Abstract
Cardiovascular diseases (CVDs) remain a global health challenge, with programmed cell death (PCD) mechanisms like apoptosis and necroptosis playing key roles in the progression. Circular RNAs (circRNAs) have recently been recognized as crucial regulators of gene expression, especially in modulating PCD. In current researches, circRNA regulation of apoptosis is the most studied area, followed by autophagy and ferroptosis. Notably, the regulatory role of circRNAs in pyroptosis and necroptosis has also begun to attract attention. From a mechanistic perspective, circRNAs influence cellular processes through several modes of action, including miRNA sponging, protein interactions, and polypeptide translation. Manipulating circRNAs and their downstream targets through inhibition or overexpression offers versatile therapeutic options for CVD treatment. Continued investigation into circRNA-mediated mechanisms may enhance our understanding of CVD pathophysiology and underscore their potential as novel and promising therapeutic targets.
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Facts
CircRNAs regulate multiple types of programmed cell death (PCD) in cardiovascular diseases (CVDs), including apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis, with apoptosis being the most extensively studied.
CircRNAs primarily function as molecular sponges for miRNAs, influencing signaling pathways such as NF-κB, PI3K/AKT, and TGF-β1, thereby affecting cardiomyocyte survival and death.
CircRNAs have potential as diagnostic and prognostic biomarkers in CVDs due to their stability, specificity, and detectability in extracellular vesicles.
Recent studies suggest that circRNAs play an essential role in regulating ferroptosis and its interaction with autophagy, offering a novel target for therapeutic intervention in conditions such as myocardial infarction and ischemia/reperfusion injury.
Despite advancements, challenges remain in understanding circRNA biogenesis, standardizing circRNA nomenclature, and translating circRNA-based research into clinical applications.
Open Questions
What are the precise molecular mechanisms by which circRNAs regulate pyroptosis and necroptosis in CVDs, and how do these processes interact with other forms of PCD?
How can circRNA-based therapeutics be safely and effectively applied in clinical settings, minimizing off-target effects while maximizing therapeutic benefits?
How do circRNAs interact with other non-coding RNAs and protein networks to coordinate cell death regulation in CVDs?
Introduction
Cardiovascular disease (CVD), which encompasses systemic vascular diseases affecting the heart and brain, poses a significant threat to human health [1] due to its high mortality, disability rates, recurrence rates, and numerous complications [2]. Despite advancements in research aimed at improving patient outcomes, clinical morbidity and mortality rates continue to rise [3, 4]. Consequently, there is a growing focus on discovering new treatment methods for CVD.
Programmed cell death (PCD), including apoptosis [5,6,7,8,9,10,11,12,13], necroptosis [14,15,16], pyroptosis [17,18,19,20], ferroptosis [6, 21,22,23,24,25], and autophagy-related cell death [26,27,28,29], is considered a key player in various cellular processes [30]. The abnormal activation of PCD pathways is implicated in the pathogenesis of various CVDs, such as ischemia/reperfusion (I/R) injury, myocardial infarction (MI), cardiomyopathy [31, 32] and atherosclerosis [33]. Accordingly, regulating cell death represents a significant potential measure for treating CVDs, and the timely activation of PCD can reshape the structure and function of the heart after injury [34].
Circular RNA (circRNA) is a large class of animal RNA with regulatory effects and typically shows tissue/developmental stage-specific expression [35]. Most circRNAs exhibit a high degree of conservation, while their expression patterns within individuals display tissue-specific or developmental specificity [36,37,38]. CircRNAs can regulate gene expression by serving as microRNA (miRNA) sponges or as scaffolds to facilitate contact between two or more proteins, thus representing potential regulators of cellular function [39,40,41,42]. Aberrant expression of circRNAs has been observed in certain CVDs like atherosclerosis, heart failure (HF), MI, and cardiomyopathy [43,44,45,46,47,48]. Studies also show that circRNA plays a key role in regulating cardiomyocyte apoptosis [49].
