Recent global disease burden data indicates that cardiovascular and cerebrovascular diseases pose a heavy burden. These diseases not only lead to increased mortality rates but also result in high disability rates and disease burden, severely affecting public health and quality of life (Li et al., 2023; Li et al., 2024). Antiplatelet drugs are central to the prevention and treatment of cardiovascular and cerebrovascular diseases by inhibiting platelet aggregation, playing a crucial role in the prevention and treatment of cardiovascular and cerebrovascular diseases (Stanger et al., 2023; Greco et al., 2023; Kamarova et al., 2022). However, due to individual differences and the complexity of molecular mechanisms, these drugs may encounter varying degrees of resistance in clinical applications. Notably, approximately 20% of patients exhibit dual high on-treatment platelet reactivity to aspirin and clopidogrel (Breet et al., 2011). Aspirin resistance occurs in up to 60% of cases (Sambu et al., 2013), while clopidogrel resistance reaches 40% (Angiolillo et al., 2007), both correlating with increased risks of atherothrombotic events. Approximately 10%–30% of patients with antiplatelet resistance experience ischemic events (Udell et al., 2016; Li et al., 2012; Reny et al., 2012). A prospective multicenter registry study demonstrated significantly elevated stent thrombosis risk, particularly showing 1.49-fold increased risk in clopidogrel high-responders (Stone et al., 2013). Overall, patients with antiplatelet resistance face 2- to 3-fold higher cardiovascular event risks compared to normal responders (Gum et al., 2003; Gurbel et al., 2003).

Antiplatelet drug resistance currently lacks a standardized definition but is broadly categorized into laboratory resistance and clinical resistance. This refers to the phenomenon where patients experience thrombotic events or demonstrate laboratory-confirmed failure of platelet function inhibition despite receiving standard antiplatelet therapy (Hankey and Eikelboom, 2006; Floyd and Ferro, 2015). Based on mechanistic characteristics, it can be divided into two types: primary resistance and secondary resistance. Primary resistance stems from the patient’s inherent inherited pharmacogenetic abnormalities, including genetic polymorphisms of drug-metabolizing enzymes (such as CYP2C19 loss-of-function alleles) or target receptor variations (like P2Y12 receptor polymorphisms), resulting in the inability of the drug to achieve the expected antiplatelet effect from the outset of therapy (Hou, 2024; Fitzgerald and Pirmohamed, 2011; Pereira et al., 2019; Akkaif et al., 2021). Secondary resistance occurs after initially effective treatment and is triggered by acquired factors, commonly including drug-drug interactions (e.g., proton pump inhibitors competitively inhibiting clopidogrel metabolism), disease-related enhancement of platelet activation (e.g., in inflammatory conditions such as diabetes), accelerated platelet turnover, or poor patient adherence (Hankey and Eikelboom, 2006; Huang et al., 2025; Kaur et al., 2018). Resistance not only leads to reduced therapeutic efficacy but also increases the risk of vascular events, thereby affecting the overall prognosis of patients (Hankey and Eikelboom, 2006; Spanos et al., 2017; Ball, 2009). The mechanisms of antiplatelet drug resistance are complex and are often closely related to factors such as variations in drug-metabolizing enzymes, mutations in target proteins, and epigenetic regulation (Fitzgerald and Pirmohamed, 2011; Pereira et al., 2019; Kim et al., 2024). Traditional research has primarily focused on the genetic factors of drug resistance, with relatively few exploration into the epigenetic mechanisms, particularly non-coding RNAs.

