Atherosclerosis is a chronic inflammatory vascular disease that begins with endothelial cell dysfunction. Endothelial cells act as the first line of defense in the vascular wall, playing a key role in maintaining vascular homeostasis. They regulate vascular tone, suppress inflammation, and prevent thrombosis. However, under risk factors such as hemodynamic changes, hypercholesterolemia, hypertension, diabetes, and smoking, endothelial cells transition from an anti-inflammatory and anticoagulant state to a pro-inflammatory and pro-thrombotic state. This process, termed endothelial dysfunction and activation, represents the initial step in atherosclerosis (13). Here, we explore the molecular mechanisms of endothelial dysfunction in atherosclerosis, focusing on reduced nitric oxide bioavailability, upregulation of adhesion molecules and chemokines, as well as endothelial cell apoptosis and endothelial-mesenchymal transition.

Atherosclerosis is a chronic inflammatory vascular disease, and its progression is closely linked to lipid metabolism disorders. The retention and modification of lipids, particularly low-density lipoprotein (LDL), within the arterial wall represent a central event in atherogenesis. This process involves not only classical mechanisms such as lipoprotein oxidation and foam cell formation but also emerging perspectives like metabolomics and organelle function. Therefore, elucidating these mechanisms is essential for a comprehensive understanding of atherosclerosis.

Atherosclerotic plaques are not merely lipid accumulations but highly complex immune microenvironments. Innate and adaptive immune responses interact via intricate cellular and molecular networks, collectively driving disease onset and progression (Figure 2). Deeply elucidating these immune mechanisms is essential for developing novel prevention and treatment strategies.

Atherosclerosis is a chronic vascular condition characterized by arterial wall thickening, hardening, and loss of elasticity. Its pathogenesis involves complex interactions among multiple cellular and molecular events. Vascular smooth muscle cells (VSMCs), as the primary cellular component of the medial layer, play a central role in this pathological process. Under normal physiological conditions, VSMCs maintain a contractile phenotype to regulate vascular tone; however, under pathological stimuli, they can undergo phenotypic switching from contractile to synthetic. This transition enables VSMCs to proliferate, migrate, secrete extracellular matrix components and inflammatory factors, thereby driving neointima formation and vascular remodeling (49). Consequently, a deeper understanding of the molecular mechanisms underlying VSMC phenotypic switching is essential for elucidating the progression of atherosclerosis.

In the complex pathology of atherosclerosis, the diversity of cell death modes and their subsequent effects are critical determinants of plaque stability and disease progression. Beyond traditional apoptosis, novel forms of programmed cell death—such as necroptosis, pyroptosis, and ferroptosis—have been increasingly uncovered (Figure 3). These processes collectively shape the inflammatory microenvironment and plaque fate in atherosclerosis through distinct molecular mechanisms.

In atherosclerosis, cells alter their metabolic pathways through metabolic reprogramming to adapt to environmental stress. The metabolic states of vascular and immune cells profoundly influence their functions and phenotypes. Recently, mitochondrial one-carbon metabolism has emerged as a critical pathway, demonstrated to regulate T follicular helper (Tfh) cell differentiation. For example, in transplant atherosclerosis models, CD34⁺ lineage cells differentiate into Tfh cells via this pathway, promoting tertiary lymphoid structure formation and vascular remodeling. Specifically, MTHFD2 enzyme deficiency significantly suppresses Tfh cell differentiation and delays atherosclerosis progression, suggesting that targeting this pathway may offer a new interventional strategy (45). Meanwhile, lactylation modification—an emerging post-translational modification—has been increasingly implicated in atherosclerosis. Integrated single-cell and bulk transcriptome data, combined with machine learning, have identified hub genes such as SOD1, DDX42, and PDLIM1. These genes participate in inflammatory and metabolic processes and may serve as diagnostic markers or therapeutic targets (62). Furthermore, classic metabolic pathways including glycolysis, fatty acid oxidation, and amino acid metabolism contribute to disease progression. For instance, pro-inflammatory macrophage polarization is accompanied by increased glycolytic flux, while endothelial dysfunction correlates with mitochondrial impairment. These metabolic alterations not only regulate energy supply but also drive atherosclerosis through inflammatory cytokine secretion and oxidative stress (2). In conclusion, multiple metabolic pathways intertwine in atherosclerosis and collectively shape the immune and metabolic microenvironment, providing a rationale for developing precision therapies targeting metabolic networks.

