Triple-negative breast cancer (TNBC) is a common malignant disease among females and severely threatens the health of women worldwide. Nowadays, circular RNAs (circRNAs) aroused our interest for their functions in human cancers, including TNBC. However, the mechanism of most circRNAs in the progression of TNBC remains unclear. We found a novel circRNA named circATP5C1, whose function in TNBC remains uncovered. Tissue microarray was used to analyze the association between the expression of circATP5C1 and the prognoses of TNBC patients. Gain-and loss-of-function experiments were performed to validate the biological functions of circATP5C1 in different TNBC cell lines. RNA-seq analyses were conducted to find out the target genes regulated by circATP5C1. RNA pull-down assay and mass spectrometry were used to select the proteins associated with circATP5C1. RNA FISH-immunofluorescence and RNA immunoprecipitation (RIP) were complemented to validate the interaction between circATP5C1 and its binding protein. CircATP5C1 was identified to have predictive function in prognosis of TNBC patients. CircATP5C1 advanced the progression of TNBC cells. Mechanistically, Colony stimulating factor 1 (CSF-1) is a vital downstream gene regulated by circATP5C1. The alteration of CSF-1 expression level was validated due to the interaction between circATP5C1 and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Rescue experiments demonstrated that circATP5C1 accelerates the progression of TNBC partly via binding with IGF2BP2 to increase the secretion of CSF-1. This study uncovers a novel mechanism of circATP5C1/IGF2BP2/CSF-1 pathway in regulating progression of TNBC.

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. Among these, miR-660, located on chromosome Xp11.23, is increasingly studied for its role in cancer due to its abnormal expression in various biological contexts. It is regulated by 8 competing endogenous RNAs (ceRNAs), which adds complexity to its function. miR- 660 targets 19 genes involved in 6 pathways such as PI3K/AKT/mTOR, STAT3, Wnt/β-catenin, p53, NF‑κB, and RAS, influencing cell cycle, proliferation, apoptosis, and invasion/migration. It also plays a role in resistance to chemotherapies like cisplatin, gemcitabine, and sorafenib in lung adenocarcinoma (LUAD), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC), thus highlighting its clinical importance. Additionally, leveraging liposomes as nanocarriers presents a promising avenue for enhancing cancer drug delivery. Our comprehensive study not only elucidates the aberrant expression patterns, biological functions, and regulatory networks of miR-660 and its ceRNAs but also delves into the intricate signaling pathways implicated. We envisage that our findings will furnish a robust framework and serve as a seminal reference for future investigations of miR-660, fostering advancements in cancer research and potentially catalyzing breakthroughs in cancer diagnosis and treatment paradigms.

This study explores the role of circ_0000467 in colorectal cancer (CRC) progression and its potential as a therapeutic target. Circ_0000467 expression was analyzed using public datasets and clinical samples from 103 CRC patients. Functional assays evaluated its influence on CRC cell proliferation, migration, and stem-like properties. Molecular interactions with miR-520g and TCF4 were examined, and in vivo experiments assessed tumor growth. Circ_0000467 was significantly overexpressed in CRC and associated with poor prognosis. Its upregulation enhanced tumor growth, invasion, epithelial-mesenchymal transition, and stem-like characteristics by increasing key markers (CD44, EpCAM, SOX2, and Nanog). Mechanistically, circ_0000467 acted as a molecular sponge for miR-520g, leading to increased TCF4 expression and activation of the Wnt/β-catenin pathway. Silencing TCF4 or overexpressing miR-520g reversed these effects. Circ_0000467 promotes CRC progression by regulating the TCF4/Wnt/β-catenin pathway through miR-520g, highlighting its potential as a biomarker and therapeutic target for CRC.

Circular RNAs (circRNAs) have emerged as critical regulators of biological processes, but their roles in avian muscle development remain less explored. Here we characterize circMKNK2, a novel circRNA derived from the MKNK2 gene, which is highly expressed in slow-growing Silky chickens compared to fast-growing broilers. Functional studies demonstrate that circMKNK2 acts as a sponge for miR-15a, with overexpression inhibiting myoblast proliferation, differentiation, apoptosis, and glucose metabolism, while miR-15a knockdown produces similar effects except for enhanced glucose uptake. RNA-seq analysis identified 2189 differentially expressed genes regulated by circMKNK2 in chicken primary myoblasts, including key targets of the circMKNK2/miR-15a axis such as PIK3R1 (a core node regulating PI3K-Akt signaling), BHLHE41, KANK1, and ARHGAP20. Pathway analysis revealed modulation of myogenesis through Calcium signaling pathway, ECM-receptor interaction, Neuroactive ligand-receptor interaction and immune-related pathways (Toll-like receptor, cytokine-cytokine receptor interactions). Further analysis highlighted the circMKNK2/miR-15a axis's role in suppressing myogenesis through transcriptional regulation of key factors (e.g., SOX7, MAF) and metabolic reprogramming. Unlike pro-myogenic circRNAs, circMKNK2 uniquely inhibited muscle development and glucose metabolism, suggesting its involvement in breed-specific phenotypic differences. This study provides insights into circRNA-mediated regulation of muscle biology and offers potential targets for improving poultry production through genetic and metabolic modulation.

Non-coding RNAs (ncRNAs) are functional RNA molecules that do not code for proteins. Among these, circular RNAs (circRNAs) represent a recently identified class of endogenous ncRNAs with a pivotal role in gene regulation, alongside short ncRNAs (e.g., microRNAs or miRNAs) and long non-coding RNAs (lncRNAs). CircRNAs are characterized by their single-stranded, covalently closed circular structure, which lacks polyadenylated tails and 5'-3' ends. This unique circular conformation makes them resistant to exonuclease degradation, rendering them more stable than linear RNAs, such as mRNAs in human blood cells, which highlights their potential as biomarkers. Both linear and circular RNAs are derived from pre-mRNA precursors. However, while linear RNAs are produced through conventional splicing, circRNAs are primarily formed through a process known as reverse splicing. CircRNAs can be categorized into five basic types: exon circRNAs, circular intronic RNAs, exon-intron circRNAs, intergenic circRNAs, and fusion circRNAs. These molecules have been shown to significantly influence key hallmarks of cancer, including sustained growth signaling, proliferation, angiogenesis, resistance to apoptosis, unlimited replicative potential, and metastasis. This article will delve into the biogenesis and functions of circRNAs, explore their roles in cancer, and discuss their potential applications as therapeutic options and diagnostic biomarkers.