This article reviews the role of circRNA in CVD by regulating cell death patterns. It explores the origins, categorization, defining features, and functional roles of circRNA, and examines the distinctive attributes of PCD and its pivotal significance in cardiovascular ailments. We highlight the immense potential, future outlook, and therapeutic relevance of circRNA in modulating PCD to address CVD.
Overview of CircRNA
CircRNA was first discovered in 1976 in plant viruses and demonstrated by electron microscopy in 1979 [50, 51]. CircRNAs consist of a large class of noncoding RNAs whose formation is associated with a back-splicing process that covalently links a downstream splice donor site to an upstream splice acceptor site [52]. Current research has established that circRNAs are derived from the cleavage of pre-mRNA by the spliceosome or group I and group II ribozymes, and the competitive dynamic between the formation of linear RNA and circRNA during transcription in eukaryotic cells is also proved [53]. However, the precise molecular mechanisms underlying circRNA biogenesis remain incompletely understood [54]. The lariat-or-exon skipping model and the direct backsplicing model are two major mechanisms in canonical spliceosomes [55]. Most circRNAs are derived from known protein-coding genes through back-splicing events, identified as exonic circRNAs (ecircRNAs), intronic RNAs (ciRNAs), and exon-intron circRNAs (EIciRNAs) [56]. EcircRNA functions in the cytoplasm, while ciRNA and EIciRNA primarily operate within the nucleus [57]. CiRNA enhances the transcription rate of target genes by regulating the elongation activity of the RNA polymerase II complex [58], and EIciRNA is a crucial factor in influencing differential gene expression between cells [58,59,60]. Mitochondria-derived circular RNAs (mecciRNAs) from animals were newly discovered in 2020, and there remains significant potential for further exploration. These ciRNAs can exert their functions in the mitochondria, nucleus, and cytoplasm [61,62,63,64]. Some studies have also investigated tRNA intron circRNAs (tricRNAs) [65], interior circRNAs (i-circRNAs) [66], antisense circRNAs [67,68,69,70], and intergenic circRNAs [56, 71, 72]. In summary, circRNAs primarily function as molecular sponges that sequester specific miRNAs, thereby targeting and regulating mRNA translation. Additionally, circRNAs act as protein sponges, to serve as auxiliary or regulatory molecules for proteins, mRNA, and DNA. They can also serve as templates for translation and scaffolds for nuclear translocation [73,74,75]. They exhibit remarkable stability against RNase R digestion, and are abundantly expressed in various organisms, and demonstrate specificity to tissues, diseases, and developmental stages. These characteristics endow circRNAs with significant potential as biomarkers.
Circular RNAs modulate cell death in cardiovascular diseases
CircRNAs, attributable to their stability and ability to circulate via exosomes, have shown promise as potential biomarkers for diagnosing and monitoring various diseases. There has been growing interest in its role in CVD in recent years. Studies on apoptosis are relatively abundant, demonstrating that circRNAs modulate apoptosis through miRNA sponging and signaling pathways such as TGF-β1 and NF-κB, providing flexible therapeutic strategies. Investigations into autophagy have revealed that it frequently coexists with apoptosis in target cells, with circRNAs playing key roles in modulating these processes, suggesting therapeutic potential for myocardial cells. In terms of ferroptosis, researchers highlight its impact on cardiomyocyte death and cardiac function, with a growing focus on circRNA-regulated signaling pathways, particularly in animal models. Though studies regarding pyroptosis are still limited, emerging findings suggest that circRNAs’ involvement in its regulation shows promise for clinical treatment. Similarly, while necroptosis research remains in its early stages, the regulatory role of circRNAs is becoming more apparent, offering potential new therapeutic targets for CVDs (Fig. 1).
CircRNAs are non-coding RNAs formed via back-splicing, primarily through the lariat (exon-skipping) model or the direct back-splicing model. Based on their origin, circRNAs are categorized into EcircRNAs, ciRNAs, EIciRNAs, and mecciRNAs. They function through mechanisms such as miRNA sponging, regulation of pre-mRNA splicing, and protein scaffolding, with potential applications as therapeutic targets, therapeutic agents, and biomarkers.