Non-coding RNAs refer to RNA molecules that do not encode proteins, primarily including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). These non-coding RNAs influence various biological processes by regulating gene expression, cellular physiological processes, and other biological functions (Chen and Kim, 2024). miRNAs, small RNA molecules of approximately 22 nucleotides, play a key role in regulating complex genetic networks and cellular signaling pathways (Bushati and Cohen, 2007; Bartel, 2004; Lee et al., 1993). In addition to being potential biomarkers and diagnostic tools, miRNAs have shown great promise in disease treatment (Diener et al., 2022; MicroRNAs, 2017). Studies have demonstrated the regulatory role of miRNAs in platelet function. For instance, the effector complex formed by miR-223 and Ago2 can specifically target the purinergic receptor P2Y12, which is involved in platelet aggregation, thereby modulating platelet activation (Landry et al., 2009). Existing studies have demonstrated that miRNAs play an important role in regulating platelet function and reactivity, as well as in the mechanisms of antiplatelet drug resistance (Stojkovic et al., 2019; Singh et al., 2021; Willeit et al., 2013). lncRNAs, typically composed of hundreds to thousands of nucleotides, are widely involved in transcriptional regulation, epigenetic regulation, translation, and other cellular processes (Bridges et al., 2021; Hangauer et al., 2013). Research has revealed that MT1P3 upregulates P2Y12 by sponging miR-126, thereby promoting platelet hyperreactivity in diabetes (Zhou et al., 2019). The role of lncRNAs in antiplatelet drug resistance has gradually become a research hotspot (Wang et al., 2020). circRNAs are RNA molecules with a closed-loop structure, primarily regulate gene expression through functions such as acting as miRNA sponges and regulating protein translation (Zhou WY. et al., 2020). CircRNAs are abundantly expressed in human platelets (Alhasan et al., 2016), Platelet-derived circRNAs can interact with protein complexes of varying sizes, as exemplified by the platelet-specific circRNA Plt-circR4 (Preußer et al., 2018). Although research on circRNAs in antiplatelet drug resistance is still in its early stages, existing findings suggest that circRNAs hold significant potential in resistance mechanisms (Xu et al., 2025). Recent studies have also suggested that RNA modifications, such as N6-methyladenosine (m6A), may affect the functional roles of circRNAs and other non-coding RNAs in modulating gene expression and contributing to antiplatelet drug resistance (Yu et al., 2023). m6A modification, a prevalent and dynamic RNA modification, has been implicated in the regulation of RNA stability, splicing, translation, and the degradation of non-coding RNAs (Yue et al., 2019; Lence et al., 2017), thus influencing their role in drug resistance mechanisms (Liu and Pan, 2016). However, there are currently no reported studies on the roles of other RNA epigenetic modifications (such as m5C, Ψ, etc.) in antiplatelet drug resistance, and this field urgently requires further investigation.

This article primarily reviews the role of non-coding RNAs in the resistance to antiplatelet drugs, exploring their potential molecular mechanisms and providing an outlook on future research directions. In addition, the article also discusses the emerging field of RNA modifications, with a particular focus on m6A modification, and its potential impact on antiplatelet drug resistance.

Aspirin, as a core drug for the prevention and treatment of cardiovascular and cerebrovascular diseases, has been consistently recommended as a Class I medication in both domestic and international guidelines (Dawson et al., 2022; Abdelaziz et al., 2019; Li and Zhao, 2024). However, approximately 20%–60% of patients develop resistance to aspirin, which not only weakens its therapeutic effect but also presents a significant challenge for clinicians when formulating treatment plans (Sambu et al., 2013; Fiolaki et al., 2017; Khan et al., 2022). Previous studies have revealed that the mechanisms of aspirin resistance are primarily linked to genetic factors, drug interactions, patient adherence, and inflammatory responses (Hankey and Eikelboom, 2006; Fitzgerald and Pirmohamed, 2011; Floyd and Ferro, 2014). With the rapid development of high-throughput genomics and chip technologies, scientists have gradually recognized the potential role of non-coding RNAs in the mechanisms of aspirin resistance. Recent research has also gradually unveiled the complex mechanisms of non-coding RNAs in aspirin resistance (Table 1), providing new directions for the development of novel biomarkers and drug intervention strategies.

Clopidogrel is a commonly used antiplatelet drug for cardiovascular and cerebrovascular diseases, known for its high safety and effectiveness. It significantly reduces the risk of cardiovascular and cerebrovascular events and plays an important role in prevention and treatment (Gimbel et al., 2020; Valgimigli et al., 2024; Chen et al., 2024). However, approximately 30%–45% of patients may develop clopidogrel resistance (Fiolaki et al., 2017; Ray, 2014). Clopidogrel resistance remains an important challenge in clinical treatment, particularly closely related to individual differences in platelet reactivity. The mechanisms of clopidogrel resistance are complex, involving genetic factors, drug interactions, clinical factors, and other aspects (Pereira et al., 2019; Nguyen et al., 2005). In recent years, significant progress has been made in research on the role of non-coding RNAs in the response to clopidogrel antiplatelet therapy (Table 2). Increasing evidence suggests that changes in the expression of non-coding RNAs during clopidogrel treatment have a profound impact on resistance, making it a key focus of research on this issue.