Epigenetic mechanisms regulate gene expression without altering the DNA sequence and serve as a key interface between environmental factors and genetic background. They extensively modulate vascular cell functions and immune responses in atherosclerosis, with histone modifications and non-coding RNAs playing central roles. Specifically, histone deacetylases (HDACs) regulate endothelial function, VSMC phenotypic switching, and inflammatory responses by modifying the acetylation status of histones and non-histone proteins. Aberrant HDAC expression is closely linked to atherosclerosis; for example, HDAC9 overexpression promotes vascular inflammation and plaque formation, whereas HDAC inhibitors ameliorate atherosclerotic lesions in experimental animals (2). Additionally, HDACs influence atherosclerosis progression by regulating cholesterol metabolism and autophagy-related gene expression (63). On the other hand, non-coding RNAs are vital components of epigenetic regulation. Multiple miRNAs—such as miR-133a and miR-30a-3p—and circular RNAs fine-tune various aspects of atherosclerosis by modulating target gene expression. For instance, miR-133a participates in lower extremity atherosclerosis by targeting the RhoA signaling pathway (64), while miR-30a-3p inhibits VSMC proliferation and migration by suppressing ROCK2 expression (50). Concurrently, circular RNAs influence disease progression by acting as miRNA sponges or regulating transcription factor activity (65). Together, these mechanisms unveil the intricate network of epigenetic regulation in atherosclerosis and offer a theoretical basis for developing targeted therapeutic strategies.

Atherosclerosis is not driven by a single cause but is a complex network disease involving multiple molecular pathways. The dominant pathological mechanisms can vary significantly among patients and even across different plaques within the same individual. For instance, processes such as inflammatory responses, lipid metabolism abnormalities, oxidative stress, calcification, and immune cell infiltration contribute differently across individuals or disease stages (66). This high heterogeneity poses a major obstacle to developing universal therapies. Drugs targeting specific pathways, such as monoclonal antibodies against particular inflammatory factors, may be effective in certain patient subgroups but show limited efficacy in others (16). Therefore, future treatment strategies must shift from a “one-size-fits-all” approach to precision interventions based on molecular subtyping.

Current clinical diagnosis of atherosclerosis still relies heavily on imaging to detect obvious plaque formation or luminal stenosis. By this stage, the disease has often progressed to mid- or late phases, missing the optimal window for intervention. Thus, the lack of highly sensitive and specific early molecular diagnostic markers remains a core bottleneck for early prevention. Although circulating non-coding RNAs (e.g., miRNAs and circRNAs), metabolites, and proteomes are considered promising biomarkers, their translational application faces challenges such as poor reproducibility, lack of standardization, and inconsistent detection techniques (67). Moreover, integrating these emerging markers with traditional clinical risk scores (e.g., Framingham risk score) to construct more accurate risk prediction models is a critical issue requiring resolution (68). Future studies should promote biomarker standardization and model integration using multi-center, large-scale cohorts to enhance early identification and risk assessment of atherosclerosis.

Even after effective control of low-density lipoprotein cholesterol (LDL-C) with statins, patients still face residual cardiovascular risks driven by factors such as inflammation, elevated triglycerides, and dysfunctional high-density lipoprotein. Effectively targeting these non-LDL-C pathways is a central challenge in current lipid-lowering therapy. Studies indicate that persistent inflammatory states (e.g., elevated high-sensitivity C-reactive protein) remain independent predictors of cardiovascular events even when LDL-C levels are controlled (6). Additionally, cholesterol from triglyceride-rich lipoprotein remnants has been independently associated with the development and progression of atherosclerosis (8). Therefore, developing new drugs targeting residual risks—such as inflammation inhibitors (e.g., IL-1β antagonists) and novel triglyceride-lowering agents—and exploring their combination with existing therapies are key future directions.

Converting unstable vulnerable plaques into stable ones is critical for preventing acute events such as acute coronary syndromes and strokes. However, current therapies face multiple challenges, including how to precisely suppress intraplaque inflammation while promoting collagen synthesis without exacerbating calcification, and how to balance vascular smooth muscle cell apoptosis and proliferation. Enhancing efferocytosis to clear apoptotic cells, thereby preventing secondary necrosis and amplification of inflammation, is recognized as a central mechanism for plaque stabilization. Furthermore, studies have demonstrated that C-type natriuretic peptide (CNP) promotes an anti-inflammatory macrophage phenotype and augments efferocytosis, leading to a reduction in the necrotic core and increased plaque stability (69). Meanwhile, growing research on novel cell death modes such as ferroptosis and pyroptosis is uncovering new perspectives and potential targets for regulating plaque stability (11). Thus, investigating these emerging mechanisms may provide more diverse and precise therapeutic avenues for cardiovascular disease management.

