Circular RNAs (circRNAs) are a unique class of covalently closed single-stranded RNA molecules that play diverse roles in normal physiology and pathology. Among the major types of circRNA, exon-intron circRNA (EIciRNA) distinguishes itself by its sequence composition and nuclear localization. Recent RNA-seq technologies and computational methods have facilitated the detection and characterization of EIciRNAs, with features like circRNA intron retention (CIR) and tissue-specificity being characterized. EIciRNAs have been identified to exert their functions via mechanisms such as regulating gene transcription, and the physiological relevance of EIciRNAs has been reported. Within this review, we present a summary of the current understanding of EIciRNAs, delving into their identification and molecular functions. Additionally, we emphasize factors regulating EIciRNA biogenesis and the physiological roles of EIciRNAs based on recent research. We also discuss the future challenges in EIciRNA exploration, underscoring the potential for novel functions and functional mechanisms of EIciRNAs for further investigation.

Non-coding RNAs (ncRNAs) have gained significant attention in recent years due to advancements in biotechnology, particularly high-throughput total RNA sequencing. These developments have led to new understandings of non-coding biology, revealing that approximately 80% of non-coding regions in the genome possesses biochemical functionality. Among ncRNAs, circular RNAs (circRNAs), first identified in 1976, have emerged as a prominent research field. CircRNAs are abundant in most human cell types, evolutionary conserved, highly stable, and formed by back-splicing events which generate covalently closed ends. Notably, circRNAs exhibit high expression levels in neural tissue and perform diverse biochemical functions, including acting as molecular sponges for microRNAs, interacting with RNA-binding proteins to regulate their availability and activity, modulating transcription and splicing, and even translating into functional peptides in some cases. Recent advancements in computational and experimental methods have enhanced our ability to identify and validate circRNAs, providing valuable insights into their biological roles. This review focuses on recent developments in circRNA research as they related to neuropsychiatric and neurodegenerative conditions. We also explore their potential applications in clinical diagnostics, therapeutics, and future research directions. CircRNAs remain a relatively underexplored area of non-coding biology, particularly in the context of neurological disorders. However, emerging evidence supports their role as critical players in the etiology and molecular mechanisms of conditions such as schizophrenia, bipolar disorder, major depressive disorder, Alzheimer's disease, and Parkinson's disease. These findings suggest that circRNAs may provide a novel framework contributing to the molecular dysfunctions underpinning these complex neurological conditions.

Ovarian cancer remains a major challenge in oncology due to its complex biology and late-stage diagnosis. Recent advances in molecular biology have highlighted the crucial role of non-coding RNAs (ncRNAs) in regulating apoptosis and cancer progression. NcRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have emerged as significant players in the molecular networks governing ovarian cancer. Despite these insights, the precise mechanisms by which ncRNAs influence ovarian cancer pathology are not fully understood. This complexity, combined with the heterogeneity of the disease and the development of treatment resistance, poses substantial obstacles to effective therapeutic development. Additionally, the lack of reliable early detection methods further complicates treatment strategies. This manuscript reviews the current state of research on ncRNAs in ovarian cancer, discusses the challenges in translating these findings into clinical applications, and outlines potential future directions. Emphasis is placed on the need for integrated approaches to unravel the intricate roles of ncRNAs, improve early detection, and develop personalized treatment strategies to address the diverse and evolving nature of ovarian cancer. While these findings provide valuable insights, it is crucial to recognize that many results are based on preclinical studies and require further validation to establish their clinical applicability.

Circular RNAs (circRNAs) are an expanding class of largely unexplored RNAs which are prominently enriched in the mammalian brain. Here, we systematically interrogate their role in excitatory synaptogenesis of rat hippocampal neurons using RNA interference. Thereby, we identify seven circRNAs as negative regulators of excitatory synapse formation, many of which contain high-affinity microRNA binding sites. Knockdown of one of these candidates, circRERE, promotes the formation of electrophysiologically silent synapses. Mechanistically, circRERE knockdown results in a preferential upregulation of synaptic mRNAs containing binding sites for miR-128-3p. Overexpression of circRERE stabilizes miR-128-3p and rescues exaggerated synapse formation upon circRERE knockdown in a miR-128-3p binding site-specific manner. Overall, our results uncover circRERE-mediated stabilization of miR-128-3p as a means to restrict the formation of silent excitatory synaptic co-clusters and more generally implicate circRNA-dependent microRNA regulation in the control of synapse development and function.

This study aimed to investigate the involvement of hsa_circ_0074763 in the activation of HSCs (hepatic stellate cells ) and liver fibrosis. Additionally, it aimed to conduct a preliminary analysis of the molecular mechanism targeting miR-3667-3p/ACSL4 (Long-chain acyl-CoA synthetase 4), thereby providing novel molecular targets for liver fibrosis. The GEO database was utilized to identify differentially expressed hsa_circ_0074763 and determined its subcellular localization in LX-2 cells using fluorescence in situ hybridization. Bioinformatics analysis was employed for result prediction, and the interaction between hsa_circ_0074763 and miR-3667-3P was confirmed using dual-luciferase reporter gene assay. ACSL4 mediated ferroptosis was detected with kit. Hsa_circ_0074763 exhibits high expression levels in the fibrosis model. Validation through dual-luciferase reporter gene assays confirms the interaction between hsa_circ_0074763 and miR-3667-3P. Functional cell experiments demonstrate that overexpression of hsa_circ_0074763 promotes proliferation of LX-2 cells, elevates inflammation levels, and inhibits apoptosis. Additionally, ACSL4 has been identified as a direct target of miR-3667-3P, with overexpression of hsa_circ_0074763 counteracting the inhibitory effect on ACSL4 by suppressing miR-3667-3P. Overexpression of ACSL4 increased the expression levels of ROS (Lipid Oxidation), Iron (Ferro Orange) and MDA (Malondialdehyde), and decreased the expression levels of GPX4 (Glutathione peroxidase 4) and GSH (Glutathione). Our finding suggests that overexpression of hsa_circ_0074763 likely enhances the HSC activation through modulation of the miR-3667-3P/ACSL4 axis. Therefore, hsa_circ_0074763 holds potential as a therapeutic target for liver fibrosis.