Ticagrelor is a rapidly absorbed and reversible P2Y12 receptor antagonist, widely used in the treatment of cardiovascular diseases due to its potent antiplatelet effects (Kabil et al., 2022). Ticagrelor is generally considered an effective alternative for patients who do not respond to clopidogrel. Research on ticagrelor shows that for patients with acute coronary syndrome, switching to ticagrelor monotherapy after 3 months of dual antiplatelet therapy significantly reduces the composite risk of major bleeding and cardiovascular events year than 12 months of dual antiplatelet therapy (Kim et al., 2020). However, although ticagrelor resistance is rare, it still occurs in some patients. In a case report, the VerifyNow analyzer detected a lack of response to clopidogrel in a patient, and although the treatment was switched to ticagrelor, platelet inhibition remained suboptimal, leading to adverse events (Kuhn et al., 2024). Another study explored the existence of ticagrelor resistance and proposed management strategies for patients with ticagrelor resistance (Laurent et al., 2022). Currently, research on the role of non-coding RNAs in ticagrelor resistance is limited.

Prasugrel, as another P2Y12 antagonist, has shown similar cardiovascular adverse event rates and bleeding risks compared to ticagrelor in clinical studies (Bundhun et al., 2017). Further research indicates that patients treated with prasugrel exhibit similarities in the levels of various platelet-associated miRNAs and monocyte-platelet aggregate indicators when compared to patients treated with ticagrelor (Stojkovic et al., 2021). In patients receiving increased doses of aspirin and prasugrel, antiplatelet therapy significantly reduced the levels of circulating platelet-derived miRNAs (Willeit et al., 2013). A study on type 2 diabetic patients treated with aspirin, clopidogrel, and prasugrel monotherapy showed that prasugrel effectively suppressed platelet activity and lowered the levels of multiple platelet-associated miRNAs (Parker et al., 2020). These findings suggest that prasugrel may enhance its antiplatelet effect by regulating miRNA levels. In the future, non-coding RNA research based on miRNAs will provide new insights into the exploration of prasugrel resistance mechanisms and promote further development in this field.

Aspirin and clopidogrel are widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases and have become the core focus of antiplatelet resistance research. Existing studies suggest that non-coding RNAs play a key role in the resistance mechanisms of these two drugs, particularly the influence of platelet-related miRNAs in the formation of drug resistance. Figure 1 illustrates the mechanisms of action of antiplatelet drugs and how miRNAs regulate drug efficacy through multiple signaling pathways. However, research on the relationship between non-coding RNAs and other antiplatelet drugs (such as ticagrelor, prasugrel, etc.) in resistance is still relatively scarce, and some drugs lack related research reports.

In addition, the role of other non-coding RNAs, such as lncRNA and circRNA, in antiplatelet drug resistance is also receiving increasing attention. Figure 2 further demonstrates how lncRNAs and circRNAs regulate resistance through the sponge mechanism and the known mechanisms of non-coding RNAs and RNA modifications associated with drug resistance. With the expanding application of RNA-based therapies, future research should delve deeper into the role of non-coding RNAs and RNA modification mechanisms in antiplatelet drug resistance, providing a more accurate theoretical foundation and new perspectives for personalized treatment.

This review summarizes the biological relationship between non-coding RNAs and resistance to different antiplatelet drugs, with a focus on analyzing the potential mechanisms of action of different types of non-coding RNAs in antiplatelet drug resistance. Currently, as an important component of epigenetics, the study of non-coding RNAs in antiplatelet drug resistance is still in its early stages, but their crucial regulatory roles have been preliminarily confirmed, especially for miRNAs.