Current guidelines for cardiovascular disease prevention and treatment are primarily based on evidence from large-scale population trials. They lack precision strategies tailored to individual genetic backgrounds, molecular phenotypes, and environmental factors. For example, inter-individual variations in responses to the same lipid-lowering drug may be linked to genetic polymorphisms (e.g., in PCSK9 or APOE genotypes). Advances in single-cell sequencing have revealed remarkable cellular heterogeneity in atherosclerotic lesions, providing unprecedented resolution for understanding individual differences (12). The future challenge lies in translating multi-dimensional omics data—genomics, epigenomics, proteomics, and metabolomics—into clinically applicable decision-making tools to achieve “one-size-fits-one” personalized therapy.

Transplant atherosclerosis is a major cause of long-term graft failure after solid organ transplantation (e.g., heart or kidney). Its pathogenesis involves not only traditional risk factors but also complex interactions between persistent alloimmune responses and non-immune factors (e.g., donor organ ischemia-reperfusion injury and immunosuppressant toxicity), making prevention and treatment particularly difficult. Studies show that recipient-derived immune cells and stem cells can infiltrate graft vessels, driving vascular wall remodeling and neointimal hyperplasia (16). Recent research indicates that lymphangiogenesis plays a critical role in mediating host immune cell homing to the graft, and inhibiting the VEGF-C/VEGFR-3 signaling pathway can effectively mitigate transplant atherosclerosis (70). Furthermore, mitochondrial one-carbon metabolism has been shown to regulate T follicular helper cell differentiation, influencing tertiary lymphoid organ formation and thereby contributing to transplant vasculopathy (45). These findings highlight novel mechanisms such as immunometabolism, offering potential targets for managing this challenging complication.

Before describing novel pharmacological strategies, it is essential to acknowledge the foundational role of non-pharmacological management, which possesses robust scientific evidence and demonstrated efficacy. Lifestyle interventions constitute the first-line strategy for primary and secondary prevention of atherosclerosis (1). Regular physical exercise improves vascular endothelial function by enhancing nitric oxide bioavailability and reducing oxidative stress and inflammatory markers such as C-reactive protein (CRP). Dietary modifications, particularly the adoption of Mediterranean-style diets rich in unsaturated fats, fiber, and antioxidants, have been shown to reduce cardiovascular events by improving lipid profiles and attenuating systemic inflammation (1, 68). Smoking cessation represents another critical intervention, as it directly ameliorates endothelial dysfunction and reduces monocyte adhesion and platelet activation. Additionally, weight management through caloric restriction and physical activity not only addresses obesity-related metabolic disturbances but also directly impacts atherosclerotic progression through mechanisms involving adipokine regulation and reduced vascular inflammation. These non-pharmacological approaches provide the essential foundation upon which all pharmacological interventions are built, and their implementation remains crucial throughout the disease continuum.

Before exploring emerging treatments, a comprehensive understanding of conventional pharmacological therapies is imperative. Statins (HMG-CoA reductase inhibitors) represent the cornerstone of atherosclerotic cardiovascular disease prevention and treatment. Beyond their well-established lipid-lowering effects through inhibition of cholesterol biosynthesis, statins exert multiple pleiotropic effects that contribute to their clinical benefits. These include improvement of endothelial function via upregulation of endothelial nitric oxide synthase (eNOS), anti-inflammatory properties mediated through reduction of CRP and inhibition of leukocyte adhesion molecule expression, stabilization of vulnerable plaques by reducing macrophage content and increasing collagen formation, and potential immunomodulatory effects (2, 8). Despite intensive statin therapy, significant residual cardiovascular risk persists, driven largely by inflammatory pathways and other non-LDL-C factors (6, 8). Other conventional agents include antiplatelet therapies (e.g., aspirin, P2Y12 inhibitors) that prevent thrombotic complications, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers that counter the pro-atherogenic effects of the renin-angiotensin-aldosterone system, and newer lipid-lowering agents such as ezetimibe and PCSK9 inhibitors that further reduce atherogenic lipoproteins through complementary mechanisms (9, 71). These established therapies provide the fundamental pharmacological framework for atherosclerosis management.