Apoptosis
Apoptosis is directly induced by the intrinsic BCL-2 pathway and the extrinsic death receptor pathway, where apoptotic factors promote the activation of the caspase cascade, leading to protein cleavage and eventual cell destruction [76]. Apoptosis continues to be a focus in various fields, including CVDs, cancer, neurological disorders, and liver diseases [77,78,79,80,81,82]. The role of circular RNAs (circRNAs) in regulating apoptosis in CVDs has attracted significant attention [83], with numerous studies conducted on various cardiovascular conditions such as atherosclerosis, AMI, and myocardial I/R injury.
In the context of atherosclerosis-related circRNAs, circRSF1, circ_0007478, hsa_circ_0004831, circ_0026218, circLZIC, circ_0065149, circ_0030042, circHIPK3, circRNA-0024103, circ_0010283, hsa_circ_0001445, circ_0005699, among others, generally reduce apoptosis and mitigate ox-LDL-induced vascular endothelial cell damage by sponging miRNAs and processing downstream signals [84,85,86,87,88,89,90,91,92,93,94,95,96]. The upregulation of circNRG-1 has been demonstrated to alleviate apoptosis in atherosclerosis and hypertension model cells treated with ANGII, while circANKRD42 and circUBAC2 are believed to mitigate apoptosis in the context of atherosclerosis and MI through multiple signaling pathways, including the circUBAC2/hsa-miR-200b-3p/HIPK3 axis and circANKRD42/hsa-miR-324-5p/AP1G1 axis [97, 98]. Circ_0003645, circ_0004104, circANRIL, circTEX14, circTM7SF3, circ_USP36 (hsa_circ_0003204), circ_0029589, circMTO1, circ_0124644, circ_0005699, circUSP36, circ_0021155, circ_0006476 primarily function through miRNA sponging, but their increased levels exacerbate apoptosis in atherosclerosis model cells [7, 11, 48, 99,100,101,102,103,104,105,106,107,108].
Several studies have focused on the role of circRNAs in regulating apoptosis in AMI, involving circSAMD4A, circ_0060745, circRBMS1, circUSP39, and circ_0008842. These circRNAs primarily exert their effects by sponging miRNAs, except circ_0060745, which acts through the NF-κB pathway. When these circRNAs are upregulated, they enhance apoptosis and worsen AMI [109,110,111,112,113].
Myocardial I/R injury is another research hotspot. CircRbms1 has been shown to increase apoptosis and exacerbate hypoxia-induced cardiomyocyte injury through the miR-2355-3p/MST1 and miR‑742‑3p/FOXO1 axis [114, 115]. Other circRNAs involved include circ_0050908, circARPA1, circRNA Fbxl5, circ-0001380, circ_SMG6, and circHIPK3, which regulate apoptosis levels through various signaling pathways, primarily by sponging miRNAs, thereby influencing myocardial I/R injury [13, 116,117,118].
Beyond the aforementioned conditions, studies on circRNA regulation of apoptosis in CVDs such as abdominal aortic aneurysm, aortic aneurysm, atrial fibrillation, cancer therapy-related cardiovascular toxicity, coronary artery disease, and MI are summarized in the table (Table 1) [75, 103, 114, 116, 117, 119,120,121,122,123,124,125,126,127,128,129,130,131,132,133].
Currently, research on circRNA regulation of apoptosis in CVD treatment is relatively abundant. It is generally believed that circRNAs regulate apoptosis by sponging various corresponding miRNAs, as well as intervening in signaling pathways such as TGF-β1 and NF-κB. The inhibition or overexpression of specific circRNAs and their downstream molecular targets has different effects on apoptosis, offering flexible options in the clinical treatment of various CVDs (Fig. 2). This field has a solid research foundation and promising prospects for future studies.
