulation to specific disease contexts, timing, and patient populations will be essential to maximize therapeutic benefits and minimize potential risks (90).

In order to better understand the distinct roles that mTORC1 and mTORC2 play in various cardiovascular diseases, the following table summarizes their respective mechanisms and effects across a range of conditions. This comparison highlights how mTOR signaling pathways contribute to disease progression and how differential activation of mTORC1 and mTORC2 could off.

PCD refers to tightly regulated cellular processes involving molecular pathways that orchestrate cell demise (94). Its various forms—such as apoptosis, autophagy-dependent cell death, ferroptosis, and pyroptosis—play distinct but interconnected roles in cardiovascular pathology (95).

Apoptosis, a caspase-mediated process, is pivotal in both acute and chronic cardiovascular injury (96). In myocardial infarction, ischemia-reperfusion injury triggers mitochondrial dysfunction and cytochrome c release, activating apoptotic cascades (97).Similarly, in atherosclerosis, the apoptosis of vascular smooth muscle cells weakens plaque stability, predisposing it to rupture and thrombosis (98).

Autophagy is primarily a survival mechanism, but excessive autophagy contributes to cell death under stress conditions, such as hypoxia or oxidative stress (99). In heart failure, dysregulated autophagy exacerbates cardiomyocyte loss and disrupts myocardial contractility, while in vascular diseases, impaired autophagic clearance leads to foam cell accumulation and plaque progression (100, 101).

Iron-dependent lipid peroxidation characterizes ferroptosis, which is distinct from other PCD modalities (102). This form of cell death is implicated in oxidative stress-driven endothelial dysfunction and vascular remodeling (103). For instance, ferroptosis accelerates smooth muscle cell depletion in aortic dissection, compromising vessel integrity and facilitating aneurysm formation (104).

Gasdermin-mediated pyroptosis serves as a pivotal nexus between cell death and inflammation (105). Activation of the NLRP3 inflammasome in macrophages triggers pyroptosis, leading to the release of pro-inflammatory cytokines and subsequent destabilization of atherosclerotic plaques (106). In the context of heart failure, pyroptosis amplifies myocardial inflammation, thereby exacerbating pathological cardiac remodeling (107).

Non-PCD encompasses unregulated, passive forms of cell death, including necrosis and lysosome-mediated cell death, which are frequently observed in acute tissue damage associated with CVDs (Table 2) (108).

Necrosis is characterized by membrane rupture and the uncontrolled release of intracellular contents, leading to secondary inflammation (115). In myocardial infarction, massive necrosis induced by prolonged ischemia activates inflammatory cascades, aggravating cardiac dysfunction (116). Additionally, necrotic core formation within atherosclerotic plaques promotes plaque instability, increasing the risk of rupture (Table 2) (117).

Lysosomal membrane permeabilization releases cathepsins and other hydrolytic enzymes into the cytosol, initiating cell death (118). In diabetic cardiomyopathy, lysosomal dysfunction exacerbates oxidative stress and lipid accumulation, driving myocardial damage (119). Similarly, in heart failure, impaired lysosomal clearance of damaged organelles contributes to proteotoxic stress and cardiomyocyte loss (120).

The interactions between PCD and non-PCD amplify cardiovascular damage, creating a feedback loop of inflammation and oxidative stress (121). For example, necrosis-derived damage-associated molecular patterns (DAMPs) not only exacerbate inflammatory responses but also trigger ferroptosis and pyroptosis, amplifying endothelial and myocardial injury (122, 123). Similarly, pyroptosis-induced cytokine release can aggravate necrotic cell death in vascular lesions, perpetuating plaque vulnerability (Table 2) (124).

The dichotomy and interplay between PCD and non-PCD underscore the complexity of cell death mechanisms in CVDs. Understanding these processes at a molecular level offers opportunities for developing therapeutic strategies to mitigate cardiovascular damage by targeting specific forms of cell death. Future research focusing on the crosstalk between these pathways may pave the way for novel, integrative treatments for cardiovascular diseases (Table 2). To better illustrate these mechanisms and their respective roles in CVDs, the following table provides a structured overview of both PCD and NPCD, emphasizing their pathophysiological implications in various cardiovascular conditions.