Non-coding RNAs (ncRNAs) play crucial roles in colorectal cancer (CRC) development and progression. Recent developments in single-cell transcriptome profiling methods have revealed surprising levels of expression variability among seemingly homogeneous cells, suggesting the existence of many more cell types than previously estimated. This review synthesizes recent advances in ncRNA research in CRC, emphasizing single-cell bioinformatics approaches for their analysis. We explore computational methods and tools used for ncRNA identification, characterization, and functional prediction in CRC, with a focus on single-cell RNA sequencing (scRNA-seq) data. The review highlights key bioinformatics strategies, including sequence-based and structure-based approaches, machine learning applications, and multi-omics data integration. We discuss how these computational techniques can be applied to analyze differential expression, perform functional enrichment, and construct regulatory networks involving ncRNAs in CRC. Additionally, we examine the role of bioinformatics in leveraging ncRNAs as diagnostic and prognostic biomarkers for CRC. We also discuss recent scRNA-seq studies revealing ncRNA heterogeneity in CRC. This review aims to provide a comprehensive overview of the current state of single-cell bioinformatics in ncRNA CRC research and outline future directions in this rapidly evolving field, emphasizing the integration of computational approaches with experimental validation to advance our understanding of ncRNA biology in CRC.

Herpesviruses require the host transcriptional machinery, inducing significant changes in gene expression to prioritize viral transcripts. We examined alpha- and gamma-herpesvirus alterations to a type of alternative splicing, namely circular RNA (circRNA) synthesis. We developed "Circrnas in Host And viRuses anaLysis pIpEline" (CHARLIE) to facilitate viral profiling. This method identified thousands of back-splicing variants, including circRNA common to lytic and latent phases of infection. Ours is the first report of Herpes Simplex Virus-1 circRNAs, including species derived from ICP0 and the latency-associated transcript. We characterized back-splicing cis- and trans-elements, and found viral circRNAs resistant to spliceosome perturbation and lacking canonical splice donor-acceptors. Subsequent loss-of-function studies of host RNA ligases (RTCB, RLIG1) revealed instances of decreased viral back splicing. Using eCLIP and 4sU-Sequencing, we determined that the KSHV RNA-binding protein, ORF57, enhanced synthesis for a subset of viral and host circRNAs. Our work explores unique splicing mechanisms driven by lytic infection, and identifies a class of transcripts with the potential to function in replication, persistence, or tumorigenesis.

Pulmonary hypertension (PH) is a malignant cardiovascular disease with a complex etiology. 5-Methylcytosine (m5C) is a post-transcriptional RNA modification identified in both stable and highly abundant RNAs, with a lower frequency of occurrence in circular RNAs (circRNAs). Nevertheless, the function of m5C-modified circRNAs in the pathogenesis of PH remains uncertain. The objective of this study was to investigate the biological role and molecular mechanisms of m5C-modified circRNA-CCNL2 in hypoxic PH pulmonary vascular remodeling. Our findings revealed that hypoxia downregulates circCCNL2 expression, and overexpression of circCCNL2 attenuates PH progression and inhibits the proliferation of pulmonary artery smooth muscle cell (PASMCs). Bioinformatics predictions indicated the presence of m5C modification sites in circCCNL2, which NSUN2 mediated. The downregulation of NSUN2 resulted in a reduction in m5C modification of circCCNL2. It was also observed that the stability of circRNAs was associated with the proliferation of PASMCs. From a mechanistic standpoint, low expression of circCCNL2 resulted in reduced binding of FXR2, while increased association of free FXR2 with CDKL3 led to enhanced proliferation of PASMCs. Notably, circCCNL2 expression was found to be regulated by alternative splicing involving SRSF2, with reduced pre-CCNL2 splicing resulting from low SRSF2 expression, ultimately leading to decreased circCCNL2 expression. This is the first demonstration that m5C-modified circCCNL2 can slow the development of PH and inhibit the proliferation of PASMCs by binding to FXR2. These findings offer new insights into the regulation of circRNAs through m5C modifications and the role of epigenetic reprogramming in PH.

Circular RNAs (circRNAs) are a class of novel RNA molecules featured by single-strand covalently closed circular structure, which not only are extensively found in eukaryotes and are highly conserved, but also conduct paramount roles in the occurrence and progression of pancreatic cancer (PC) through diverse mechanisms. As recent studies have demonstrated, circRNAs typically exhibit tissue-specific and cell specific expression patterns, with strong potential as biomarkers for disease diagnosis and prognosis. On the basis of their localization and specific interactions with DNA, RNA, and proteins, circRNAs are considered to possess specific biological functions by acting as microRNA (miRNA) sponges, RNA binding protein (RBP) sponges, transcriptional regulators, molecular scaffolds and translation templates. On that account, further addressing the technical difficulties in the detection and research of circRNAs and filling gaps in their biological knowledge will definitely push ahead this comparatively young research field and bring circRNAs to the forefront of clinical practice. Thus, this review systematically summarizes the biogenesis, function, molecular mechanisms, biomarkers and therapeutic targets of circRNAs in PC.

Background: Abnormal activation of microglia occurs in the early stage of Alzheimer's disease (AD) and leads to subsequent neuroinflammation and major AD pathologies. Circular RNAs (circRNAs) are emerging as great potential therapeutic targets in AD. However, the extent of circRNAs entwined and the underlying mechanism in microglia-driven neuroinflammation in AD remain elusive. Methods: The circular RNA Dlg1 (circDlg1) was identified using circRNA microarray screening in magnetic-isolated microglia of APP/PS1 mice. CircDlg1 expression in microglia of APP/PS1 mice and AD patients was validated by FISH. Flow cytometry and immunostaining were conducted to explore the roles of circDlg1 in microglia. Adeno-associated virus 9 preparations for interfering with microglial circDlg1 were microinjected into mouse lateral ventricle to explore influences on microglial response, neuroinflammation and AD pathologies. Y-maze, novel object recognition and Morris water maze tasks were performed to assess cognitive performance. RNA pulldown assays, mass spectrometry analysis, RNA immunoprecipitation, and co-immunoprecipitation were performed to validate the underlying regulatory mechanisms of circDlg1. Results: A novel circular RNA circDlg1 was observed elevated using circRNA microarray screening in microglia isolated from APP/PS1 mice and validated increased in intracerebral microglia of AD patients. Microglia-specific knockdown of circDlg1 remarkably ameliorated microglial recruitment and envelopment of amyloid-β (Aβ), mitigated neuroinflammation, and prevented cognitive decline in APP/PS1 mice. Mechanistically, circDlg1 interfered with the interaction between phosphodiesterase 4b (PDE4B) and Smurf2, an E3 ubiquitin ligase of PDE4B. The formed ternary complex protected PDE4B from ubiquitination-dependent degradation via unique N-terminal targeting domain, thus consequently decreasing cAMP levels. We further confirmed that microglial circDlg1 downregulation significantly activated PKA/CREB anti-inflammatory pathway by decreasing PDE4B protein levels in APP/PS1 mice. Conclusion: The novel microglia-upregulated circDlg1 tightly involves in neuroinflammation in APP/PS1 mice via determining the protein fate of PDE4B. Microglial loss of circDlg1 promotes microglial protective response to Aβ deposition and relieves neuroinflammation, thus suggesting a potential therapeutic strategy that specifically targets the microglial response in AD.