In addition to conventional anti-atherosclerotic pharmacotherapies, emerging hypoglycemic agents—particularly glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i)—have demonstrated significant cardiovascular protective benefits. These therapeutic effects extend well beyond glycemic control, offering novel opportunities for the integrated management of atherosclerotic cardiovascular disease.

Preclinical studies have elucidated multiple direct anti-atherogenic mechanisms of GLP-1 RAs, including suppression of pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6) in macrophages, inhibition of monocyte adhesion to endothelial cells through downregulation of adhesion molecules, reduction of oxidized LDL-induced foam cell formation, and attenuation of atherosclerotic plaque development in murine models (72–74). These effects appear mediated through GLP-1 receptor-dependent pathways in endothelial cells, with studies demonstrating that GLP-1 RAs improve endothelial function, reduce vascular oxidative stress, and increase NO bioavailability (75, 76). Clinical trials have substantiated these mechanistic insights, demonstrating cardiovascular benefits across diverse patient populations. The SELECT trial showed a 20% reduction in major adverse cardiovascular events (MACE) with semaglutide in overweight or obese individuals without diabetes (77). Similarly, the LEADER (liraglutide), SUSTAIN-6 (semaglutide), and REWIND (dulaglutide) trials demonstrated significant MACE reduction in patients with type 2 diabetes (78, 79). These findings position GLP-1 RAs as a therapeutically important class for atherosclerosis management, particularly in patients with concurrent metabolic diseases.

SGLT2i also demonstrate anti-atherosclerotic effects. Preclinical evidence indicates that SGLT2i exert direct atheroprotective effects by modulating inflammatory pathways, reducing oxidative stress, improving endothelial function, and enhancing plaque stability (80–82). Specifically, empagliflozin and dapagliflozin have been shown to suppress the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6, MCP-1), inhibit NLRP3 inflammasome activation, reduce foam cell formation, and attenuate leukocyte adhesion and migration into the vascular intima (80–82). Additionally, SGLT2i promote autophagy and reduce cellular senescence through pathways involving AMPK, GSK3β, SIRT3, and mTOR, thereby mitigating vascular aging and dysfunction (83, 84). In terms of vascular remodeling, SGLT2i improve endothelial function by increasing nitric oxide bioavailability, inhibiting vascular smooth muscle cell proliferation, and reducing neointimal formation (85, 86). Clinically, SGLT2i have shown benefits across various atherosclerotic manifestations. In coronary artery disease, empagliflozin and dapagliflozin reduce ischemic area, infarct size, and MACE, particularly in patients with prior myocardial infarction or established ASCVD (87, 88). These findings underscore the multifaceted atheroprotective profile of SGLT2i, supporting their use in combination with conventional therapies for comprehensive cardiovascular risk management.

Atherosclerosis management is shifting from conventional risk factor control to precision strategies targeting specific molecular pathways. Recently, drug development focusing on emerging molecular targets has achieved remarkable progress, providing new directions for therapy. As chronic inflammation is a core driver of atherosclerosis, interventions against specific inflammatory pathways have become crucial. For example, NLRP3 inflammasome inhibitors alleviate vascular inflammation by blocking IL-1β and IL-18 maturation (2). Meanwhile, drugs targeting the IL-6 signaling pathway, such as tocilizumab, are under clinical evaluation. On the other hand, AIP1, a key negative regulator of vascular endothelial inflammation, significantly attenuates atherosclerotic lesions by inhibiting the ASK1-JNK/p38 pathway (89). Additionally, targeting the CCL21-CXCR3 axis has been shown to suppress tertiary lymphoid structure formation and delay transplant arteriosclerosis (16). These findings expand our understanding of inflammation in atherosclerosis and provide a basis for novel anti-inflammatory therapies.

In the field of cell death regulation, the inhibition of specific modes of cell death provides novel strategies for improving plaque stability. Ferroptosis inhibitors mitigate atherosclerosis by upregulating the expression of SLC7A11 and GCL and suppressing lipid peroxidation (11). Caspase-1 inhibitors, which target pyroptosis, reduce the release of inflammatory factors and slow plaque progression. Moreover, recent studies demonstrate that modulation of the mitochondrial one-carbon metabolism enzyme MTHFD2 influences T follicular helper cell differentiation and immune responses associated with atherosclerosis (45). These findings underscore the promising therapeutic potential of targeting cell death and metabolic pathways in the treatment of atherosclerosis.