Programmed cell death (PCD) refers to a controlled process by which cells undergo death in response to specific signals (126). It includes various forms, such as apoptosis, autophagy, ferroptosis, and pyroptosis, each of which plays distinct roles in cardiovascular pathophysiology (127). mTOR is a key player in regulating PCD, acting as a switch that can either promote or inhibit these processes depending on the cellular context.

Non-programmed cell death, primarily represented by necrosis, is characterized by uncontrolled cell rupture and inflammation (126). While less regulated than PCD, necrosis is a significant driver of acute tissue injury in cardiovascular diseases, and mTOR plays a role in its regulation (140).

PMs represent a critical mechanism linking mTOR signaling to cell death pathways, serving as a dynamic regulatory bridge in CVDs (148). These modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, and glycosylation, orchestrate the balance between cell survival and death by modulating the activity, stability, and interactions of mTOR signaling components (149, 150).

Phosphorylation is one of the most extensively studied PMs in mTOR regulation (151). It enhances mTOR activity under physiological conditions but, when dysregulated, can trigger maladaptive responses such as apoptosis, ferroptosis, or pyroptosis (Table 3) (152). For instance, hyper-phosphorylation of mTOR and its downstream targets, such as p70S6 K or 4E-BP1, contributes to oxidative stress and cell death during ischemia-reperfusion injury (153, 154). Conversely, targeted inhibition of aberrant phosphorylation has been shown to mitigate myocardial damage in preclinical models (155).

Ubiquitination also plays a pivotal role in regulating mTOR signaling and cell death (Table 3) (163). K48-linked ubiquitination typically mediates proteasomal degradation, thereby suppressing mTOR activity, while K63-linked ubiquitination stabilizes the mTOR complex, promoting survival signals (164). Dysregulation of ubiquitination in conditions such as atherosclerosis exacerbates foam cell formation and apoptosis, destabilizing plaques and worsening disease progression (Table 3) (165, 166).

SUMOylation, a reversible PM involving the attachment of small ubiquitin-like modifiers, fine-tunes the activity of mTOR pathway components such as Raptor and TSC2 (167, 168). This modification can either promote autophagy during early stress adaptation or facilitate apoptosis under sustained oxidative stress (Table 3) (169). In VSMCs, SUMOylation influences phenotypic switching, playing a dual role in vascular remodeling and disease progression, as seen in aortic dissection and hypertension (170, 171).

Acetylation, another critical PM, regulates mTOR-mediated mitochondrial function and cardiomyocyte survival (Table 3) (172). For example, the acetylation status of mTOR targets can alter energy metabolism and redox balance during heart failure, while deacetylation therapies targeting the SIRT1-mTOR axis have shown potential in alleviating diabetic cardiomyopathy (173, 174).

Among the various PTMs involved in cardiovascular regulation of mTOR signaling, ubiquitination and acetylation are particularly well-characterized (175). Ubiquitination, mediated by E1 activating enzymes, E2 conjugating enzymes, and E3 ligases (such as FBXW7 and TRAF6), regulates mTOR complex stability and degradation (176, 177). K48-linked ubiquitination often targets mTORC1 components for proteasomal degradation, especially under stress conditions such as hypoxia or oxidative injury, leading to autophagy activation (178). In contrast, K63-linked ubiquitination may promote mTOR signaling under inflammatory conditions (179). Deubiquitinases (e.g., USP9X, OTUD7B) can stabilize mTOR and suppress cell death pathways (180, 181). Acetylation, catalyzed by enzymes such as p300/CBP or GCN5, modulates mTOR signaling by modifying upstream regulators (e.g., TSC2) or mTORC1 components (e.g., Raptor) (182). For instance, stress-induced acetylation of Raptor has been shown to enhance its interaction with mTOR, thereby suppressing autophagy (183). Conversely, deacetylases like SIRT1 can promote autophagy and inhibit apoptosis by deacetylating Atg proteins or FoxO transcription factors (184). These modifications often occur in a stimulus- and context-dependent manner, serving as rapid switches in the cellular response to cardiovascular injury.

These diverse PMs not only regulate mTOR activity but also mediate its downstream impact on cell fate, highlighting their therapeutic potential (185, 186). Pharmacological modulation of specific PMs has emerged as a promising approach to mitigate CVD progression (187). Drugs such as rapamycin derivatives (targeting phosphorylation), proteasome inhibitors (modulating ubiquitination), and SUMOylation inhibitors (e.g., TAK-981) have shown preclinical efficacy in restoring mTOR homeostasis and reducing pathological cell death (188).

