circular RNA (circRNA) is a covalently closed single-stranded RNA that lacks 5' and 3' ends and has long been considered a noncoding RNA. With the development of high-throughput sequencing and bioinformatics technology, the understanding of circRNA has become increasingly advanced. Recent studies have shown that some cytoplasmic circRNAs can be effectively translated into detectable proteins, further indicating the importance of circRNA in cellular pathology and physiological functions. Internal ribosome entry site (IRES) and N6-methyladenosine (m6A) mediated cap-independent translation initiation are considered potential mechanisms of circRNA translation. Multiple circRNAs have been shown to play crucial roles in human cancer. This paper provides an overview of the nature and functions of circRNA and describes the possible mechanisms underlying the initiation of circRNA translation. We summarized the emerging functions of circRNA-encoded proteins in human cancer. Finally, we discuss the therapeutic potential of circRNAs and the challenges of research in this field. This review on circRNA translation will reveal a hidden human proteome and enhance our understanding of the importance of circRNAs in human malignant tumors.

Circular RNAs (circRNAs) have been gradually revealed to regulate the progression of heart disease in depth, showing their clinical significance. However, a mass of cardiac circRNAs still has not been functionally characterized. We aimed to explore the potential candidates that are involved in pathological cardiac hypertrophy.

Public substantial RNA-sequencing data of cardiac circRNAs were utilized to search the cardiac hypertrophy-related circRNAs. Cardiomyocyte hypertrophy in vitro was induced by Ang II (angiotensin II) treatment. Mice were subjected to Ang II infusion to induce cardiac hypertrophy in vivo. Gain-of-function and loss-of-function assays were conducted to detect the effect of RNAs or proteins in cardiac hypertrophy.

A circRNA derived from the cdyl (chromodomain Y-like) gene was screened out and named circCDYL. Our results showed that the expression of circCDYL in primary rat cardiomyocytes was significantly induced by Ang II. Gain-of-function and loss-of-function assays demonstrated that circCDYL effectively promoted cardiomyocyte hypertrophy in vitro. CircCDYL could encode a ≈100-aa truncated CDYL peptide (tCDYL-100), whose sequence highly overlaps that of full-length CDYL. The translation of tCDYL-100 was activated by N6-methylation of circCDYL under prohypertrophic stimulation. tCDYL-100 fulfilled the prohypertrophic of circCDYL. Mechanistically, tCDYL-100 competed with CDYL for binding REST (RE1-silencing transcription factor) and further disrupted the formation of REST-CDYL-EHMT2 (euchromatic histone-lysine N-methyltransferase 2) transcriptional repression complex, resulting in transcriptional activation of rhoa and nppb. Silence of circCDYL in mouse hearts could inhibit Ang II-induced cardiac hypertrophy, while forced expression of tCDYL-100 could cause cardiac hypertrophy.

In summary, our study uncovered an important circRNA-derived peptide and a regulatory mechanism on transcription mediated by N6-methyladenosine-circRNA-histone methylation in pathological cardiac hypertrophy.

The emergence of circRNA-encoded peptides has sparked significant debate in recent years as a novel mode of action for circRNAs. A mounting body of evidence suggests that these peptides play vital roles in cancer development and immune responses. This review initially elucidates the presence of circRNA-encoded peptides and delineates their specific functions across various biological processes and pathological conditions. It goes on to furnish illustrative instances to underscore the pivotal involvement of circRNA-encoded peptides in both innate and adaptive immune responses. The study sheds new light on the biological roles of circRNAs, their potential tumor-promoting and tumor-suppressing functions of circRNA-encoded peptides in specific tumor environment, and their significance in immunological contexts. Meanwhile, the limitations of existing studies on circRNA-encoded peptides are discussed in depth. In particular, circRNA-encoded peptides are critically analyzed as biomarkers and therapeutic targets. Intriguingly, the review concludes with a more organized discussion of future research on circRNA-encoded peptides.

The human genome harbors approximately twenty thousand protein-coding genes, and a significant portion of life science research focuses on elucidating their functions and the underlying mechanisms. Recent studies have revealed that small open reading frame (sORF), originating from non-coding RNAs or the 5' leader sequences of messenger RNAs, can be translated into small peptides called microproteins through cap-dependent or cap-independent mechanisms. These microproteins interact with diverse molecular partners to modulate gene expression at multiple regulatory levels, thereby playing critical roles in various biological processes. Notably, sORF-encoded microproteins exhibit aberrant expression patterns in cancer and are implicated in tumor initiation and progression, expanding our understanding of cancer biology. In this review, we introduce the translational mechanisms and identification methods of microproteins, summarize their dysregulation in cancer and their biological functions in regulating gene expression, and emphasize their roles in driving hallmark events of cancer. Furthermore, we discuss their clinical significance as diagnostic and prognostic biomarkers, as well as therapeutic targets.