Dental stem cells are widely viewed as good options for bone regeneration because of their ease of acquisition, innate ability to renew themselves, and ability to differentiate into different types of cells. However, the process of osteogenic differentiation of dental stem cells is orchestrated by an intricate system of regulatory mechanisms. Recent studies have demonstrated the critical impacts of circular RNAs (circRNAs) on osteogenic differentiation of dental stem cells. Exploring the roles and regulatory pathways of circRNAs in dental stem cells could identify novel targets and approaches for utilizing dental stem cell therapy in clinical settings. This review provides a comprehensive overview of the functions and mechanisms of circRNAs, with a particular focus on their expression patterns and regulatory roles in osteogenic differentiation of various dental stem cell types. Furthermore, this review discusses current research challenges in this field and proposes future directions for advancing our understanding of circRNA-mediated regulation in dental stem cell biology.

Circular RNAs are a class of non-coding RNAs with covalently closed loops. They have been revealed to regulate immune responses by affecting gene expression. Although initially considered splicing byproducts, new studies have indicated their role in transcriptional and post-transcriptional control, especially with TLRs. TLRs start inflammatory signaling and let the innate immune system recognize PAMPs. circRNAs interact context-dependently with TLR pathways to influence immune homeostasis and inflammation in either pathogenic or protective roles. In autoimmune diseases, dysregulated circRNA expression can aggravate immune responses and damage tissue. CircRNAs can interact with RNA-binding proteins, function as molecular sponges for miRNAs, and change inflammatory pathways like the NF-κB signaling cascade, influencing immune responses. They control adaptive immunity, function of antigen-presenting cells, and cytokine generation. The stability and presence of circRNAs in many body fluids make them therapeutic targets and biomarkers for inflammatory and autoimmune diseases. The several immune control roles of circRNA-TLR interactions are discussed in this review, as well as their consequences for immunologically mediated disease diagnosis and treatment.

Bladder cancer (BCa) is an aggressive malignancy of urinary system. Aerobic glycolysis refers to the phenomenon wherein cancer cells increase glucose consumption and produce lactic acid. Our study focused on the role and mechanism of circST6GALNAC6 in BCa glycolysis. The 24 h glucose intake was detected using flow cytometry. Lactic acid and ATP were detected in BCa cells utilizing commercially provided kits. Extracellular acidification rate was measured using Seahorse XF-96p Extracellular Flux Analyzer. Cell proliferation was determined using colony formation assay. RNA immunoprecipitation and co-immunoprecipitation experiments were adopted to validate molecular interactions. BALB/C nude mice were utilized to establish xenograft tumor model. CircST6GALNAC6 was decreased in BCa cells, and overexpression of circST6GALNAC6 inhibited glycolysis and proliferation of BCa cells. Additionally, overexpression of circST6GALNAC6 promoted the degradation of glycolytic regulatory protein HK1 and decreased its expression, and PRKN facilitated ubiquitination-related degradation of HK1. CircST6GALNAC6 enhanced the mRNA stability and expression of PRKN by recruiting FUS. Furthermore, the inhibitory impact of circST6GALNAC6 overexpression on glycolysis in BCa cells was reversed by PRKN knockdown. Finally, overexpression of circST6GALNAC6 suppressed tumor growth through increasing PRKN in nude mice. CircST6GALNAC6 suppressed glycolysis in BCa through FUS/PRKN/HK1 axis. Targeting circST6GALNAC6 holds promise as a novel approach for treating BCa.

Lung cancer remains a leading cause of cancer-related mortality worldwide. Its progression is intricately associated with the dynamic regulation of autophagy and RNA-binding proteins (RBPs), which play crucial roles in mRNA stability, alternative splicing, and cellular stress responses.

This review aims to systematically analyze the mechanisms through which RBPs and autophagy contribute to lung cancer progression and explore potential therapeutic strategies targeting these pathways.

We reviewed recent studies on the molecular mechanisms by which RBPs regulate tumor proliferation, metabolic adaptation, and their interaction with autophagy. The review also examines the dual roles of autophagy in lung cancer, highlighting its context-dependent effects on cell survival and death.

The interactions and regulatory networks between RBPs and autophagy involve multiple levels of regulation. RBPs can directly influence autophagy processes and act as microRNA (miRNA) sponges to regulate mRNA stability. The modulation of RBPs affects the expression of autophagy-related genes (ATGs) and autophagosome formation. Additionally, RBPs participate in complex regulatory interactions with non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other proteins.

This review proposes innovative therapeutic strategies that combine RBP-targeting approaches (e.g., small molecule inhibitors, CRISPR gene editing) with autophagy modulators (e.g., mTOR inhibitors, chloroquine) to enhance treatment efficacy. Nanoparticle drug delivery systems and epigenetic regulation offer further opportunities for targeted interventions. This review lays a theoretical foundation for advancing lung cancer research and provides novel insights into synergistic therapies that target both RBPs and autophagy to improve treatment outcomes for lung cancer.

Circular RNA (circRNA) is a new type of non-coding RNA that has gained significant attention in recent years, especially in tuberculosis research. Tuberculosis poses a major global public health threat. Its complex pathological mechanisms and worsening drug resistance urgently necessitate new research breakthroughs. The role of circRNA in mycobacterium tuberculosis infection is being gradually revealed, highlighting its importance in regulating gene expression, immune response, and inflammation. Additionally, researchers are interested in circRNA because of its potential for early tuberculosis diagnosis and its role as a biomarker. This article systematically analyzes existing literature to provide new insights into early tuberculosis diagnosis and personalized treatment. We also emphasize the need for future research to enhance the application of circRNA in tuberculosis prevention and control.

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event associated with high mortality and significant morbidity. Recent studies have highlighted the emerging role of ferroptosis, a novel form of regulated cell death, in the pathogenesis of SAH. Circular RNAs (circRNAs), have been found to play essential roles in various cellular processes, including gene regulation and disease pathogenesis. The expression profile of circRNAs in neural tissues, particularly in the brain, suggests their critical role in synaptic function and neurogenesis. Moreover, the interplay between circRNAs and ferroptosis-related pathways, such as iron metabolism and lipid peroxidation, is explored in the context of SAH. Understanding the functional roles of specific circRNAs in the context of SAH may provide potential therapeutic targets to attenuate ferroptosis-associated brain injury. Furthermore, the potential of circRNAs as diagnostic biomarkers for SAH severity, prognosis, and treatment response is discussed. Overall, this review highlights the significance of studying the intricate interplay between circRNAs and ferroptosis in the context of SAH. Unraveling the mechanisms by which circRNAs modulate ferroptotic cell death may pave the way for the development of novel therapeutic strategies and diagnostic approaches for SAH management, ultimately improving patient outcomes and quality of life.