In summary, protein modifications serve as a crucial bridge between mTOR signaling and cell death mechanisms, offering novel insights into the pathophysiology of CVDs. By targeting these modifications, innovative therapies could be developed to finely tune mTOR activity and improve cardiovascular outcomes.

The intricate interplay between PMs represents a fundamental mechanism in regulating mTOR-dependent cell death pathways (147). These modifications, including phosphorylation, ubiquitination, and SUMOylation, rarely act in isolation; instead, they form a dynamic network of cross-talk that orchestrates mTOR activity and downstream signaling (189). By influencing the stability, localization, and functional output of mTOR and its associated proteins, this cross-regulation ensures cellular adaptation to environmental stresses (190). Disruptions in this delicate balance, however, can drive pathological cell death processes, such as apoptosis and necrosis, contributing to the progression of CVDs (191, 192). Exploring the cooperative and antagonistic interactions among PMs unveils new therapeutic possibilities for targeting mTOR in CVDs.

Notably, several PTMs regulating mTOR also impact other key signaling pathways involved in cardiovascular pathogenesis (193). For example, K63-linked ubiquitination of TRAF6 can activate both mTORC1 and NF-κB signaling under inflammatory stress (194). Similarly, acetylation of STAT3 and mTOR by p300 under oxidative conditions promotes pro-hypertrophic gene expression and suppresses autophagy (195). These shared modifications reflect a level of multi-pathway integration in which PTMs serve as central regulatory nodes, coordinating diverse cellular outcomes in cardiovascular injury.

By influencing mTOR activity and its downstream signaling, specific PMs such as phosphorylation, ubiquitination, SUMOylation, and acetylation orchestrate the balance between cell survival and death (240). Dysregulation of these processes contributes to various CVDs, including atherosclerosis, myocardial infarction, heart failure, diabetic cardiomyopathy, and hypertension (241, 242).

In atherosclerosis, hyperactivation of the mTOR pathway exacerbates oxidative stress and foam cell apoptosis, destabilizing plaques and promoting vascular inflammation (243, 244). Phosphorylation of mTOR downstream effectors like p70S6 K and 4E-BP1 is often aberrant, driving endothelial dysfunction and VSMC phenotypic switching (245, 246). Concurrently, ubiquitination dysregulation modulates foam cell formation and inflammatory responses (247). Therapeutically, rapamycin and its derivatives, such as everolimus, mitigate these effects by attenuating mTOR phosphorylation (248).Proteasome inhibitors like bortezomib adjust the ubiquitination machinery, reducing foam cell apoptosis and stabilizing plaques (249, 250). These interventions highlight the potential of targeting mTOR-associated PMs to address the underlying pathology of atherosclerosis.

In ischemia-reperfusion injury (IRI) and myocardial infarction, the role of mTOR in cell death becomes evident through its modulation of apoptosis, necrosis, and ferroptosis (251, 252). SUMOylation of TSC2 during ischemia enhances mTOR activity, worsening oxidative stress and apoptotic signaling (Table 4) (253). Upon reperfusion, excessive phosphorylation of mTOR downstream proteins exacerbates inflammation, promoting cell death and myocardial dysfunction (254). Moreover, acetylation abnormalities impair mitochondrial function and energy metabolism, aggravating injury (Table 4) (255, 256). Interventions such as metformin, which activates AMPK and indirectly suppresses mTOR phosphorylation, have demonstrated cardioprotective effects by reducing apoptosis (257, 258). SUMOylation inhibitors like TAK-981 attenuate oxidative stress and protect mitochondrial integrity, while SIRT1 activators, including resveratrol, restore acetylation balance and metabolic homeostasis, reducing infarct size in preclinical studies (259, 260).

In chronic heart failure, aberrant PMs exacerbate pathological remodeling and cell death (Table 4) (267). Persistent mTOR overactivation, driven by excessive phosphorylation, leads to maladaptive cardiac hypertrophy and fibrosis (268). Ubiquitination dysregulation amplifies inflammatory cascades, while impaired acetylation compromises mitochondrial function and energy production (269). Rapamycin derivatives alleviate fibrosis by suppressing mTOR phosphorylation, whereas proteasome inhibitors adjust ubiquitination to curb inflammation and cell death (270). Additionally, acetylation modulators such as resveratrol enhance mitochondrial function, mitigating heart failure progression (271, 272).