The immunoproteasome, a key component in antigen presentation and immune responses, exhibits synergistic mechanisms when its LMP2 and LMP7 subunits are jointly inhibited. This strategy reduces IgG-secreting and plasma cell numbers while activating the unfolded protein response to suppress antibody production, thereby alleviating transplant arteriosclerosis (48). This dual inhibition outperforms single-subunit targeting, offering a new paradigm for managing immune-mediated vascular pathologies.

Epigenetic regulation also plays a critical role in atherosclerosis progression. Histone deacetylase inhibitors influence disease development by altering chromatin structure and gene expression. Selective HDAC inhibitors like TSA and SAHA suppress phenotypic switching and inflammation in vascular smooth muscle cells (2). Inhibitors targeting specific HDAC subtypes are being developed to balance efficacy and safety. Moreover, scATAC-seq technology enables the analysis of dynamic chromatin accessibility in atherosclerosis, expanding the target space for epigenetic therapies (90). These advances collectively drive atherosclerosis treatment toward more precise and diversified strategies. The discovery of these emerging targets and corresponding drug development signifies the dawn of a precision-targeting era in atherosclerosis therapy. Future efforts should explore synergistic effects among different targeting strategies and validate long-term efficacy and safety through clinical trials.

Given the immune-inflammatory nature of atherosclerosis, immunomodulatory strategies show broad potential for prevention and treatment. Atherosclerosis is not merely a lipid deposition disease; its pathology involves innate and adaptive immune systems, where aberrant activation of T cells, B cells, and antigen-presenting cells drives chronic vascular inflammation (10). Recently, immunotherapy and vaccination have emerged as novel interventions to halt disease progression by inducing antigen-specific immune tolerance or regulatory cell networks.

In antigen-specific tolerance studies, researchers aim to re-establish immune “ignorance” toward disease-related antigens. For instance, vaccines based on apolipoprotein B-100 (apoB-100) peptides can induce protective antibodies or regulatory T cells (Tregs), specifically suppressing immune-inflammatory responses in atherosclerosis (10). As apoB-100 is a core component of LDL and critical in atherosclerosis initiation, immune tolerance against this antigen effectively blocks subsequent inflammatory cascades and reduces plaque burden in animal models (10). Nanotechnology also offers new platforms for antigen delivery; for example, oral chitosan-DNA nanoparticles encapsulating MHC antigens are taken up by the intestinal lymphatic system, mimicking natural oral tolerance pathways to induce antigen-specific Treg differentiation and suppress intimal hyperplasia in transplant arteriosclerosis models (91). These advances highlight the promise of precise immunomodulation for chronic inflammatory diseases.

Mesenchymal stem cells (MSCs), with their multipotent differentiation capacity and immunomodulatory functions, play key roles in regulating local immune microenvironments through cell therapy. Local infusion of autologous MSCs upregulates IL-10, IFN-γ, and indoleamine 2,3-dioxygenase (IDO), inducing Tr1-like regulatory cells and suppressing transplant arteriosclerosis (92). IDO, a key enzyme in tryptophan metabolism, not only promotes Treg expansion and inhibits effector T cell function but also enhances the immunosuppressive capacity of MSC-induced Tr1-like cells when combined with prostaglandin E2 (PGE2), outperforming MSCs alone in suppressing vascular pathology (93). Further studies indicate that lymphangiogenesis is critical in transplant arteriosclerosis; VEGF-C-mediated lymphatic vessel formation promotes tertiary lymphoid organ development and exacerbates local immune responses, while inhibiting this pathway delays disease progression (70). This provides a theoretical basis for targeting the lympho-immunological axis and opens new directions for optimizing future therapies.

Despite the promise of immunotherapy, challenges remain in antigen specificity, durability of immune tolerance, and individual variability. The safety and standardized delivery systems for cell therapies also require optimization. Future research should focus on precise immunomodulation, integrating multi-omics and personalized medicine to advance clinical translation. In summary, immunoregulatory strategies may open new avenues for atherosclerosis prevention and treatment.