Micro-RNAs play essential roles in developing and progressing nonsmall cell lung cancer (NSCLC) and drug resistance. Nevertheless, the functions and mechanisms are partly explored. Therefore, the present study analyzes the effect of circ_0006528 and the mechanism of regulation of NSCLC cell progression by sponging miR-892a to regulate neuroblastoma rat sarcoma viral oncogene (NRAS) expression. Initially, circ_0006528 is identified using divergent primers-based PCR and RNase R exonuclease treatments. After administration of the designed circ_0006528-specific siRNA, the RT-qPCR analysis is used to determine the interference efficiency of siRNA. At the same time, cell growth, invasion, and migration are assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), Transwell, and scratch assays in the NSCLC cell lines [secretory pathway Ca2+-ATPase isoform 1 (SPCA-1) and A549] in vitro, respectively. Further, miR-892a inhibitor is added to the cells for functional recovery assay. Finally, the xenograft mouse model is constructed to explore the effect of circ_0006528 on tumor growth in vivo . The RT-qPCR analysis in 66 pairs of NSCLC cancer and noncancerous tissues revealed that circ_0006528 is highly expressed in NSCLC patient tissues. The RNase R experiments revealed that HSA_circ_0006528 is unaffected by RNase R exonuclease. MTT assay showed that knockdown of hsa_circ_0006528 by siRNA significantly decreased cell proliferation and viability in A549 and SPCA-1 cells. The luciferase reporter assay showed direct binding of hsa_circ_0006528 to miR-892a, and miR-892a targets binding NRAS. In addition, the miR-892a inhibitor terminated the hsa_circ_0006528 siRNA, triggering inhibition of proliferation, invasion, and migration of NSCLC cells. In summary, the study revealed that the knockout of hsa_circ_0006528 downregulation of NRAS expression by sponging miR-892a inhibited NSCLC cell growth and invasion.

Antisense circular RNA is a special type of circular RNA that is derived from the antisense complementary strand of parental mRNA. However, the function of antisense circRNA in hepatocellular carcinoma (HCC) is still unclear. Here, we reported that CSF3R-AS was upregulated in HCC and correlated with a poor prognosis. CSF3R-AS promoted the proliferation, angiogenesis, and metastasis of HCC, and inhibited apoptosis. Mechanistically, CSF3R-AS has a 180-base complementary pairing sequence with its parental mRNA CSF3R, which can directly bind to CSF3R and recruit RBMS3 to stabilize its parental mRNA, and finally activate JAK2/STAT3 signaling pathway. Interestingly, STAT3 can act as a transcription factor of CSF3R-AS, which means that there is a CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop in HCC. Finally, the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop was also activated in HCC sorafenib-resistant cells, and blocking this loop was expected to improve the sensitivity of HCC to sorafenib. These findings suggested that the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop could promote HCC progression and sorafenib resistance. Blocking this loop is expected to provide new research directions and therapy targets for HCC.

circRNAs are a type of single-stranded non-coding RNA molecules, and their unique feature is their closed circular structure. The interaction between circRNAs and RNA-binding proteins (RBPs) plays a key role in biological functions and is crucial for studying post-transcriptional regulatory mechanisms. The genome-wide circRNA binding event data obtained by cross-linking immunoprecipitation sequencing technology provides a foundation for constructing efficient computational model prediction methods. However, in existing studies, although machine learning techniques have been applied to predict circRNA-RBP interaction sites, these methods still have room for improvement in accuracy and lack interpretability. We propose CR-deal, which is an interpretable joint deep learning network that predicts the binding sites of circRNA and RBP through genome-wide circRNA data. CR-deal utilizes a graph attention network to unify sequence and structural features into the same view, more effectively utilizing structural features to improve accuracy. It can infer marker genes in the binding site through integrated gradient feature interpretation, thereby inferring functional structural regions in the binding site. We conducted benchmark tests on CR-deal on 37 circRNA datasets and 7 lncRNA datasets, respectively, and obtained the interpretability of CR-deal and discovered functional structural regions through 5 circRNA datasets. We believe that CR-deal can help researchers gain a deeper understanding of the functions and mechanisms of circRNA in living organisms and its critical role in the occurrence and development of diseases. The source code of CR-deal is provided free of charge on https://github.com/liuliwei1980/CR .

Non-coding RNAs (ncRNAs) are a class of RNAs that largely lack the capacity to encode proteins. They have garnered significant attention due to their central regulatory functions across numerous cellular and physiological processes at transcriptional, post-transcriptional, and translational levels. Over the past decade, ncRNA-based therapies have gained considerable attention in the diagnosis, treatment, and prevention of diseases, and many studies have revealed a significant relationship between ncRNAs and diseases. At the same time, due to their tissue specificity, an increasing number of projects have focused on the application of ncRNAs as biomarkers in diseases, as well as the design and development of novel ncRNA-based vaccines and therapies for clinical use. These ncRNAs may also drive research into the potential molecular mechanisms and complex pathogenesis of related diseases. However, new biomarkers need to be validated for their clinical effectiveness. Additionally, to produce safe and stable RNA products, factors such as purity, precise dosage, and effective delivery methods must be ensured to achieve optimal bioactivity. These challenges remain key issues in the clinical application of ncRNAs. This review summarizes the prospects of ncRNAs as potential biomarkers, as well as the current research status and clinical applications of ncRNAs in therapies and vaccines, and discusses the challenges and expectations of ncRNAs in disease diagnosis and drug therapy.

Nucleic acid therapeutics have become increasingly recognized in recent years for their capability to target both coding and non-coding sequences. Several types of nucleic acid modalities, including siRNA, mRNA, aptamer, along with antisense oligo, have been approved by regulatory bodies for therapeutic use. The field of nucleic acid therapeutics has been brought to the forefront by the rapid development of vaccines against COVID-19, followed by a number of approvals for clinical use including much anticipated CRISPR-Cas9. However, obstacles such as the difficulty of achieving efficient and targeted delivery to diseased sites remain. This review provides an overview of nucleic acid therapeutics and highlights substantial advancements, including critical engineering, conjugation, and delivery strategies, that are paving the way for their growing role in modern medicine.