Pulmonary hypertension (PH) is a devastating disease marked by elevated pulmonary artery pressure, resulting in right ventricular (RV) failure and mortality. Despite the identification of several dysregulated genes in PH, the involvement of circular RNAs (circRNAs), a subset of long noncoding RNAs, remains largely unknown.

In this study, high-throughput RNA sequencing was performed to analyze the genome-wide expression patterns of circRNAs in pulmonary arteries from three models of PH rats induced by hypoxia (Hyp), hypoxia/Sugen5416 (HySu), and monocrotaline (MCT). Differentially expressed circRNAs (DEcircRNAs) were identified, and a weighted gene coexpression network was constructed to explore circRNA networks associated with PH pathogenesis. A circRNA-miRNA-mRNA regulatory network was built, and the functional significance of targeted mRNAs was evaluated. Single-cell RNA sequencing provided insights into the distribution of cell type-specific circRNAs across PH progression.

Our analysis revealed 45 circRNAs exhibiting significant changes across all three PH rat models, with their host genes participating in the calcium signaling and muscle contraction. We identified 372 PH-related circRNA-miRNA-mRNA interactions, shedding light on the regulatory networks during PH development. Furthermore, we uncovered 186, 195 and 311 Hyp-, Hysu- and MCT-specific circRNAs, respectively. These circRNAs were enriched in distinct biological processes, emphasizing their unique regulatory roles. Single-cell spatial distribution analysis of these circRNAs in the pulmonary arteries of PH patients revealed that Hyp-specific circRNA predominantly appeared in the pulmonary vascular structural cells, while HySu- and MCT-specific circRNAs exhibited broader distribution, including significant enrichment in immune-related cells.

Our study presents the first comprehensive view of circRNA regulatory networks in the pulmonary arteries of three PH rat models. We provide insights into PH-associated circRNAs, particularly their involvement in calcium signaling and muscle contraction.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in cell proliferation and metastasis and is upregulated in a variety of cancers. However, the biological function and regulatory mechanism of NSUN2-mediated m5C modification have not been well studied in HCC. Our results showed that NSUN2 is upregulated and associated with poor prognosis in HCC patients after hepatectomy. NSUN2 overexpression significantly promoted HCC growth and metastasis, whereas NSUN2 knockdown had the opposite effect. m5C RNA immunoprecipitation sequencing (m5C-RIP-Seq) revealed that m5C hypermethylation correlates with mRNA overexpression and that NSUN2-mediated m5C hypermethylation promotes metabolism in HCC patients. Mechanistically, our data revealed that PKM2, a terminal enzyme in the glycolytic pathway, is a downstream target of NSUN2-mediated m5C modification. Specifically, NSUN2 could stabilize PKM2 mRNA by increasing the m5C level of the m5C site C773 in the 3'-UTR of PKM2 mRNA. In addition, rescue assays revealed that NSUN2 promotes HCC glycolysis and progression by upregulating PKM2. In conclusion, this study revealed that NSUN2-mediated m5C modification promotes glycolysis and the progression of hepatocellular carcinoma by stabilizing PKM2 mRNA, and provides a potential prognostic factor and therapeutic target for HCC patients.

Circular RNA (circRNA), a subtype of noncoding RNA, has emerged as a significant focus in RNA research due to its distinctive covalently closed loop structure. CircRNAs play pivotal roles in diverse physiological and pathological processes, functioning through mechanisms such as miRNAs or proteins sponging, regulation of splicing and gene expression, and serving as translation templates, particularly in the context of various cancers. The hallmarks of cancer comprise functional capabilities acquired during carcinogenesis and tumor progression, providing a conceptual framework that elucidates the nature of the malignant transformation. Although numerous studies have elucidated the role of circRNAs in the hallmarks of cancers, their functions in the development of chemoradiotherapy resistance remain unexplored and the clinical applications of circRNA-based translational therapeutics are still in their infancy. This review provides a comprehensive overview of circRNAs, covering their biogenesis, unique characteristics, functions, and turnover mechanisms. We also summarize the involvement of circRNAs in cancer hallmarks and their clinical relevance as biomarkers and therapeutic targets, especially in thyroid cancer (TC). Considering the potential of circRNAs as biomarkers and the fascination of circRNA-based therapeutics, the "Ying-Yang" dynamic regulations of circRNAs in TC warrant vastly dedicated investigations.

Breast cancer (BC) is a malignant tumor, that damages the physical health of female patients. It is crucial to develop new treatment strategies for BC, as this disease significantly affects the quality of life of women in both developing and developed countries, despite the existence of effective treatment options to reduce mortality. Recently, several researchers have been studying circular RNAs (circRNAs) in BC due to their stability and sponge function. In the present study, a new circRNA, hsa_circ_0001508, was discovered using Gene Chip's prediction. This gene is important because it is novel in BC. However, due to financial constraints, the study was designed as a pilot study for future research. The present study included several common biomedical experimental techniques, such as reverse transcription-quantitative PCR, flow cytometry, cell counting, cell invasion, wound healing assay and western blotting. It also involves the use of DNA microarray (gene chip) and prediction of microRNA and mRNA interactions using bioinformatics tools such as TargetScan. The findings revealed that hsa_circ_0001508 exhibits carcinogenic properties that facilitate the progression of BC. Furthermore, potential binding sites were identified as crucial areas for future investigation.