Gene therapy and RNA therapeutics, as core strategies of precision medicine, offer breakthroughs in atherosclerosis management. These approaches use antisense oligonucleotides, small interfering RNAs (siRNAs), or microRNA (miRNA) mimics/inhibitors to modulate disease-related gene expression, intervening in key pathological processes like vascular smooth muscle cell (VSMC) activation, inflammatory responses, and immune cell migration (94). In gene therapy, viral vector-based delivery systems show significant potential. For example, adenovirus-mediated antisense ERK2 gene therapy specifically inhibits extracellular signal-regulated kinase 2 (ERK2) expression, blocking abnormal VSMC activation and pathological angiogenesis, thereby reducing vascular wall thickening and lumen stenosis in transplant arteriosclerosis models (94). This confirms the central role of the ERK pathway and highlights the advantages of gene therapy in targeting specific molecular mechanisms.

RNA therapeutics represent a powerful strategy for precise gene regulation via non-viral approaches, among which miRNA mimics and antagonists are particularly noteworthy. For example, miR-30a-3p, which is down-regulated in patients with arteriosclerosis obliterans, suppresses vascular smooth muscle cell (VSMC) proliferation, migration, and phenotypic switching by targeting Rho-associated coiled-coil containing protein kinase 2 (ROCK2), thereby delaying neointima formation. In animal studies, lentivirus-mediated delivery of miR-30a-3p significantly attenuated neointimal hyperplasia following carotid artery injury (50). Similarly, miR-142-3p inhibits CD4+ T cell migration and activation via the RAC1/ROCK2 pathway, thereby mitigating perivascular inflammation and offering novel insights into immune-mediated atherosclerosis (95). Beyond miRNAs, siRNA-based therapies have also shown progress in preclinical research. siRNAs directed against proinflammatory cytokines or adhesion molecules effectively suppress endothelial cell activation. Recently, lipid nanoparticle-delivered siRNA targeting VEGF-C successfully inhibited lymphangiogenesis (96). Collectively, these findings underscore the preclinical success of RNA therapeutics and highlight their potential as a promising strategy for treating vascular diseases.

Although gene and RNA therapies hold promise, challenges in delivery efficiency, tissue specificity, and long-term safety remain. Future research should optimize vector design, identify new targets using multi-omics data, and validate efficacy through clinical trials. By integrating gene regulation with immune interventions, this field may open a precision-based, personalized era in atherosclerosis management, indicating the growing role of these therapies in future cardiovascular disease care.

Advances in materials science and engineering have introduced new strategies for atherosclerosis prevention and treatment. Magnesium-based absorbable stents exemplify “drug-device combination” therapy, overcoming limitations of permanent metal stents that may cause chronic inflammation or restenosis. These stents provide initial mechanical support and gradually degrade in vivo, releasing magnesium ions with direct anti-atherosclerotic effects. Recent studies show that magnesium ions activate the MAPK pathway, inhibit ERK protein dephosphorylation, and upregulate solute carrier family 7 member 11 and glutamate-cysteine ligase expression, significantly suppressing ferroptosis in vascular endothelial cells (11). This mechanism, validated in multiple animal models (mice, rats, rabbits), demonstrates that magnesium-based stents not only restore blood flow but also actively delay atherosclerosis by regulating cell death and lipid metabolism.

In early screening and dynamic risk management, wearable devices address the limitations of conventional vascular imaging in continuous monitoring. For example, flexible ultrasonic sensor arrays with automatic phase calibration conform comfortably to neck skin, enabling high-resolution imaging and long-term continuous monitoring of carotid arteries. This allows non-invasive, real-time assessment of vascular wall thickness, plaque formation, and elasticity changes (97). Drug-coated balloons and targeted delivery systems also show potential; paclitaxel-coated balloons combined with separable microneedles enable sustained drug release at lesion sites, improving efficacy and reducing restenosis risk (98). Future integration of wearables with AI algorithms and bioactive materials will make atherosclerosis management more precise, dynamic, and personalized, offering comprehensive patient care.

Beyond lifestyle and pharmacological interventions, innovations in biomaterials and medical devices provide new strategies for atherosclerosis control. Recent studies on atherosclerosis and transplant arteriosclerosis reveal the potential of advanced material-based therapies. In transplant arteriosclerosis, lymphatic vessel formation begins at anastomotic sites and is driven by fibroblast-derived VEGF-C; inhibiting this pathway significantly reduces lymphangiogenesis, neointima formation, and adventitial fibrosis (70). This suggests that developing devices with localized VEGF-C inhibitor coatings could offer new approaches for preventing transplant arteriosclerosis. Meanwhile, biodegradable magnesium alloy stents show promise; magnesium ions activate the MAPK pathway, upregulate SLC7A11 and GCL expression, inhibit endothelial cell ferroptosis, and downregulate ACSL4 to modulate lipid metabolism, delaying atherosclerosis in various animal models (11). This lays the foundation for next-generation stents with both mechanical support and active anti-atherosclerotic functions.