Glioblastoma, a type of brain tumor, is well-known for its aggressive nature and can affect individuals of all ages. Glioblastoma continues to be a difficult cancer to manage because of various resistance mechanisms. The blood-brain barrier restricts the delivery of drugs, and the heterogeneity of tumors, along with overlapping signaling pathways, complicates its effective treatment. Patients diagnosed with glioblastoma typically survive for no more than 2 years. Innovative therapies and early diagnostic tools for glioblastoma are essential. Circular RNAs have emerged as significant contributors to glioblastoma, and influence cancer mechanisms such as cell growth, death, invasion, and resistance to treatment. The circRNAs presence makes them essential candidates for treatment and practical diagnostic tools for glioblastoma. This review highlights the therapeutic approaches and diagnostic potential of circRNAs and explores their role in the molecular mechanisms underlying glioblastoma.

Unusual symptoms, rapid progression, lack of reliable early diagnostic biomarkers, and lack of efficient treatment choices are the ongoing challenges of pancreatic cancer. Numerous research studies have demonstrated the correlation between exosomes and various aspects of pancreatic cancer. In light of these facts, exosomes possess the potential to play functional roles in the treatment, prognosis, and diagnosis of the pancreatic cancer. In the present study, we reviewed the most recent developments in approaches for exosome separation, modification, monitoring, and communication. Moreover, we discussed the clinical uses of exosomes as less invasive liquid biopsies and drug carriers and their contribution to the control of angiogenic activity of pancreatic cancer. Better investigation of exosome biology would help to effectively engineer therapeutic exosomes with certain nucleic acids, proteins, and even exogenous drugs as their cargo. Circulating exosomes have shown promise as reliable candidates for pancreatic cancer early diagnosis and monitoring in high-risk people without clinical cancer manifestation. Although we have tried to reflect the status of exosome applications in the treatment and detection of pancreatic cancer, it is evident that further studies and clinical trials are required before exosomes may be employed as a routine therapeutic and diagnostic tools for pancreatic cancer.

The intricate interaction among host, pathogen, and environment significantly influences aquatic health, yet the influence of hypoxic stress combined with bacterial infection on host response is understudied. Circular RNAs with stable closed-loop structures have emerged as important regulators in immunity, yet remain ill-defined in fish. In this study, we systematically explored the circRNA response in yellow catfish subjected to combined hypoxia-bacterial infection (HB) stress. Following HB stress, H&E and TUNEL staining identified heightened hepatocyte apoptosis, intracellular vacuolation, and inflammatory tissue damage. RT-qPCR elucidated that differentially expressed genes stimulated by HB synergistically enhanced apoptosis and inflammatory responses. Importantly, we systematically evaluated differentially expressed circRNAs (DEcirs) in yellow catfish under hypoxia with and without Aeromonas veronii infection and identified a novel HB-specific DEcir, designated as circArid4b, whose parental gene Arid4b is highly associated with apoptosis. Experiments confirmed the circular structure of circArid4b and revealed that under HB stimulation, specific knockdown of circArid4b inhibited the expression of Arid4b, while concurrent alterations in multiple apoptosis- and inflammation-related genes synergistically indicated the promotion of apoptotic and inflammatory pathways. Notably, the downregulation of circArid4b expression significantly reduced the susceptibility to bacterial infection in yellow catfish during hypoxia. These results suggest that HB-induced suppression of circArid4b promotes cell apoptosis and inflammation by inhibiting its parental gene and thereby facilitating resistance to bacterial infection during hypoxia. Our study enriches the understanding of fish circRNA mechanisms and offers novel preventive and control strategies for bacterial infections in fish under hypoxic environments.

β-globin gene cluster regulation involves complex mechanisms to ensure proper expression and function in RBCs. During development, switching occurs as γ-globin is replaced by β-globin. Key regulators, like BCL11A and ZBTB7A, repress γ-globin expression to facilitate this transition with other factors, like KLF1, LSD1, and PGC-1α; these regulators ensure an orchestrated transition from γ- to β-globin during development. While these mechanisms have been extensively studied, circRNAs have recently emerged as key contributors to gene regulation, but their role in β-globin gene cluster regulation remains largely unexplored. Although discovered in the 1970s, circRNAs have only recently been recognized for their functional roles, particularly in interactions with RNA-binding proteins. Understanding how circRNAs contribute to switching from γ- to β-globin could lead to new therapeutic strategies for hemoglobinopathies, such as sickle cell disease and β-thalassemia. This review uses the circAtlas 3.0 database to explore circRNA expressions in genes related to switching from γ- to β-globin expression, focusing on blood, bone marrow, liver, and spleen. It emphasizes the exploration of the potential interactions between circRNAs and RNA-binding proteins involved in β-globin gene cluster regulatory mechanisms, further enhancing our understanding of β-globin gene cluster expression.

Current anti-epileptic drugs remain to be unsatisfactory, new therapeutic approaches are needed. Circular RNA is a promising class of therapeutic RNAs. Recent studies have shown the role of circRNA in the pathologic process of epilepsy. In this study, we identified the circRNA in epileptic patients in remission that inhibited the epileptic course. By comparing the profiles of differentially expressed circRNAs in peripheral serum between patients in remission and those not in remission, we found that the level of hsa_circ_0000288 (circ288) was markedly elevated in the epileptic patients in remission. We established a kainic acid-induced status epilepticus model in mice. Overexpression of Circ288 by injecting adeno-associated virus (AAV)-circ288-overexpression vector into hippocampi significantly ameliorated epilepsy-induced neuronal injury, promoted hippocampus neurogenesis, and inhibited abnormal migration of newborn neurons into the dentate hilus. Moreover, circ288 overexpression significantly decreased the epileptiform discharges and the spontaneous seizures in the chronic phase of epileptogenesis and alleviated mood disorders (anxiety, depression), and cognitive deficits in epileptic mice. We revealed that circ288 directly bound to an RNA-binding protein caprin1 and inhibited its degradation. The protective action of circ288 was reversed by the knockdown of caprin1 in an in vitro epileptic model and lost in the neuron-specific caprin1 knockout mice (CaMK2α-Cre:Caprin1f/f). Overexpression of circ288 or caprin1 raised the mRNA level of NMDA receptor 3B, a negative modulator of NMDA receptors, suggesting the involvement of the carpin1-NMDA receptor 3B pathway in the role of circ288. Given the disadvantages of circ288 overexpression by a virus, we constructed exosomes-encapsulated circ288 (EXO-circ288) and demonstrated that tail vein injection of EXO-circ288 exerted robust protective effects. This study provides a new avenue for developing anti-epileptic therapeutic RNAs.