Current research reveals the significant role of non-coding RNAs in the mechanisms of aspirin resistance, particularly the potential regulatory mechanisms of molecules such as miRNAs, lncRNAs, and circRNAs in platelet function and aspirin response. The expression changes of miRNAs such as miR-19b-1-5p, miR-92a, and miR-34b-3p are closely related to aspirin resistance, offering new biomarkers that could aid in early diagnosis and personalized treatment. Furthermore, lncRNAs such as H19 play a role in platelet reactivity and aspirin response, further supporting the potential of non-coding RNAs as predictive tools for resistance. Although research on circRNAs in aspirin resistance is still limited, their unique function in gene regulation makes them a promising area for future research. At the same time, RNA modifications, especially m6A methylation, are also considered key factors influencing platelet function and aspirin efficacy, potentially exhibiting different drug responses, particularly in elderly patients. By considering the interplay between non-coding RNAs and RNA modifications, future studies could provide more precise strategies for personalized treatment.

The significance of non-coding RNAs in the mechanisms of clopidogrel resistance is also highly important. The role of miRNAs in regulating clopidogrel resistance in patients with CAD is an important area of research. In addition to miR-223, several other miRNAs, such as miR-142-3p, miR-24-3p, miR-411-3p, miR-199a-5p, and miR-107, are involved, providing new insights into the molecular mechanisms driving resistance to antiplatelet therapy. Furthermore, the interaction between miRNAs and genetic factors, particularly the CYP2C19 genotype, highlights the complexity of individual differences in clopidogrel response. In addition, circRNAs and lncRNAs regulate platelet function and key signaling pathways, offering new insights into the molecular mechanisms driving resistance. RNA modifications, especially m6A methylation, add another layer of complexity by influencing gene expression and further affecting therapeutic outcomes. As we move towards personalized medicine, non-coding RNAs provide a promising tool to predict which patients will have a poor response to clopidogrel treatment. Their potential as biomarkers to identify high-risk individuals could enable healthcare providers to more effectively tailor antiplatelet therapy, thereby reducing the risk of major adverse cardiovascular events. Integrating non-coding RNA analysis into clinical practice could help identify patients who require alternative or additional treatments, ultimately improving the overall management of cardiovascular and cerebrovascular diseases.

For ticagrelor, despite its proven efficacy in treating cardiovascular diseases, some patients may still develop resistance. Research indicates that non-coding RNAs, such as miR-126-3p and circFAM13B, may serve as potential biomarkers for predicting ticagrelor resistance and associated adverse ischemic events. Although the exact mechanisms of non-coding RNAs in ticagrelor resistance are still not fully understood, their potential in personalized treatment strategies is evident. Furthermore, prasugrel also enhances its antiplatelet effect by regulating miRNA levels, further confirming the crucial role of non-coding RNAs in modulating drug efficacy. In-depth investigation of these molecular mechanisms could provide new insights for optimizing clinical strategies and improving patient treatment responses and outcomes.

Although aspirin and clopidogrel remain cornerstone therapies for cardiovascular and cerebrovascular disease prevention, their drug resistance issues and potential adverse effects warrant significant clinical attention. From a pharmacoeconomic perspective, while clopidogrel demonstrates cost-effectiveness advantages and remains the most widely prescribed antiplatelet agent (van den Broek et al., 2022; Morris et al., 2022), substantial evidence indicates that ticagrelor shows superior efficacy in reducing composite endpoints of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel (Wallentin et al., 2009), whereas prasugrel significantly decreases ischemic events (Wiviott et al., 2007; Ruff et al., 2012). Comprehensive analysis of clinical data reveals that both prasugrel and ticagrelor exhibit markedly better therapeutic outcomes than clopidogrel (Kumar et al., 2023; Orban et al., 2021; Schnorbus et al., 2020). Notably, for NSTE-ACS patients aged ≥70 years, clopidogrel remains the safer option due to its reduced bleeding risk (Gimbel et al., 2020). For clopidogrel non-responders, we recommend non-coding RNA profiling (e.g., miR-223) to guide clinical decisions, with ticagrelor or prasugrel serving as preferred alternatives given their efficacy advantages and lower resistance rates. Studies indicate that patients exhibiting miRNA-26a upregulation should consider switching to ticagrelor or prasugrel (Giantini et al., 2022). From a translational medicine perspective, future development should focus on targeted therapies modulating ncRNA networks (e.g., the miR-223-P2Y12 signaling axis) to precisely regulate platelet activation pathways and improve clinical outcomes. Regarding aspirin, while this low-cost conventional drug remains first-line therapy for cerebrovascular diseases, meta-analyses demonstrate that cilostazol offers multiple advantages in secondary stroke prevention: reduced composite vascular events, lower bleeding incidence (Dinicolantonio et al., 2013), and significantly better efficacy in preventing post-stroke vascular events (Kamal et al., 2011). Particularly, its combination with clopidogrel further decreases recurrent ischemic stroke risk (Hoshino et al., 2021). Therefore, for patients with aspirin treatment failure, in addition to considering switching to cilostazol, novel therapeutic strategies targeting pathways such as the H19/8-iso-PGF2α axis could be developed.