CircRNAs influence apoptotic processes by interacting with specific miRNAs and modulating associated signaling cascades. Pro-apoptotic circRNAs intensify myocardial damage, while anti-apoptotic ones provide protective effects. The illustration highlights how various circRNAs contribute to the regulation of apoptosis during the progression of CVDs.
Autophagy
Autophagy refers to the process where autophagosomes encapsulate damaged proteins or organelles and transport them to lysosomes or vacuoles for degradation and recycling, typically to maintain homeostasis. Though, it is also implicated in cell death under certain circumstances [134]. Autophagy has garnered continuous attention in the fields of CVDs, cancer, neurodegenerative diseases, and metabolic disorders [135,136,137,138,139,140]. CircRNAs play a crucial role in regulating autophagy in CVDs [135, 141].
Studies have found that apoptosis and autophagy often occur simultaneously in the regulation of PCD in CVDs by circRNAs. CircRNA_101237 regulates IGF2BP3-dependent autophagy by sponging let-7a-5p, and the downregulation of IGF2BP3 resulting from circRNA_101237 downregulation reduces hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis and inhibits autophagy [140]. Ox-LDL-induced atherosclerosis remains a popular research focus. Circ_0002331 can enhance CCND2 activity to reduce autophagy and apoptosis, while circSQSTM1 exerts its effects through two pathways: one involves sponging miR-23b-3p, leading to increased Sirt1 expression, and the other enhances Sirt1 via the eIF4A3/FOXO1/Sirt1 axis [142, 143]. Knockdown of circPAN3 effectively alleviates autophagy and apoptosis, and improves cardiac function in MI mice via the miR-221/PTEN/AKT/PI3K pathway [144]. Circ-HIPK2 positively regulates ATG101 expression by sponging miR-485-5p, to accelerate apoptosis and cell death in myocardial oxidative damage induced by H2O2 [29]. Silencing circ_0010729 increases the viability of primary mouse cardiomyocytes and reduces OGD-induced myocardial cell injury by inhibiting apoptosis and autophagy through the miR-338-3p/CALM2 axis [145].
Research has proposed that circ-SIRT1 can promote autophagy in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and H9c2 cardiomyocytes by activating SIRT1, thus mitigating Ang II-induced cardiac hypertrophy (CH), based on the finding that autophagy deficiency leads to CH [28].
In patients with coronary heart disease (CHD), hsa_circ_0030042 is significantly downregulated in peripheral blood. In ApoE−/− mice fed a high-fat diet, hsa_circ_0030042 counteracts eIF4A3-induced plaque instability and inhibits autophagy by sponging eIF4A3, preventing it from recruiting beclin1 and FOXO1 mRNA [27].
CircRNA ACR inhibits autophagy via the ACR-Pink1-FAM65B axis, where Pink1 suppresses autophagy and its downstream target FAM65B. When phosphorylated by Pink1, it also inhibits autophagy and cell death in the heart. ACR reduces myocardial I/R injury and MI area through this signaling pathway [146].
Several studies on circRNA regulation of CVDs through autophagy have noted that apoptosis and autophagy frequently coexist in target cells [147,148,149]. Furthermore, the exploration of circRNA regulatory mechanisms on autophagy and their downstream signals has advanced, particularly in deciphering molecular pathways associated with their miRNA-sponging functions (Fig. 3) [150,151,152,153]. The promotion or inhibition of autophagy by circRNAs may hold potential therapeutic value for myocardial cells in various CVDs.
CircRNAs modulate autophagic activity by acting as miRNA sponges and altering the activity of critical signaling pathways. The diagram depicts the roles of circRNAs in regulating three distinct forms of autophagy: (a) macroautophagy, (b) chaperone-mediated autophagy, and (c) microautophagy, within the context of CVDs.
Ferroptosis
Ferroptosis is a form of iron-dependent PCD in which the accumulation of lipid peroxides and reactive oxygen species generated by iron metabolism leads to lipid membrane damage and cell failure [154]. Ferroptosis continues to attract attention in the fields of CVDs, tumors, inflammation, kidney damage, etc. [155,156,157,158,159,160]. Circular RNA regulates ferroptosis and plays an important role in CVD [161, 162].