Multiple Myeloma (MM) is the second most common hematologic malignancy, which exhibits strong resistance to bortezomib, the first-line treatment. Circular RNAs (circRNAs) are increasingly considered as important drivers of drug resistance across various cancers, but their roles in multiple myeloma are not well understood.

To investigate and identify potential circRNA targets and their roles in the mechanisms of bortezomib resistance.

Bortezomib-resistant MM patient-specific circRNAs were screened using Arraystar circRNA microarrays. The MM circRNA dataset from the GEO database was analyzed with GEO2R to identify candidate circRNAs associated with MM progression and drug resistance. CircRNA-forming and loop-forming sites, along with their structures, were identified via Sanger sequencing. The identified circRNA was validated by qRT-PCR in MM patients with and without bortezomib resistance. Bioinformatic analysis through CircInteractome was conducted to predict potential miRNA and RBP binding for the core circRNAs. Metascape was employed to perform RBP pathway analysis to identify specific biological processes in circRNAs.

The hsa_circ_0058191 was found to be overexpressed in bortezomib-resistant MM patient samples, suggesting its pivotal role in drug resistance mechanisms. The interaction of hsa_circ_0058191 with miR-660 and AGO2 as determined through bioinformatic predictions, indicated that it regulates RNA modification and mRNA regulation pathways. These molecular interactions expand our understanding of the mechanisms of drug resistance in multiple myeloma.

This study identified the role of hsa_circ_0058191 in the development of drug resistance in MM, which provides a theoretical foundation for designing potential therapeutic strategies to prevent drug resistance.

Distant metastasis is a primary factor contributing to the low survival rate of patients with nasopharyngeal carcinoma (NPC). Circular RNAs (circRNAs) are increasingly recognized for their roles in cancer initiation and progression. However, the mechanisms underlying the abnormal expression and biological function of circRNA in NPC remain unclear. In this study, we identified a new circRNA, circINADL, which was upregulated in NPC tissues and positively correlated with the clinical stage of NPC. We found that the FUS RNA binding protein (FUS) promoted the transcription of circINADL in NPC cells. Elevated circINADL levels were shown to enhance NPC cells metastasis. Mechanistically, circINADL attenuated the interaction between human antigen R (HuR) and the E3 ubiquitin ligase β-TrCP, thereby inhibited the ubiquitination and degradation of HuR. Consequently, CircINADL enhanced the stability of the HuR target gene Yes1-associated transcriptional regulator (YAP1), leading to the dysregulation of the Hippo signaling pathway. In conclusion, our study reveals the function of circINADL in promoting NPC metastasis and highlights its potential as a biomarker and therapeutic target for NPC treatment.

Esophageal cancer (EC) is one of the most fatal malignancies worldwide, with a dramatic increase in incidence in the western world occurring over the past few decades. Chromosome instability (CIN) is a major contributor to EC progression, drug resistance, relapse, and the development of intratumoral heterogeneity. This study revealed a striking elevation of AURKB expression in EC patients, with a strong correlation to poor clinical outcomes. AURKB overexpression promoted cellular proliferation and induced drug resistance in both cell culture and animal models. Conversely, genetic targeting of AURKB abrogated these effects. Mechanistically, enforced AURKB expression triggered CIN, a key driver of poor EC outcomes, primarily through CEP250 phosphorylation. Interestingly, we identified a novel circular form of AURKB (circAURKB_288aa) harboring the AURKB kinase domain and encoding a 288-amino acid protein. Elevated levels of circAURKB_288aa in EC peripheral blood samples mirrored poor patient outcomes and synergistically enhanced CIN alongside AURKB. Furthermore, EC cells were capable of secreting circAURKB_288aa, influencing tumor microenvironmental cells similarly to full-length AURKB protein. Notably, AURKB siRNA targeting the shared kinase domain of both AURKB and circAURKB_288aa significantly inhibited EC malignancy. Collectively, these findings establish AURKB and circAURKB_288aa as promising targets for EC prognosis and therapy.

Exosomes, as key mediators of intercellular communication, have been increasingly recognized for their role in the oncogenic processes, particularly in facilitating drug resistance. This article delves into the emerging evidence linking exosomal lncRNAs to the modulation of drug resistance mechanisms in cancers such as ovarian, cervical, and endometrial cancer. It synthesizes current research findings on how these lncRNAs influence cancer cell survival, tumor microenvironment, and chemotherapy efficacy. Additionally, the review highlights potential therapeutic strategies targeting exosomal lncRNAs, proposing a new frontier in overcoming drug resistance. By mapping the interface of exosomal lncRNAs and drug resistance, this article aims to provide a comprehensive understanding that could pave the way for innovative treatments and improved patient outcomes in female reproductive system cancers.

Circular RNAs (circRNA) lack 5' or 3' ends; their unique covalently closed structures prevent RNA degradation by exonucleases. These characteristics provide circRNAs with high pharmaceutical stability and biostability relative to current standard-of-care linear mRNAs. CircRNA levels are reportedly associated with certain human diseases, making them novel disease biomarkers and a noncanonical class of therapeutic targets. In this study, the endogenous circRNAs underlying the response to BNT162b2 mRNA vaccination were evaluated. To this end, peripheral blood samples were subjected to full-length sequencing of circRNAs via nanopore sequencing and transcriptome sequencing. Fifteen samples, comprising pre-, first, and second vaccination cohorts, were obtained from five healthcare workers with no history of SARS-CoV-2 infection or previous vaccination. A total of 4706 circRNAs were detected; following full-length sequencing, 4217 novel circRNAs were identified as being specifically expressed during vaccination. These circRNAs were enriched in the binding motifs of stress granule assemblies and SARS-CoV-2 RNA binding proteins, namely poly(A) binding protein cytoplasmic 1 (PABPC1), pumilio RNA binding family member 1 (PUM1), and Y box binding protein 1 (YBX1). Moreover, 489 circRNAs were identified as previously reported miRNA sponges. The differentially expressed circRNAs putatively originated from plasma B cells compared to circRNAs reported in human blood single-cell RNA sequencing datasets. The pre- and post-vaccination differences observed in the circRNA expression landscape in response to the SARS-CoV-2 BNT162b2 mRNA vaccine.