Circular RNAs (circRNAs), a type of head-to-tail closed RNA molecules, have been implicated in various aspects of plant development and stress responses through transcriptome sequencing; however, the precise functional roles of circRNAs in plants remain poorly understood. In this study, we identified a highly expressed circular RNA, circZmMED16, derived from exon 8 of the mediator complex subunit 16 (ZmMED16) across different maize (Zea mays L.) inbred lines using circRNA-seq analysis. This circRNA is predominantly expressed in maize tassels and functions in the cytoplasm. Overexpression of circZmMED16 resulted in increased expression of ZmMED16/AtMED16 and delayed flowering in both maize and Arabidopsis thaliana, compared with that in wild-type plants. In contrast, overexpression of the parent gene ZmMED16 did not alter the flowering time of transgenic plants in Arabidopsis, suggesting that circZmMED16 plays a specific role in regulating flowering, distinct from that of linear ZmMED16. To further understand the mechanisms underlying the regulation of flowering time by circZmMED16, we performed RNA pull-down, dual-luciferase, RNA interference (RNAi), and ribonuclease protection assays (RPA). These results indicate that circZmMED16 interacts with small subunit 1 of ADP-glucose pyrophosphorylase (APS1) mRNA in both maize and Arabidopsis. The knockdown of circZmMED16 increased the expression of ZmAPS1, whereas the overexpression of circZmMED16 led to the downregulation of ZmAPS1 RNA and protein. By affecting ZmAPS1 expression, circZmMED16 reduced ADP-glucose pyrophosphorylase (AGPase) activity and led to delayed flowering. These results revealed a novel regulatory mechanism for circRNAs in flowering time and shed light on their functional and regulatory roles in plants.

Advancements in bioinformatic tools and breakthroughs in high throughput RNA sequencing have unveiled the potential role of non-coding RNAs in influencing the overall expression of disease-responsive genes. Owing to the increasing need to develop resilient crop varieties against environmental constraints, our study explores the functional relationship of various non-coding RNAs in wheat during leaf rust pathogenesis. MicroRNAs (miRNAs) and circular RNAs (circRNAs) were retrieved from SAGE and RNA-Seq libraries, respectively, in the susceptible (HD2329) and resistant (HD2329 + Lr28) wheat Near-Isogenic Lines (NILs). Here we explored the previously published circRNAs for their differential expression and correlated the data with the differentially expressed miRNAs (DEMs) through various in silico methods to acquire the target miRNAs of circRNAs and the downstream target mRNAs of miRNAs. Finally, a competing endogenous RNA (ceRNAs) regulatory network was constructed and validated through RT-qPCR method. We have identified the ceRNA regulatory network of four differentially expressed circRNAs (DECs) and five DEMs to highlight their crucial roles in the robust enhancement of the temporal expression profiles of five defense responsive genes (mRNAs) in wheat NILs against leaf rust infection. The study confirms the synergistic expression of circRNAs and mRNAs with an antagonistic correlation with the expression profile of the corresponding miRNAs. The vital role of leaf rust-resistant gene Lr28 has also been highlighted for driving the efficiency of the circRNAs to upregulate target gene expression. Thus, understanding the circRNA-miRNA-target gene interaction during leaf rust pathogenesis can help to identify stress-specific regulatory biomarkers to enhance defense responses in wheat for improved resilience through multi-omics integration of transcriptomics, proteomics and metabolomics.

The prominence of circular RNAs (circRNAs) has surged in cancer research due to their distinctive properties and impact on cancer development. This review delves into the role of circRNAs in four key cancer types: colorectal cancer (CRC), gastric cancer (GC), liver cancer (HCC), and lung cancer (LUAD). The focus lies on their potential as cancer biomarkers and drug targets. Our study analyses the reported circRNAs in the mentioned malignancies, examining their nature, functions, targets, origins, and contributions as tumor enhancers or suppressors. The approach involved assessing full-text reports on PMC, utilizing keywords such as "CircRNA" and "Cancer types," coupled with bioinformatics, experimental assays, or clinical investigations. Exclusions encompassed non-English publications, conference abstracts, letters, and expert opinions. The findings unveil 577 identified circRNAs across these cancer types: 124 in CRC, 177 in GC, 93 in HCC, and 183 in LUAD. Mechanistic insights into how circRNAs modulate gene expression in cancer are explored, particularly their interactions with microRNAs and RNA-binding proteins. Dysregulation of circRNAs across various cancers and their potential as diagnostic and prognostic indicators are synthesized. The exploration extends to the potential of targeting circRNAs as a novel cancer therapy strategy, either through inhibiting oncogenic circRNAs or reinstating tumor-suppressive ones. This article discusses the challenges and prospects in harnessing circRNAs for cancer diagnostics and therapies. These comprehensive analyses hold promise for advancing cancer research and fostering the development of innovative therapies and diagnostics.

Chickens are vital agricultural animals that supply a significant portion of the protein consumed by humans. In society today, enhancing the productive performance of chickens in a safe and efficient manner has become a central focus of research. This performance is determined by various production traits that are primarily influenced by multiple factors, including epigenetics-a critical aspect of gene regulation. Circular RNAs (circRNAs), a unique class of non-coding RNAs, have emerged as key epigenetic regulators. Recent studies have demonstrated that circRNAs are extensively engaged in numerous production traits, which include skeletal muscle formation, fat deposition, ovarian follicle development, liver function, bone development, immunity, and resistance to environmental stress. These processes play crucial roles in determining the overall productivity of chickens. Given the significance of circRNAs in these various traits, this article provides a comprehensive review of the functional circRNAs associated with different traits in chickens, serving as a valuable theoretical reference for future research. Further investigation into the role of circRNAs may reveal novel insights into the molecular mechanisms underlying key economic traits in chickens and pave the way for innovative strategies in molecular breeding aimed at enhancing chicken productive performance.

Laryngeal cancer remains a significant global health concern, with poor prognosis for advanced-stage disease highlighting the need for novel diagnostic, prognostic, and therapeutic approaches. Circular RNAs (circRNAs), a class of covalently closed non-coding RNAs, have emerged as important regulators of gene expression and cellular processes in various cancers, including laryngeal cancer. This review summarizes the current understanding of circRNAs in laryngeal cancer, covering their biogenesis, regulatory mechanisms, and potential clinical applications. We explore the diverse functions of circRNAs, including their roles as miRNA sponges, protein interactors, and direct mRNA regulators, and their influence on key cellular processes such as proliferation, invasion, and metastasis. The review highlights promising circRNAs as diagnostic and prognostic biomarkers, as well as potential therapeutic targets. We also outline current strategies for circRNA modulation, including suppression techniques like RNA interference and CRISPR/Cas systems, and overexpression methods using vectors and synthetic circRNAs.

Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide, posing a substantial public health burden. Despite advancements in treatment, the complex etiology of CHD necessitates ongoing exploration of novel diagnostic markers and therapeutic targets. Circular RNAs (circRNAs), a distinct class of non‑coding RNAs with a covalently closed loop structure, have emerged as significant regulators in various diseases, including CHD. Their high stability, tissue‑specific expression and evolutionary conservation underscore their potential as biomarkers and therapeutic agents in CHD. This review discusses the current knowledge on circRNAs in the context of CHD and explores the molecular mechanisms by which circRNAs influence the pathophysiology of CHD, including cardiomyocyte death, endothelial injury, vascular dysfunction and inflammation. It also summarizes the emerging evidence highlighting the differential expression of circRNAs in patients with CHD and their potential utilities as non‑invasive diagnostic and prognostic biomarkers and therapeutic targets for this disease.

The specific expression profile and function of circular RNA (circRNA) in follicular atresia remain largely unknown. Here, the circRNA expression profiles of granulosa cells derived from healthy follicles (HFs) and antral follicles (AFs) in buffalo were analyzed by RNA-seq, and the mechanism of a differentially expressed circRNA (DEcircRNA) circTEC regulating the granulosa cell function that affects follicular atresia was further explored. RNA-seq results showed that a total of 112 DEcircRNAs were identified. Among them, circTEC was highly expressed in HF, and its circular structure was confirmed by RNase R digestion assay, reversed PCR and Sanger sequencing. Functional experiments demonstrated that circTEC promotes the proliferation and steroid hormone synthesis of buffalo granulosa cells (bGCs), and it also inhibits their apoptosis. In-depth mechanism analysis showed that the expression level of circTEC in bGCs from AFs was adversely related to miR-144-5p and consistent with FZD3. CircTEC acts as an endogenous sponge of miR-144-5p to regulate the expression of the target gene FZD3 in AFs, which promotes the proliferation of bGCs and inhibits bGCs apoptosis, thereby inhibiting follicular atresia in buffalo. In summary, our study revealed the regulatory role of the circTEC/miR-144-5p/FZD3 axis during follicular atresia in buffalo. These results provided new insights into the biological mechanism underlying follicular atresia.

Circular RNAs (circRNAs) are important players involved in a variety of physiological and pathological processes. However, their functions and mechanisms during myocardial ischaemic injury and protection remain largely unknown. We recently found significant alterations of many circRNAs including circCHSY1 following myocardial ischaemia/reperfusion (I/R) injury, whereas their exact functions are unclear. Here, we investigated the roles of circCHSY1 in the acute myocardial I/R injury and the potential mechanisms involved.

The expression of circCHSY1 was detected in cardiomyocytes from mouse, rat, and human embryonic stem cells (hESC-CMs). It was further up-regulated in mouse I/R (30 min/24 h) hearts, oxygen glucose deprivation/reperfusion (OGD/R, 6 h/2 h) primary neonatal rat ventricular cardiomyocytes (NRCMs) and OGD/R (48 h/2 h) hESC-CMs. Adenovirus-mediated circCHSY1 overexpression significantly decreased infarct size and lactate dehydrogenase (LDH) release in mouse I/R hearts. Consistently, circCHSY1 overexpression reduced the LDH release in the OGD/R NRCMs and hESC-CMs, improved cell viability, and preserved mitochondrial function in the OGD/R NRCMs, whereas there were no significant differences in cell viability and LDH release between the OGD/R NRCMs with and without small interfering RNA (siRNA)-mediated circCHSY1 knockdown. Mechanistically, circCHSY1 was detected to bind with miR-24-3p analysed by dual-luciferase assay and RNA pull-down assays. CircCHSY1 overexpression-mediated protective effects on cells and mitochondria in OGD/R NRCMs were reversed by the miR-24-3p mimic. Furthermore, dual-luciferase assay showed that miR-24-3p was directly bound to heme oxygenase 1 (HO1) via its 3'UTR. The protein level of HO1 was down-regulated by miR-24-3p mimic in OGD/R NRCMs but enhanced by the circCHSY1 overexpression in vitro and in vivo. Functionally, the HO1 knockdown by adenovirus in vivo and by siRNA in vitro eliminated cardioprotective effects of circCHSY1 overexpression.

CircCHSY1 is up-regulated following myocardial I/R injury. The higher level of circCHSY1 protects I/R hearts and cardiomyocytes. The protection of circCHSY1 is mediated through enhancement of the HO1 level, resulting in preserving mitochondrial homoeostasis via targeting miR-24-3p in cardiomyocytes. These findings suggest circCHSY1 as a protective factor.

The human intestinal epithelium has an impressive ability to respond to insults and its homeostasis is maintained by well-regulated mechanisms under various pathophysiological conditions. Nonetheless, acute injury and inhibited regeneration of the intestinal epithelium occur commonly in critically ill surgical patients, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Effective therapies for the preservation of intestinal epithelial integrity and for the prevention of mucosal hemorrhage and gut barrier dysfunction are limited, primarily because of a poor understanding of the mechanisms underlying mucosal disruption. Noncoding RNAs (ncRNAs), which include microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and small vault RNAs (vtRNAs), modulate a wide array of biological functions and have been identified as orchestrators of intestinal epithelial homeostasis. Here, we feature the roles of many important ncRNAs in controlling intestinal mucosal growth, barrier function, and repair after injury-particularly in the context of postoperative recovery from bowel surgery. We review recent literature surrounding the relationships between lncRNAs, microRNAs, and RNA-binding proteins and how their interactions impact cell survival, proliferation, migration, and cell-to-cell interactions in the intestinal epithelium. With advancing knowledge of ncRNA biology and growing recognition of the importance of ncRNAs in maintaining the intestinal epithelial integrity, ncRNAs provide novel therapeutic targets for treatments to preserve the gut epithelium in individuals suffering from critical surgical disorders.

The biological role of circ_0004858 (circYTHDF1) in pregnancy-induced hypertension (PIH) and the underlying mechanisms were unknown, and which were explored in this study.

ELISA was employed to detect the level of inflammatory cytokines and biochemical parameters; flow cytometry was employed to detect cell apoptosis; western blot and qRT-PCR were employed to examine expression level.