The link between autophagy and ferroptosis is gaining attention in the study of the molecular mechanisms by which circRNAs regulate CVDs. CircRNA1615 regulates the expression of LRP6 by sponging miR-152-3p, thereby preventing LRP6-mediated autophagy-associated ferroptosis in cardiomyocytes through the miRNA152-3p/LRP6 molecular axis, ultimately controlling the pathological process of MI [24].
CircPIK3C2A promotes ferroptosis in AIC-treated H9c2 cells by sponging miR-31-5p, which upregulates TFRC, thereby exacerbating I/R injury [163]. Circ_0091761 enhances ferroptosis and reduces cell viability in H9c2 cells under simulated heart failure conditions through the miR-335-3p/ASCL4 axis and the TFRC axis [164]. Similarly, circ_005077 aggravates the adverse cardiac effects in various myocardial lipotoxicity models by enhancing ferroptosis, but its effects are not mediated by sponging miRNA. Instead, it upregulates CyPA and downregulates p47PHOX [165].
Overexpression of circRNA FEACR can suppress H/R-induced ferroptosis, inhibit MI, and improve cardiac function. This effect is mediated through the circRNA FEACR-induced NAMPT-Sirt1-FOXO1-FTH1 signaling axis. FEACR and its downstream factors can be considered novel targets for mitigating ferroptosis-related MI in ischemic heart disease [25].
In a pathological CH model using transverse aortic constriction (TAC) mice, circCmss1 was significantly increased in normal TAC mice but decreased in NSD2−/− TAC mice. CircCmss1 interacts with the transcription factor EIF4A3 to induce the expression of transferrin receptor 1 (TfR1), thereby activating ferroptosis in cardiomyocytes [166].
The potential circRNA target for heart failure, circSnx12, can act as an endogenous sponge binding to miR-224-5p and regulating the miRNA binding site in the 3’UTR region of FTH1. Knockdown of circSnx12 increases ferroptosis, which is associated with mitochondrial abnormalities and myocardial cell death, exacerbating heart failure [167].
The role of circRNA-regulated ferroptosis in CVDs focuses on affecting cardiac function through the induction of cell death in cardiomyocytes and other cells. Current research frequently employs animal models of corresponding CVDs. The combined regulation of autophagy and ferroptosis by circRNAs is also receiving significant attention. Molecular information in this process, such as signaling axes involved in circRNA-regulated ferroptosis in CVDs, is gradually being elucidated, offering substantial targeted therapeutic potential for CVDs (Fig. 4).
Through their interaction with specific miRNAs and modulation of key signaling networks, circRNAs exert regulatory control over ferroptosis. The figure illustrates the involvement of various circRNAs in the regulation of ferroptotic pathways in CVDs.
Pyroptosis
Cell pyroptosis is a form of PCD associated with inflammatory responses [168]. Pyroptosis can be triggered by oxidative stress, hyperglycemia, inflammation, and other stimuli [169]. It is dependent on caspase-1 and is characterized by the release of large amounts of pro-inflammatory factors, making it a form of apoptosis specific to single cells [170]. Pyroptosis continues to receive widespread attention in the fields of CVDs, cancer, and metabolic diseases [171,172,173,174]. Its role in disease mechanisms, particularly through causing inflammation and tissue damage, is especially emphasized. Pyroptosis plays a crucial role in CVDs [175]. Currently, research on circRNA regulation of pyroptosis in the field of CVDs is relatively limited, primarily focusing on atherosclerosis, diabetic cardiomyopathy, heart failure, I/R injury, and MI.