Alzheimer's disease (AD) is a neurodegenerative disease that primarily affects the elderly population and is the leading cause of dementia. Meanwhile, the vascular hypothesis suggests that vascular damage occurs in the early stages of the disease, leading to neurodegeneration and hindered waste clearance, which in turn triggers a series of events including the accumulation of amyloid plaques and Tau protein tangles. Non-coding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), have been found to be involved in the regulation of AD. Furthermore, lncRNAs and circRNAs can act as competitive endogenous RNAs to inhibit miRNAs, and their interactions can form a complex regulatory network. Exosomes, which are extracellular vesicles (EVs), are believed to be able to transfer ncRNAs between cells, thus playing a regulatory role in the brain by crossing the blood-brain barrier (BBB). Exosomes are part of the intercellular carrier system; therefore, utilizing exosomes to deliver drugs to recipient cells might not activate the immune system, making it a potential strategy to treat central nervous system diseases. In this review, we review that AD is a multifactorial neurological disease and that ncRNAs can regulate its multiple pathogenic mechanisms to improve our understanding of the etiology of AD and to simultaneously regulate multiple pathogenic mechanisms of AD through the binding of ncRNAs to exosomes to improve the treatment of AD.

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.

Cardiac remodelling involves structural, cellular and molecular alterations in the heart after injury, resulting in progressive loss of heart function and ultimately leading to heart failure. Circular RNAs (circRNAs) are a recently rediscovered class of non-coding RNAs that play regulatory roles in the pathogenesis of cardiovascular diseases, including heart failure. Thus, a more comprehensive understanding of the role of circRNAs in the processes governing cardiac remodelling may set the ground for the development of circRNA-based diagnostic and therapeutic strategies. In this review, the current knowledge about circRNA origin, conservation, characteristics and function is summarized. Bioinformatics and wet-lab methods used in circRNA research are discussed. The regulatory function of circRNAs in cardiac remodelling mechanisms such as cell death, cardiomyocyte hypertrophy, inflammation, fibrosis and metabolism is highlighted. Finally, key challenges and opportunities in circRNA research are discussed, and orientations for future work to address the pharmacological potential of circRNAs in heart failure are proposed. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.

Breast cancer, a prevalent and aggressive malignancy among females worldwide, poses a significant challenge due to resistance to chemotherapy and tyrosine kinase inhibitors. In breast cancer, ABC transporters play a pivotal role by contributing to chemoresistance and drug efflux, a phenomenon observed also in various cancers. This study aims to elucidate the role of oncomiRs miR-15, miR-21, and miR-let-7 in breast cancer etiology and their impact on chemotherapy-resistant oncogenes ABCA1, ABCB1, and ABCC1. Blood samples from female breast cancer patients were analyzed to assess the expression levels of miRNAs and oncogenes by qPCR. Significantly, miR-21 exhibited a positive correlation with ABCA1 in newly diagnosed patients, while miR-15 and miR-let-7 displayed a positive correlation with ABCA1 in the metastasis group. Additionally, miR-let-7 demonstrated a negative correlation with ABCC1 in newly diagnosed patients. This study's findings provide valuable insights into the cancer etiology of these miRNAs and their interactions with ABCA1, ABCB1, and ABCC1. Targeting these interactions holds promise for mitigating drug efflux and chemoresistance in breast cancer, potentially enhancing current treatments and improving patient outcomes.

CircRNA is stable due to its ring structure and is abundant in humans, which not only exists in various tissues and biofluids steadily but also plays a significant role in the physiology and pathology of human beings. CircPVT1, an endogenous circRNA, has recently been identified from the PVT1 gene located in the cancer risk region 8q24. CircPVT1 is reported to be highly expressed in many different tumors, where it affects tumor cell proliferation, apoptosis, invasion, and migration. We summarize the biosynthesis and biological functions of circPVT1 and analyze the relationship between circPVT1 and tumors as well as its significance to tumors. Further, it's noteworthy for the diagnosis, treatment, and prognosis of cancer patients. Therefore, circPVT1 is likely to become an innovative tumor marker.

Viral myocarditis (VMC) is an inflammatory disease of the myocardium caused by cardioviral infection, especially coxsackievirus B3 (CVB3), and is a major contributor to acute heart failure and sudden cardiac death in children and adolescents. LncRNA MALAT1 knockdown reportedly inhibits the differentiation of Th17 cells to attenuate CVB3-induced VMC in mice. Moreover, long non-coding RNAs (lncRNAs) interact with RNA-binding proteins (RBPs) to regulate UPF1-mediated mRNA decay. However, it remains unclear whether MALAT1 can bind to UPF1 to mediate the mRNA decay of its target genes in VMC. Herein, we aimed to explore the effect of lncRNA MALAT1 on UPF1-mediated SIRT6 mRNA decay in VMC using in vivo and in vitro experiments. CVB3-infected BABL/C mice were used as VMC models, and MALAT1 interfering adenovirus was injected to achieve MALAT1 knockdown. The heart function of the VMC mice was assessed using echocardiography. Pathological changes in myocardial tissues were assessed after hematoxylin-eosin staining. Myocardial injury and inflammation were evaluated by measuring creatine kinase isoenzyme B, cardiac troponin T, interleukin (IL)-1β, and IL-18. TUNEL staining was performed to assess apoptosis in myocardial tissues. In vitro experiments were performed using H9c2 cells after transfection and CVB3 infection. The lactic dehydrogenase release, caspase-1 activity, and IL-1β and IL-18 levels in the cellular supernatant were detected. Western blotting was performed to determine the expression of pyroptosis-related proteins (GSDMD-N, NLRP3, ASC, and Cleaved-Caspase-1) and Wnt/β-catenin signal pathway-related proteins (Wnt1, β-catenin, and p-GSK-3β). RNA immunoprecipitation and RNA stability assays assessed the relationship between MALAT1, UPF1, and SIRT6. CVB3-infected mice and H9c2 cells exhibited elevated MALAT1 and reduced SIRT6 expression. MALAT1 knockdown or SIRT6 overexpression suppressed inflammation and pyroptosis and inhibited the activation of the Wnt/β-catenin signal pathway in myocardial tissues and cells. MALAT1 enhanced the enrichment of SIRT6 mRNA by UPF1 and disturbed the stability of SIRT6 mRNA to promote the development of VMC. MALAT1 can bind UPF1 to mediate SIRT6 mRNA decay and activate the Wnt/β-catenin signal pathway in VMC.