Although the association between non-coding RNAs and antiplatelet drug resistance has been confirmed by multiple studies, current evidence still exhibits significant limitations: Firstly, as shown in our article’s tables, most studies suffer from inadequate sample sizes and lack multicenter validation; secondly, circRNA-related research remains in its preliminary stages, requiring large-scale cohort studies to verify its clinical translational value; furthermore, miRNA expression profiles reported by different research teams demonstrate marked heterogeneity, which may stem from sample integrity and degradation issues during processing or be closely related to selection biases in library preparation methods (Ludwig et al., 2018; Lopez et al., 2015; Loudig et al., 2025). While epigenetic biomarkers show promising predictive potential, the sensitivity of current detection technologies still fails to meet clinical application requirements (Pirritano et al., 2018). Pharmacoeconomic evaluations indicate that personalized dosing strategies based on CYP2C19 genotypes offer significant cost-effectiveness advantages (Carroll et al., 2024), whereas the high costs associated with high-throughput sequencing technologies underscore the need for future research to focus on developing more economically viable detection platforms. Future studies should establish a clinical translation pathway for ncRNA research findings by: 1) implementing a three-tier detection system (CYP2C19 initial screening → ncRNA rapid panel secondary screening → sequencing confirmation); 2) developing CRISPR-Cas13a-based POCT devices; and 3) formulating biomarker-guided treatment decision matrices (e.g., switching to ticagrelor for patients with high miR-223 expression).

Currently, bioinformatics tools, such as miRBase, MiRNA-BD, and CRAFT databases, can help gain a deeper understanding of the specific roles of non-coding RNAs in antiplatelet drug resistance and assist in predicting target genes (Kozomara et al., 2019; Lin et al., 2018; Dal Molin et al., 2022). However, the application of existing databases also presents significant limitations: many microRNA entries may lack precise tissue-specific origin or expression information, which could lead to misinterpretations in disease diagnosis or gene regulation studies (Singh, 2017; de Amo et al., 2022). In the past, there has been considerable genetic research on antiplatelet drug resistance, with some findings already applied in clinical practice (Pereira et al., 2019; Carroll et al., 2024; Feher et al., 2009). However, some patients continue to exhibit resistance. Additionally, the field of epigenetics, such as non-coding RNAs and DNA methylation, is also associated with antiplatelet drug resistance (Yang et al., 2020; Li et al., 2017). Therefore, future research urgently needs to address three key challenges: first, establishing standardized ncRNA detection protocols to resolve inter-laboratory reproducibility issues; second, enhancing the reliability of findings by expanding sample sizes and conducting multicenter collaborative studies; and third, developing integrated multi-omics prediction models that incorporate genomic, epigenomic, and clinical indicators. Figure 3 illustrates the potential targets of antiplatelet drug resistance and the strategies for drug modulation.

In conclusion, non-coding RNAs play a crucial role in the study of antiplatelet drug resistance, and the importance of RNA modifications in gene expression regulation cannot be overlooked. Future research should place greater emphasis on epigenetics, particularly exploring the potential of non-coding RNAs as biomarkers and therapeutic targets. Precision antiplatelet drugs offer new hope for resistance management and personalized treatment, while resistance testing based on the integration of epigenetic and genetic markers will be a key focus of future research.