In atherosclerosis mouse models and HUVECs treated with ox-LDL, upregulation of circ-USP9× has been observed. Circ-USP9× promotes ox-LDL-induced pyroptosis in HUVECs by binding to EIF4A3 and enhancing GSDMD stability in the cytoplasm. Conversely, the knockdown of circ-USP9× inhibits ox-LDL-induced pyroptosis in HUVECs [176]. CircRNA DICAR is considered an important endogenous regulator of diabetic cardiomyopathy and cardiomyocyte pyroptosis, functioning through DICAR-VCP-Med12 degradation. Studies have found that DICAR-deficient (DICAR+/−) mice exhibit spontaneous cardiac dysfunction and abnormal cardiomyocyte morphology, and DICAR knockout also enhances diabetic cardiomyocyte pyroptosis. Clinical samples have shown that DICAR expression in the circulating blood of diabetic patients is lower than in healthy controls [46].
The sponging function of circRNAs is significant in regulating pyroptosis. In the context of heart failure, circ-0006332 has been found to exacerbate pyroptosis and apoptosis, while also worsening cardiac dysfunction and myocardial fibrosis. This effect is mediated by sponging miR-143, leading to the upregulation of TLR2 [177]. As mentioned earlier, knockdown of circPAN3 has been shown to effectively alleviate autophagy and apoptosis, while another study focused on the reduction of pyroptosis following circPAN3 knockdown under I/R injury conditions, achieved by decreasing its sponging of miR-29b-3p [178]. CircDGKZ, via the miR-345-5p/TLR4/NF-κB axis, reduces pyroptosis while increasing autophagy, thereby mitigating I/R injury [179]. In cardiomyocytes, miR-133a-3p inhibit NLRP3 inflammasome activation induced by MI, while circHelz acts as an endogenous sponge for miR-133a-3p, inhibiting its activity and enhancing pyroptosis. CircHelz can also directly trigger NLRP3 inflammasome-mediated pro-inflammatory responses, causing MI. Therefore, silencing circHelz holds potential therapeutic value for alleviating ischemic heart disease [180].
Although the number of studies on circRNA regulation of pyroptosis in CVD treatment is still limited, the potential regulatory mechanisms of circRNAs on pyroptosis have gradually been uncovered. CircRNAs may serve as candidate drugs for the clinical treatment of CVDs or as upstream molecular signals, demonstrating significant research potential (Fig. 5).
Cell pyroptosis is dependent on caspase-1 and is characterized by the release of large amounts of pro-inflammatory factors, with or without sponging miRNA. The figure highlights pro-pyroptotic circRNAs in the context of CVD progression like circ-0006332, circ-Helz and circ-USP9x, underscoring their therapeutic potential.
Necroptosis
Necroptosis is a pathway independent of caspase activation, characterized morphologically by distinctive plasma membrane rupture, and induces an inflammatory response [181, 182]. Necrosis continues to attract attention in the fields of CVDs, tumors, neurological disorders, renal injury, and other diseases [155, 160, 183,184,185,186,187]. At present, there is a relatively limited amount of research on circRNA regulation of necroptosis in the field of CVDs.
In H2O2-induced necroptosis of human aorta smooth muscle cells, an upregulation of circHIPK3 was observed. CircHIPK3 impairs mitochondrial energy production and induces cell death by acting on DRP1, but its mechanism of action on mitochondrial function is independent of DRP1 abundance. In vivo experiments revealed that the downregulation of circHIPK3 can regulate necroptosis and vulnerable plaque formation in ApoE−/− mice, making it a promising therapeutic target for atherosclerosis [188].
Mmu_circ_000338, a cardiac-necroptosis-associated circRNA, is observed to be downregulated in cardiomyocytes exposed to H/R and in the hearts of mice with I/R injury. Overexpression of CNEACR reduces necroptosis and improves cardiac function in I/R injured hearts. The CNEACR/HDAC7/Foxa2/RIPK3 axis involved in this process may serve as an effective target for mitigating MI caused by necroptosis in ischemic heart disease (Table 2) [189].