Diabetic cardiomyopathy (DCM) exemplifies the interplay between metabolic derangements and PM dysregulation (Table 4) (273).In hyperglycemic conditions, disrupted ubiquitination destabilizes mTOR complexes, leading to heightened oxidative stress and apoptosis (274). Simultaneously, acetylation imbalance undermines mitochondrial function, exacerbating inflammation and fibrosis (275). Therapeutic agents like HDAC inhibitors (e.g., vorinostat) restore acetylation homeostasis and mitochondrial function, reducing inflammation in diabetic hearts (276). AMPK activators, including metformin, indirectly suppress mTOR hyperactivation and alleviate metabolic stress, improving cardiac outcomes in DCM models (Table 4) (277, 278).

Hypertension-induced vascular remodeling is another context in which PMs and mTOR dysregulation converge (Table 4) (279).Excessive SUMOylation in VSMCs drives their phenotypic switching, contributing to vascular stiffening and thickening (280). Additionally, hyperphosphorylation of mTOR effectors exacerbates endothelial dysfunction, increasing oxidative stress and apoptosis (281). Therapeutic strategies targeting these modifications, such as SUMOylation inhibitors to prevent VSMC phenotypic changes and rapamycin derivatives to curb mTOR hyperphosphorylation, show promise in mitigating vascular remodeling and improving vascular health (282, 283).

In summary, the intricate interplay between PMs, mTOR signaling, and cell death mechanisms highlights a promising therapeutic avenue for combating CVDs. Targeting specific PMs not only restores mTOR homeostasis but also addresses the underlying pathophysiological processes driving disease progression. Future research focusing on the development of PM-modulating drugs may unlock novel strategies to improve cardiovascular outcomes.

The growing understanding of protein modifications and mTOR signaling in cardiovascular diseases has paved the way for the development of targeted therapies (Table 5). Rapamycin and its analogs have demonstrated efficacy in reducing atherosclerotic plaque burden by modulating mTORC1 ubiquitination pathways (284). Meanwhile, histone deacetylase inhibitors that affect acetylation status of mTOR regulators show promise in limiting ischemia-reperfusion injury (285). These therapies focus on modulating key pathways, including mTOR inhibition, regulation of protein modifications, and attenuation of pathological cell death. The table below summarizes critical drugs, their mechanisms of action, and their clinical relevance in cardiovascular diseases (Table 5).

This table provides a comprehensive overview of the therapeutic landscape targeting protein modifications and mTOR signaling in cardiovascular diseases, emphasizing both established treatments and promising drug candidates.

Notably, several ongoing clinical trials support the translational relevance of targeting mTOR or PTM pathways in cardiovascular diseases (193). For instance, everolimus, an mTORC1 inhibitor, is being evaluated in patients with coronary artery disease via bioresorbable scaffolds (NCT03039751) (298). In addition, the HDAC inhibitor vorinostat, which affects protein acetylation, is under investigation in ischemic heart conditions for its potential to modulate myocardial remodeling (NCT02455034) (299). These studies highlight the clinical momentum toward PTM- and mTOR-based therapies in CVD.

Despite the promising advances in targeting mTOR signaling and PTM pathways for cardiovascular disease treatment, several translational hurdles remain (300). A key concern is the lack of tissue and cell-type specificity of many mTOR inhibitors and PTM modulators, which may lead to off-target effects such as metabolic imbalance, immune suppression, or unintended cell death in non-target tissues (301). Additionally, the intracellular delivery of these agents is often inefficient, particularly for compounds targeting specific protein modifications that require nuclear or organelle-level access (302). Conventional systemic administration may result in suboptimal bioavailability and dose-limiting toxicity. Furthermore, the temporal dynamics of PTMs pose a challenge, as modulating transient or reversible modifications in vivo requires precise control (303). Overcoming these obstacles will require improved delivery systems (e.g., nanoparticle carriers or tissue-specific vectors), enhanced selectivity of inhibitors, and deeper understanding of context-dependent mTOR–PTM–cell death networks in various CVD settings (193).