The level of IL-1β, TNF-α, IL-6, TGF-β1, ET-1, and Ang-II were significantly elevated in the peripheral blood of PIH patients. The co-culture of HUVEC and CD4+ T cells isolated from the peripheral blood of PIH patients significantly elevated the apoptosis and expression level of NRF2/HO-1 but reduced the protein level of ferroptosis-related markers (GPX4, FSP, and CoQ10B) in HUVEC. Also, the expression of circYTHDF1 and YTHDF1 were markedly up-regulated in HUVEC co-cultured with CD4+ T cells isolated from PIH patients, but miR-19b-3p expression was markedly down-regulated, and the similar results were observed in Ang-II-treated HUVEC. Based on the predicted binding sites, the luciferase reporter assay confirmed the interaction between miR-19b-3p and circYTHDF1 or YTHDF1. The results of qRT-PCR and western blot further demonstrated that circYTHDF1 competitively bound to miR-19b-3p to up-regulate YTHDF1 in HUVEC. Functionally, deleting circYTHDF1markedly reduced ferroptosis and apoptosis in Ang-II-treated HUVEC, but both which were reversed by miR-19b-3p inhibitor, suggesting the involvement of circYTHDF1/miR-19b-3p/YTHDF1 axis in vascular endothelial cell injury in PIH.

This study may provide a novel insight into the pathogenesis of PIH as well as a new treatment strategy.

Circular RNAs (circRNAs) exert diverse biological functions in different processes. However, the role of circRNAs during virus infection is mostly unknown. Herein, we explored the characteristics of host circRNAs using alphaherpesvirus pseudorabies virus (PRV) as a model. PRV infection upregulated the expression of circRNA circ29164, which does not encode a protein. RNA pulldown assays identified that circ29164 interacts with the microRNA ssc-miRNA-24-3p. Further analysis indicated that ssc-miR-24-3p targets the mRNA encoding kelch-like ECH-associated protein 1 (KEAP1), and circ29164 competitively binds to ssc-miR-24-3p to prevent it binding to Keap1. Apoptosis detection demonstrated that circ29164 or Keap1 overexpression, but not knockdown, induced caspase 3 activity and the release of cytochrome C from mitochondria, and inhibited PRV replication. Taken together, these data identified a previously undiscovered circRNA, circ29164, which inhibits PRV replication by competitively binding to ssc-24-3p to maintain KEAP1 levels.

Glioma is a highly lethal brain cancer in humans. Despite advancements in treatment, the prognosis for patients remains unfavorable. Epigenetic factors, along with their interactions and non-coding RNAs (ncRNAs), are crucial in glioma cells' development and aggressive characteristics. MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that modulate the expression of various genes by binding to target mRNA molecules. They play a critical role in regulating essential biological mechanisms such as cell proliferation and differentiation, cell cycle, and apoptosis. MiR-146a/miR-146b is a significant and prevalent miRNA whose expression alterations are linked to various pathological changes in cancer cells, as well as the modulation of several cellular signaling pathways, including NF-κB, TGF-β, PI3K/Akt, and Notch-1. Scientists may identify novel targets in clinical settings by studying the complicated link between Mir-146a/mir-146b, drug resistance, molecular pathways, and pharmacological intervention in gliomas. Additionally, its interactions with other ncRNAs, such as circular RNA and long non-coding RNA, contribute to the pathogenesis of glioma. As well as miR-146 holds potential as both a diagnostic and therapeutic biomarker for patients with this condition. In the current review, we investigate the significance of miRNAs in the context of glioma, with a particular focus on the critical role of Mir-146a/mir-146b in glioma tumors. Additionally, we examined the clinical relevance of this miRNA, highlighting its potential implications for diagnosis and treatment.

Gastric cancer (GC) is a global health concern, contributing significantly to cancer-related mortality rates. Early detection is vital for improving patient outcomes. Recently, circular RNAs (circRNAs) have emerged as crucial players in the development and progression of various cancers, including GC.

This comprehensive review underscores the promising potential of circRNAs as innovative biomarkers for the early diagnosis of GC, as well as their possible utility as therapeutic targets for this life-threatening disease. Specifically, the review focuses on recent findings, mechanistic insights, and clinical applications of circRNAs in GC.

Dysregulation of circRNAs has been consistently observed in GC tissues, offering potential diagnostic value due to their stability in bodily fluids such as blood and urine. For instance, circPTPN22 and hsa_circ_000200. Furthermore, the expression levels of circRNAs such as circCUL2, hsa_circ_0000705 and circSHKBP1 have shown strong associations with critical clinical features of GC, including diagnosis, prognosis, tumor size, lymph node metastasis, tumor-node-metastasis (TNM) stage, and treatment response. Additionally, circRNAs such as circBGN, circLMO7, and circMAP7D1 have shown interactions with specific microRNAs (miRNAs), proteins, and other molecules that play key roles in development and progression of GC. This further highlighting their potential as therapeutic targets. Despite their potential, several challenges need to be addressed to effectively apply circRNAs as GC biomarkers. These include standardizing detection methods, establishing cutoff values for diagnostic accuracy, and validating findings in larger patient cohorts. Moreover, the functional mechanisms by which circRNAs contribute to GC pathogenesis and therapeutic resistance warrant further investigation. Advances in circRNAs research could provide valuable insights into the early detection and targeted treatment of GC, ultimately improving patient outcomes.

Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells plays key roles in the pathogenesis of multiple vitreoretinal diseases, leading to profound and permanent vision loss. Circular RNAs (circRNAs) are widespread and functional endogenous RNAs that could regulate gene expression in eukaryotes. The functions of circRNAs in mediating EMT has been reported in several diseases. In the current study, we investigated the role of circRNA HIPK3 (circHIPK3) in EMT process of RPE cells (RPE-EMT). circHIPK3 is one abundant circRNA generated from the second exon of HIPK3 mRNA. We found that circHIPK3 expression was significantly increased in TGF-β1-induced RPE-EMT model. Silencing of circHIPK3 attenuated TGF-β1-induced RPE-EMT process, whereas forced expression of circHIPK3 could trigger EMT in RPE cells. Mechanistically, circHIPK3 regulates RPE-EMT process via sponging multiple microRNAs (miRNAs). This study provides novel insights into the mechanism of RPE-EMT. Targeting circHIPK3 might serve as a therapeutic strategy in RPE-EMT associated vitreoretinal diseases.

Increasingly studies highlight the crucial role of the ancestral retrovirus envelope protein ERVWE1 in the pathogenic mechanisms of schizophrenia, a severe psychiatric disorder affecting approximately 1% of the global population. Recent studies also underscore the significance of circular RNAs (circRNAs), crucial for neurogenesis and synaptogenesis, in maintaining neuronal functions. However, the precise relationship between ERVWE1 and circRNAs in the etiology of schizophrenia remains elusive.