A growing body of research highlights the role that N6-methyladenosine (m6A) modification and circular RNAs (circRNAs) play in gastric cancer (GC) cases. However, studies elucidating the function and mechanism of the recently discovered circRNA hsa_circ_0112136 in GC are limited. This study aimed to examine the pathophysiology of GC progression due to fat mass and obesity-associated protein (FTO)-mediated N6-methyladenosine (m6A) modification of hsa_circ_0112136. The hsa_circ_0112136 and FTO levels in the GC samples were analyzed using qRT-PCR. The Transwell invasion assay, wound healing assay, and CCK8 assays were employed to assess alterations in GC cell invasiveness, migration, and viability due to the aberrant regulation of hsa_circ_0112136 and FTO. Phosphorylated PI3K, AKT, and mTOR (the key proteins of the PI3K/AKT/mTOR pathway) were detected via western blotting after hsa_circ_0112136 suppression. A tumor transplantation mouse model was constructed to evaluate the suppression of hsa_circ_0112136's function in vivo. The correlation among hsa_circ_0112136 and FTO was identified using the MeRIP assay. Levels of hsa_circ_0112136 and FTO were evidently elevated in GC samples. Suppression of has_circ_0112136 reduced the viability, migration, and invasive ability of GC cells in vitro, as well as delayed tumor growth in vivo via suppression of the activation of the PI3K/AKT/mTOR pathway. FTO decreased hsa_circ_0112136 m6A levels and enhanced hsa_circ_0112136 expression. Furthermore, FTO upregulation enhanced GC cell invasion, migration, and survival, which was reversed by hsa_circ_0112136 suppression. Our study proposes that hsa_circ_0112136 functions as a tumor promoter, facilitating the malignant progression of GC through m6A modification (suppressed by FTO) and activating the PI3K/AKT/mTOR pathway. This suggests that targeting FTO-m6A-hsa_circ_0112136-PI3K/AKT/mTOR may be a novel approach for GC intervention.

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.

The Guangling Large-Tailed sheep is renowned for its unique tail fat deposition, with a significant proportion of its total body fat being localized in the tail region. Fat deposition is a complex biological process regulated by various molecular mechanisms. Our previous studies have identified a large number of differentially expressed circular RNAs (circRNAs) in the tail adipose tissue of the Guangling Large-Tailed sheep. These circRNAs may play a pivotal role in the process of fat deposition. Given the potential regulatory functions of circRNAs in adipose metabolism, investigating their roles in tail fat deposition is of significant scientific importance. In this study, we identified novel circARID1A. Using various experimental methods, including lentivirus infection, RNase R treatment, actinomycin D assay, qPCR, western blotting, and dual-luciferase reporter assays, we determined that circARID1A inhibits the expression of miR-493-3p through competitive binding, thereby regulating adipocyte differentiation. Further research revealed that miR-493-3p promotes adipocyte differentiation by targeting YTH domain family 2 (YTHDF2), and this regulatory effect is also influenced by circARID1A. In conclusion, our findings suggest that circARID1A inhibits tail fat cell differentiation in the Guangling Large-Tailed sheep through the circARID1A/miR-493-3p/YTHDF2 axis, providing theoretical support for improving meat quality and fat deposition in sheep.

The dysregulation of circular RNAs (circRNAs) has been associated with OC development and progression. This study investigated the role of circZNF609 in ovarian cancer (OC) by analyzing its impact on cell proliferation, migration, and invasion. Initially, the study assessed the expression of circZNF609 in OC tissues and adjacent normal tissues. The results revealed elevated circZNF609 levels in OC tissues and cell lines, correlating with poor prognosis, lymph node metastasis, and advanced clinical stage. Subsequently, in vitro and in vivo experiments were conducted to elucidate the biological functions of circZNF609 in OC progression. The findings showed that the knockdown of circZNF609 resulted in reduced OC cell proliferation, migration, invasion, and tumor growth. Mechanistically, circZNF609 was identified to function as a sponge for miR-324-5p, thereby upregulating voltage-dependent anion channel 1 (VDAC1) expression and promoting OC progression. Our findings indicate that circZNF609 promotes OC via the miR-324-5p/VDAC1 axis, contributing to the therapeutic targeting of this disease.

: Colorectal cancer (CRC) is a common malignant tumor, and circular RNAs (circRNAs) are abnormally expressed in CRC. However, the function and underlying mechanism of circRNA pinin (circ-PNN; hsa_circ_0101802) in CRC remain unclear.

: Exosomes were isolated from the plasma of CRC patients and identified by transmission electron microscopy and Western blotting. The RNA expression levels of circ-PNN, miR-1225-5p, and fibroblast growth factor 13 (FGF13) were measured by quantitative real-time polymerase chain reaction. Cell proliferation was detected by Cell Counting K-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays. Cell apoptosis was assessed by flow cytometry. The expression of apoptosis and metastasis-related proteins was evaluated by Western blotting. The associations among circ-PNN, miR-1225-5p, and FGF13 were confirmed by dual-luciferase report assay and RNA immunoprecipitation assay. A xenograft model was used to verify the function of circ-PNN in tumor formation in vivo.

: circ-PNN expression was upregulated in plasmic exosomes derived from CRC patients. The expression of circ-PNN and FGF13 was upregulated, while miR-1225-5p expression was downregulated in CRC cells incubated with plasmic exosomes derived from CRC patients. Tumor-derived exosomes promoted the proliferation, migration, and invasion but inhibited apoptosis of CRC cells. Moreover, the addition of tumor-derived exosomes partly reversed the inhibitory effect of circ-PNN knockdown on CRC tumor progression in vitro and in vivo. Thus, circ-PNN acts as a sponge for miR-1225-5p to regulate FGF13 expression.