The research on the regulation of necroptosis by circRNAs in CVDs is still in its early stages, involving relatively few CVDs and circRNAs. However, necroptosis has garnered extensive research attention across various disease fields, including CVDs. The signaling pathways by which circRNAs regulate necroptosis are gradually being elucidated, and the application of circRNA regulation of necroptosis in CVDs could provide new therapeutic targets, presenting strong developmental prospects for this field (Fig. 6).
Necroptosis is a caspase-independent cell death pathway associated with membrane rupture and inflammation. The figure depicts circRNA-regulated necroptotic signaling, including DRP1-mediated mitochondrial dysfunction and the Foxa2/RIPK3 axis, emphasizing circRNAs as emerging modulators in CVD pathogenesis.
Conclusions and perspectives
CVDs remain a critical global health challenge, with PCD playing a pivotal role in their progression. CircRNAs have garnered considerable attention for their ability to regulate PCD through various signaling pathways, thereby influencing the development and progression of CVDs. Significant advancements in this area have been achieved. For example, Made et al. constructed a circRNA-miRNA-mRNA dysregulation network in patients with ischemic heart failure, identifying approximately 662 circRNA-miRNA-mRNA interactions in the heart, thus providing novel insights into the pathogenesis of CVDs [190]. Another study in 2023 highlighted the potential of detecting differential circRNA profiles in peripheral circulation via exosomes, underscoring their promise as biomarkers and therapeutic carriers for targeted CVD treatment [191].
Clinical approaches to improving CVD treatment by targeting PCD have already been widely applied. Drugs such as dapagliflozin, carvedilol, dexmedetomidine, simvastatin, nicorandil, and trimetazidine have demonstrated therapeutic effects through various signaling pathways [192,193,194,195,196,197]. These therapies are effective against conditions like AMI, I/RI and HF, as well as mitigating cardiotoxicity induced by chemotherapeutic agents with strong PCD-inducing capabilities, such as cisplatin and paclitaxel [198,199,200,201,202,203,204,205,206,207]. However, the range of available drugs remains limited, highlighting the urgent need to develop new therapeutic strategies for CVD management. Research on circRNAs in CVDs continues to expand, with a primary focus on their role in regulating apoptosis, followed by autophagy and ferroptosis. In contrast, the effects of circRNAs on pyroptosis and necroptosis remain underexplored. While the regulatory roles of circRNAs in various types of cell death during CVD events are significant, and mediated signaling pathways have been partially elucidated, the majority of findings have yet to be translated into clinical applications [208].
Several challenges hinder the clinical translation of circRNA research. First, the lack of a standardized nomenclature for circRNAs complicates communication among researchers [209], as the same circRNA may be referred to by different names in different studies. Second, circRNAs may also play roles in maintaining normal physiological functions, making circRNA-targeted therapies a double-edged sword [21]. Lastly, while the use of circRNAs as diagnostic biomarkers and therapeutic targets represents an emerging direction, their full potential remains to be explored [210].
In summary, the interplay between circRNAs and PCD in the context of CVDs has attracted increasing attention and made substantial progress. This promising field is poised for significant future advancements.
Data availability
All data generated or analyzed during this study are included in this article.
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We are grateful to Shaoling Li from Tongji University for her support in reading and revising the manuscript.
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This work was supported by grants from the National Natural Science Foundation of China (82204831, 82174120), the Natural Science Foundation of Shanghai (No. 21ZR1463100), the Program of Shanghai Academic Research Leader (22XD1423400), and the Shanghai Sailing Program (No. 22YF1448800).
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Runfang Pan: conceptualization, formal analysis, and writing the original draft. Chinying Koo: validation and project administration. Wenyuan Su: investigation and project administration. Qianhui You: investigation. Haidong Guo: writing - review and editing. Baonian Liu: writing - review, editing, and conceptualization. All authors contributed to the article and approved the submitted version.
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Pan, R., Koo, C., Su, W. et al. Circular RNAs modulate cell death in cardiovascular diseases. Cell Death Discov. 11, 214 (2025). https://doi.org/10.1038/s41420-025-02504-x
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DOI: https://doi.org/10.1038/s41420-025-02504-x