This study observed elevated levels of hsa_circ_0001810 (circ_0001810) in the blood samples of schizophrenia patients, displaying a significant positive correlation with ERVWE1 expression. Interestingly, in vivo studies demonstrated that ERVWE1 upregulated circ_0001810 in neuronal cells. Circ_0001810, acting as a competing endogenous RNA (ceRNA), bound to miR-1197 and facilitated the release of adenylate kinase 2 (AK2). The bioinformatics analysis of the schizophrenia datasets revealed increased levels of AK2 and enrichment of mitochondrial dynamics. Notably, miR-1197 was reduced in schizophrenia patients, while AK2 levels were increased. Additionally, AK2 showed positive correlations with ERVWE1 and circ_0001810. Further studies demonstrated that AK2 led to mitochondrial dysfunction, characterized by loss of intracellular ATP, mitochondrial depolarization, and disruption of mitochondrial dynamics. Our comprehensive investigation suggested that ERVWE1 influenced ATP levels, promoted mitochondrial depolarization, and disrupted mitochondrial dynamics through the circ_0001810/AK2 pathway.

Circ_0001810 and AK2 were increased in schizophrenia and positively correlated with ERVWE1. Importantly, ERVWE1 triggered mitochondrial dysfunction through circ_0001810/miR-1197/AK2 pathway. Recent focus on the impact of mitochondrial dynamics on schizophrenia development had led to our discovery of a novel mechanism by which ERVWE1 contributed to the etiology of schizophrenia, particularly through mitochondrial dynamics. Moreover, these findings collectively proposed that circ_0001810 might serve as a potential blood-based biomarker for schizophrenia. Consistent with our previous theories, ERVWE1 is increasingly recognized as a promising therapeutic target for schizophrenia.

Circular RNAs (circRNAs) are differentially expressed in various cardiovascular diseases, including myocardial infarction (MI) injury. However, their functional role in necroptosis-induced loss of cardiomyocytes remains unclear. We identified a cardiac necroptosis-associated circRNA transcribed from the Cacna1c gene (circCacna1c) to investigate the involvement of circRNAs in cardiomyocyte necroptosis.

To investigate the role of circCacna1c during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with hydrogen peroxide (H2O2) to induce reactive oxygen species (ROS)-induced cardiomyocyte death. The N6-methyladenosine (m6A) modification level of circCacna1c was determined by methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP-qPCR) analysis. Additionally, an RNA pull-down assay was performed to identify interacting proteins of circCacna1c in cardiomyocytes, and the regulatory role of circCacna1c in target protein expression was tested using a western blotting assay. Furthermore, the MI mouse model was constructed to analyze the effect of circCacna1c on heart function and cardiomyocyte necroptosis.

The expression of circCacna1c was found to be reduced in cardiomyocytes exposed to oxidative stress and in mouse hearts injured by MI. Overexpression of circCacna1c inhibited necroptosis of cardiomyocytes induced by hydrogen peroxide and MI injury, resulting in a significant reduction in myocardial infarction size and improved cardiac function. Mechanistically, circCacna1c directly interacts with heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in the cytoplasm, preventing its nuclear translocation and leading to reduced Hnrnpf levels within the nucleus. This subsequently suppresses Hnrnpf-dependent receptor-interacting protein kinase 1 (RIPK1) expression. Furthermore, fat mass and obesity-associated protein (FTO) mediates demethylation of m6A modification on circCacna1c during necrosis and facilitates degradation of circCacna1c.

Our study demonstrates that circCacna1c can improve cardiac function following MI-induced heart injury by inhibiting the Hnrnpf/RIPK1-mediated cardiomyocyte necroptosis. Therefore, the FTO/circCacna1c/Hnrnpf/RIPK1 axis holds great potential as an effective target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.

Circular RNAs (circRNAs) are covalently closed RNA molecules widely expressed in eukaryotes and deregulated in several pathologies, including cancer. Many studies point to their activity as microRNAs (miRNAs) and protein sponges; however, we propose a function based on circRNA-mRNA interaction to regulate mRNA fate. We show that the widely tumor-associated circHIPK3 directly interacts in vivo with the BRCA1 mRNA through the back-splicing region in human cancer cells. This interaction increases BRCA1 translation by competing for the binding of the fragile-X mental retardation 1 protein (FMRP) protein, which we identified as a BRCA1 translational repressor. CircHIPK3 depletion or disruption of the circRNA-mRNA interaction decreases BRCA1 protein levels and increases DNA damage, sensitizing several cancer cells to DNA-damage-inducing agents and rendering them susceptible to synthetic lethality. Additionally, blocking FMRP interaction with BRCA1 mRNA with locked nucleic acid (LNA) restores physiological protein levels in BRCA1 hemizygous breast cancer cells, underscoring the importance of this circRNA-mRNA interaction in regulating DNA-damage response.

Circular RNA (CircRNA), as a classical noncoding RNA, has been proven to regulate skeletal muscle development (SMD). However, the molecular genetic basis of circRNA regulation in muscle cells remains unclear. In this study, the expression patterns of circRNAs in the longissimus dorsi muscle at embryonic day 75 and postnatal day 1 in DBGs were investigated to identify the key circRNAs that play an important role in SMD in goats. A total of 140 significantly and differentially expressed circRNAs (DEcircRNAs) were identified among the groups at different developmental stages. Among the 116 host genes (HGs) of DEcircRNAs, 76 were significantly and differentially expressed, which was confirmed by previous RNA_seq data. Furthermore, the expression pattern of 10 DEcircRNAs with RT-qPCR was verified, which showed 80% concordance rate with that of RNA_seq datasets. Moreover, the authenticity of seven randomly selected DEcircRNAs was verified by PCR Sanger sequencing. Based on the functional annotation results, among the 76 significantly and differentially expressed HGs, 74 were enriched in 845 GO terms, whereas 35 were annotated to 85 KEGG pathways. The results of this study could provide a comprehensive understanding of the genetic basis of circRNAs involved in SMD and muscle growth.

Allergic rhinitis (AR) is one of the most common respiratory noninfectious diseases and chronic inflammatory diseases, the incidence of which has been increasing in recent years. The main pathological characteristics of AR are repeated inflammation, airway hyperreactivity, mucus hypersecretion, and reversible airway obstruction due to inflammatory cell response. AR occurrence is associated with various factors, including those of genetic and environmental origins. Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot be converted into polypeptides. The three main categories of ncRNAs include microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). NcRNAs play a crucial role in controlling gene expression and contribute to the development of numerous human diseases.