: Tumor-derived exosomal circ-PNN promoted CRC progression through the regulation of the miR-1225-5p/FGF13 pathway, providing a potential therapeutic target for CRC.

Exposure to fine particulate matter (PM2.5) in the ambient environment augments susceptibility to respiratory ailments. Circular RNAs, a distinctive subclass of endogenous non-coding RNAs, have been acknowledged as pivotal regulators of pathological conditions. Ferroptosis, an innovative iron-dependent form of cellular demise, has emerged as a consequential participant in numerous maladies. Despite the established association between PM2.5 exposure and the exacerbation of asthma, scant investigations have probed into the implication of circRNAs and ferroptosis in PM2.5-induced asthma. Consequently, this inquiry sought to scrutinize the potential involvement of circCDR1as and ferroptosis in PM2.5-induced asthma. Through the formulation of a PM2.5 exposure model in asthmatic mice and an in vitro cellular model, it was discerned that PM2.5 induced ferroptosis, thereby intensifying asthma progression. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed an upregulation of circCDR1as in the PM2.5-stimulated asthma cell model. Molecular biology assays demonstrated that diminished circCDR1as expression hindered the onset of ferroptosis in response to PM2.5 exposure. Notably, Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, manifested the ability to impede the advancement of asthma. Mechanistically, RNA pull-down and molecular biology experiments substantiated that circCDR1as selectively bound to insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), thereby modulating the occurrence of ferroptosis. CircCDR1as emerged as a potential orchestrator of asthma progression by regulating ferroptosis under PM2.5 exposure. Additionally, PM2.5 exposure elicited activation of the Wnt/β-catenin signaling pathway, subsequently influencing the expression of C-myc and Cyclin D1, ultimately exacerbating asthma development. In summation, the interaction between circCDR1as and IGF2BP2 in regulating ferroptosis was identified as a critical facet in the progression of asthma under PM2.5 exposure. This investigation underscores the pivotal roles of circCDR1as and ferroptosis in PM2.5-induced asthma, offering a novel theoretical foundation for the therapeutic and preventive approaches to asthma.

Circular RNAs (circRNAs) are closed RNA loops present in humans and other organisms. Various circRNAs have an essential role in diseases, including cancer. Cells can release circRNAs into the extracellular space of adjacent biofluids and can be present in extracellular vesicles. Due to their circular nature, extracellular circRNAs (excircRNAs) are more stable than their linear counterparts and are abundant in many biofluids, such as blood plasma and urine. circRNAs' link with disease suggests their extracellular counterparts have high biomarker potential. However, circRNAs and the extracellular space are challenging research domains, as they consist of complex biological systems plagued with nomenclature issues and a wide variety of protocols with different advantages and disadvantages. Here, we summarize what is known about excircRNAs, the current challenges in the field, and what is needed to improve extracellular circRNA research.

High mobility group protein A2 (HMGA2) is widely recognized as a chromatin-binding protein, whose overexpression is observed in nearly all human cancers. It exerts its oncogenic effects by influencing various cellular processes such as the epithelial-mesenchymal transition, cell differentiation, and DNA damage repair. MicroRNA (miRNA) serves as a pivotal gene expression regulator, concurrently modulating multiple genes implicated in cancer progression, including HMGA2. It also serves as a significant biomarker for cancer. Circular RNA (circRNA) plays a crucial role in gene regulation primarily by sequestering miRNAs and impeding their ability to enhance the expression of other genes, including HMGA2. Increasingly, studies have underscored the vital role of miRNA/HMGA2 interactions in cancer. Given the significance of circRNA as an upstream regulatory mediator and the complexity of regulatory mechanisms, we hereby present a comprehensive overview of the pivotal role of circRNAs as upstream regulators of the miRNA//HMGA2 axis in human cancers. This insight may herald a novel direction for future cancer research.

Exosomes derived from adipose-derived stem cells (ADSCs) have garnered significant attention for their therapeutic potential in various diseases. These vesicles are capable of transporting bioactive molecules such as noncoding RNAs and proteins. Among these noncoding RNAs, circular RNAs (circRNAs) are characterized as end-to-end circular structures, which are notably enriched within exosomes.

This study aims to investigate the impact of the circHIPK3 delivered via ADSC-derived exosomes on ovarian aging.

ADSCs were isolated, and exosomes were obtained from a cell culture medium. The exosomes were labeled with PKH26, and uptake by primary granulosa cells (pGCs) was detected. ADSCs were transfected with circHIPK3 siRNAs, and the exosomes were isolated for the treatment of aging female mice. Ovary weight was recorded, and HE staining, Masson's trichrome, and TUNEL staining were performed to detect tissue morphology and apoptosis in ovary tissues. In addition, the senescence and apoptosis of pGCs were evaluated using the S-β-gal staining kit and Annexin V/PI detection kit. Further experiments included immunoprecipitation and RNA pulldown, determined the ubiquitination of p38 protein under circHIPK3 alteration.

Results showed that ADSC-derived exosomes effectively delivered circHIPK3 to pGCs. Treatment with these exosomes significantly increased ovary weight and enhanced follicular development in aged mice. Conversely, the depletion of circHIPK3 reversed these effects, promoting cell apoptosis. ADSC-derived exosomes also mitigated senescence and apoptosis in pGCs, while circHIPK3 depletion hindered these benefits.

Exosomal circHIPK3 modulated the ubiquitination of p38 in pGCs to improve ovarian function in aging mice and to promote pGC cell viability.

Circular RNAs (circRNAs) are an interesting class of conserved single-stranded RNA molecules derived from exon or intron sequences produced by the reverse splicing of precursor mRNA. CircRNAs play important roles as microRNA sponges, gene splicing and transcriptional regulators, RNA-binding protein sponges, and protein/peptide translation factors. Abnormal functions of circRNAs and RBPs in tumor progression have been widely reported. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) are a highly conserved family of RBPs identified in humans that function as post-transcriptional fine-tuners of target transcripts. Emerging evidence suggests that IGF2BPs regulate the processing and metabolism of RNA, including its stability, translation, and localization, and participate in a variety of cellular functions and pathophysiology. In this review, we have summarized the roles and molecular mechanisms of circRNAs and IGF2BPs in cancer development and progression. In addition, we briefly introduce the role of other RNAs and IGF2BPs in cancer, discuss the current clinical applications and challenges faced by circRNAs and IGF2BPs, and propose future directions for this promising research field.