Drug-coated balloons and stents continue to evolve. For lower extremity arteriosclerosis obliterans, drug-coated devices locally release anti-proliferative agents, significantly improving revascularization outcomes in femoropopliteal artery lesions (99). Additionally, nanoscale targeting systems like hyaluronic acid-modified rapamycin liposomes specifically target the lymphatic system, more effectively modulating immune responses and reducing atherosclerotic lesions (100). These innovations expand treatment options and enable precise intervention in molecular mechanisms. With advances in materials science, drug delivery, and disease mechanism insights, intelligent devices integrating mechanical support, localized drug delivery, and biological regulation will lead future directions in atherosclerosis management.

Traditional Chinese medicine (TCM) compounds, such as Qingmai Yin and Simiao Yong’an Tang, demonstrate significant efficacy in improving arteriosclerosis obliterans in clinical practice, highlighting TCM’s holistic “multi-component, multi-target” regulatory advantages. Modern pharmacological studies gradually reveal their mechanisms, showing that these compounds modulate key signaling pathways like TGF-β/Smad and NF-κB, improving lipid metabolism disorders and suppressing vascular inflammation to delay atherosclerosis (101, 102). For example, active components in Qingmai Yin inhibit the NF-κB pathway to reduce inflammatory factor release while regulating lipid metabolism-related gene expression, synergistically exerting anti-atherosclerotic effects (101). TCM monomers like Kangle Xin specifically inhibit the PDGFR-β pathway, blocking VSMC phenotypic switching and thereby suppressing abnormal proliferation and migration to delay vascular remodeling (7). This provides new ideas for targeted therapy.

TCM also demonstrates unique value in modulating immune-inflammatory microenvironments. Certain TCM components can influence T cell differentiation and lymphangiogenesis, thereby regulating immune responses in transplant arteriosclerosis. This aligns with the TCM theory of “removing stasis and unblocking collaterals”. Future studies should integrate systems biology and network pharmacology to elucidate synergistic mechanisms of TCM compounds. Clinical efficacy should be further validated through evidence-based medicine. Such efforts will offer multidimensional strategies for atherosclerosis management and advance personalized therapy and drug development (7, 101). Together, these advances highlight the growing potential of TCM in modern medicine.

Precision medicine shows great promise in atherosclerosis management, focusing on integrating multi-omics data—genomics, proteomics, metabolomics, and single-cell sequencing—to build individualized risk prediction models and open new avenues for early warning and precise intervention. Single-cell sequencing technologies have propelled research forward; for example, in transplant arteriosclerosis models, they reveal dynamic cellular population evolution and identify the CCL21/CXCR3 signaling axis as critical for immune cell chemotaxis (16). Simultaneously, mitochondrial one-carbon metabolism influences CD34⁺ lineage cell differentiation into T follicular helper cells and tertiary lymphoid organ formation, providing new perspectives on atherosclerosis immunology (45). These findings deepen our understanding of pathogenesis and lay the groundwork for targeted therapies.

In biomarker discovery, machine learning algorithms enhance the efficiency of identifying diagnostic and prognostic markers for atherosclerosis. Lactylation-related genes exhibit specific expression profiles in carotid atherosclerotic tissues, with SOD1, DDX42, and PDLIM1 identified as core genes, offering potential therapeutic targets (62). Metabolomic analyses further reveal that cysteine-S-sulfate exacerbates atherosclerosis by promoting TH17 cell differentiation and pyroptosis (59). Based on these markers, clinical strategies are moving toward personalization; for instance, polymorphisms like ALKBH5 rs671 and MTHFR rs1801133 can be targeted as independent risk factors for multiple atherosclerosis (103). Additionally, remnant cholesterol is independently associated with disease progression, indicating that high remnant cholesterol levels increase atherosclerosis risk even when LDL cholesterol is controlled (8). These discoveries enhance our molecular understanding and support the development of precision medicine strategies.

Despite its promise, precision medicine faces challenges in integrating multi-omics data, validating novel biomarkers clinically, improving machine learning model generalizability, and translating individualized strategies into practice. Future research must address these key issues to achieve truly precise and personalized atherosclerosis prevention and treatment.