Articles are selected based on Pubmed's literature review and the author's personal knowledge. The largest and highest quality studies were included. The search selection is not standardized. Several recent studies have indicated the relationship of ncRNAs with the development of respiratory allergic diseases. NcRNAs, including miRNAs, lncRNAs, and circRNAs, are important gene expression regulatory factors. We review the expression and function of ncRNAs in AR, their role as disease biomarkers, and their prospective applicability in future research and clinically. We also discuss interactions between ncRNAs and their influence on AR comprehensively, these interactions are essential for determining the underlying pathological mechanisms further and discovering new drug therapeutic targets.

NcRNAs can be used as biomarkers for early AR diagnosis, disease surveillance and prognosis assessment. Various categories of ncRNAs play distinct yet interconnected roles and actively contribute to intricate gene regulatory networks. They are also therapeutic targets and biomarkers in other allergic diseases.

This article demonstrates ncRNAs have a wide range of applications in AR treatment. The database covers three key areas: miRNAs, lncRNAs, and circRNAs. Additionally, potential avenues for future research to facilitate the practical application of ncRNAs as therapeutic targets and biomarkers will be explore. With further research and technological development, ncRNAs may provide additional innovative, effective solutions for AR treatment.

In the current comprehensive review, we first highlighted circRNAs, which are key ncRNAs. Next, we discussed the relationships among circRNAs and breast cancer subtypes via in silico databases analysis and extensive literature search. CircRNAs, that sponge miRNA axes or act as silencers of oncogenic mRNAs, have been extensively addressed in the context of this review. During BC pathogenesis, the circRNA/microRNA/messenger RNA (mRNA) axis plays a major role in disease growth, progression, and survival/resistance and could be targeted for improved treatment options. This review also aimed to address oncogenic and tumor suppressor mRNAs, which are regulated by various circRNAs in BC. Moreover, we mentioned the relation of different circRNAs with cancer hallmarks, patient survival together with drug resistance. Additionally, we discussed circRNAs as vaccines and biomarkers in BC. Finally, we studied exosomal circRNAs as a hot interesting area in the research. REVIEW SIGNIFICANCE: Via using in silico databases, bioinformatics analysis, and a thorough literature search to first highlight circRNA as a crucial ncRNA and its biogenesis, and then we explored the connection between circRNA and breast illnesses. In the framework of the review, circRNA sponged-miRNAs axis or as silencers to oncogenic mRNAs were extensively discussed. In the pathophysiology of BC, the circular RNA/microRNA/messenger RNA axis is crucial for the propagation of the disease and resistance that may be targeted for more effective treatment options, in order to confront tumor suppressor and oncogenic mRNAs that are presently regulated by circRNAs in BC. For better patient results, we advised further mechanistic research to elucidate additional ncRNA axis that may be targeted for the therapy of BC and for prognosis/ or early diagnosis.

Exosomes, extracellular vesicles carrying a cargo rich in various non-coding RNAs (ncRNAs), have emerged as crucial mediators of intercellular communication. Their stability, abundance, and specificity make exosomal ncRNAs promising candidates for biomarker discovery. The discovery of exosomal ncRNAs has unveiled a novel avenue for the exploration of biomarkers in tumor early diagnosis. This review consolidates current knowledge on the role of exosomal ncRNAs as potential biomarkers in the early detection of various tumors. We provide an overview of recent studies demonstrating the diagnostic potential of exosomal ncRNAs across multiple cancer types, highlighting their sensitivity, specificity, and feasibility for early detection. This review underscores the potential of exosomal ncRNAs as non-invasive biomarkers for early tumor diagnosis, paving the way for improved clinical outcomes through timely intervention and personalized management strategies.

Cardiotoxicity is a serious challenge cancer patients face today. Various factors are involved in cardiotoxicity. Circular RNAs (circRNAs) are one of the effective factors in the occurrence and prevention of cardiotoxicity. circRNAs can lead to increased proliferation, apoptosis, and regeneration of cardiomyocytes by regulating the molecular pathways, as well as increasing or decreasing gene expression; some circRNAs have a dual role in cardiomyocyte regeneration or death. Identifying each of the pathways related to these processes can be effective on managing patients and preventing cardiotoxicity. In this study, an overview of the molecular pathways involved in cardiotoxicity by circRNAs and their effects on the downstream factors have been discussed.

Breast cancer (BC) is the most common cancer among women, characterized by significant heterogeneity. Diagnosis of the disease in the early stages and appropriate treatment plays a crucial role for these patients. Despite the available treatments, many patients due to drug resistance do not receive proper treatments. Recently, circular RNAs (circRNAs), a type of non-coding RNAs (ncRNAs), have been discovered to be involved in the progression and resistance to drugs in BC. CircRNAs can promote or inhibit malignant cells by their function. Numerous circRNAs have been discovered to be involved in the proliferation, invasion, and migration of tumor cells, as well as the progression, pathogenesis, tumor metastasis, and drug resistance of BC. Circular RNAs can also serve as a biomarker for diagnosing, predicting prognosis, and targeting therapy. In this review, we present an outline of the variations in circRNAs expression in various BCs, the functional pathways, their impact on the condition, and their uses in clinical applications.

Circular RNAs (circRNAs) have emerged as a prominent class of covalently closed single-stranded RNA molecules that exhibit tissue-specific expression and potential as biomarkers in extracellular vesicles (EVs) derived from liquid biopsies. Still, their characteristics and applications in EVs remain to be unveiled.

We performed a comprehensive analysis of EV-derived circRNAs (EV-circRNAs) using transcriptomics data obtained from 1082 human body fluids, including plasma, urine, cerebrospinal fluid (CSF), and bile. Our validation strategy utilized RT-qPCR and RNA immunoprecipitation assays, complemented by computational techniques for analyzing EV-circRNA features and RNA-binding protein interactions.

We identified 136,327 EV-circRNAs from various human body fluids. Significantly, a considerable amount of circRNAs with a high back-splicing ratio are highly enriched in EVs compared to linear RNAs. Additionally, we discovered brain-specific circRNAs enriched in plasma EVs and cancer-associated EV-circRNAs linked to clinical outcomes. Moreover, we demonstrated that EV-circRNAs have the potential to serve as biomarkers for evaluating immunotherapy efficacy in non-small cell lung cancer (NSCLC). Importantly, we identified the involvement of RBPs, particularly YBX1, in the sorting mechanism of circRNAs into EVs.

This study unveils the extensive repertoire of EV-circRNAs across human biofluids, offering insights into their potential as disease biomarkers and their mechanistic roles within EVs. The identification of specific circRNAs and the elucidation of RBP-mediated sorting mechanisms open new avenues for the clinical application of EV-circRNAs in disease diagnostics and therapeutics.