During the development and progression of lung cancer, cell metabolism function is altered. Thus, cells rely on aerobic glycolysis and abnormal lipid and amino acid metabolism to obtain energy and nutrients for growth, proliferation and drug resistance. Circular RNAs (circRNAs), a class of non-coding RNAs, serve important biological roles in the growth and development of tumors. Functionally, circRNAs act as molecular sponges that absorb microRNAs (miRNAs) and RNA-binding proteins and as protein scaffolds that regulate gene transcription and translation through the maintenance of mRNA stability. In addition, circRNAs are important regulators of tumor metabolism and promote tumor progression through mediating tumor cell proliferation, metastasis and the induction of chemoresistance. Results of previous studies reveal that circRNAs may serve a key role in regulating tumor metabolic processes in lung cancer, through miRNA sponging and alternative mechanisms. Thus, circRNAs demonstrate potential as therapeutic targets for lung cancer. The present study aimed to review the effects of circRNAs on lung cancer cell metabolism and provide novel insights into the clinical treatment of lung cancer. The present review may also provide a novel theoretical basis for the development of lung cancer drug targets.

Circular RNAs (circRNAs) are a significant class of endogenous RNAs that exert crucial biological functions in human and animal systems, but little is currently understood regarding their roles in plants. Here, we identified a circRNA originating from the back-splicing of exon 4 and exon 5 of a rice gene, OsWRKY9, and named it circ-WRKY9. It is upregulated in rice stripe mosaic virus (RSMV)-infected rice plants. Notably, circ-WRKY9 contains two open reading frames with an internal ribosome entry site. We found that circ-WRKY9 encoded a peptide of 88 amino acids (aa) and named it WRKY9-88aa. Overexpression of WRKY9-88aa suppresses RSMV infection in rice plants, with increased reactive oxygen species production. Furthermore, WRKY9-88aa enhances resistance to blast disease and bacterial leaf blight, suggesting its potential to provide broad-spectrum disease resistance. Our findings provide the first evidence of a peptide encoded by a circRNA in planta and highlight its potential application to control a wide spectrum of plant diseases.

Circular RNAs (circRNAs) are a large family of non-coding RNAs characterized by a single-stranded, covalently closed structure, predominantly synthesized through a back-splicing mechanism. While thousands of circRNAs have been identified, only a few have been functionally characterized. Although circRNAs are less abundant than other RNA types, they exhibit exceptional stability due to their covalently closed structure and demonstrate high cell and tissue specificity. CircRNAs play a critical role in maintaining cellular homeostasis by influencing gene transcription, translation, and post-translation processes, modulating the immune system, and interacting with mRNA, miRNA, and proteins. Abnormal circRNA expression has been associated with a wide range of human diseases and various infections. Due to their remarkable stability in body fluids and tissues, emerging research suggests that circRNAs could serve as diagnostic and therapeutic biomarkers for these diseases. This review focuses on the emerging role of circRNAs in various human diseases, exploring their biogenesis, molecular functions, and potential clinical applications as diagnostic and therapeutic biomarkers with current evidence, challenges, and future perspectives. The key theme highlights the significance of circRNAs in regulating gene expression, their involvement in diseases like cancer, neurodegenerative disorders, cardiovascular diseases, and diabetes, and their potential use in translational medicine for developing novel therapeutic strategies. We also discuss recent clinical trials involving circRNAs. Thus, this review is important for both basic researchers and clinical scientists, as it provides updated insights into the role of circRNAs in human diseases, aiding further exploration and advancements in the field.

Widespread control of gene expression through translation has emerged as a key level of spatiotemporal regulation of protein expression. A prominent mechanism by which ribosomes can confer gene regulation is via internal ribosomal entry sites (IRESes), whose functions have however, remained difficult to rigorously characterize. Here we present a set of technologies in embryos and cells, including IRES-mediated translation of circular RNA (circRNA) reporters, single-molecule messenger (m)RNA isoform imaging, PacBio long-read sequencing, and isoform-sensitive mRNA quantification along polysome profiles as a new toolbox for understanding IRES regulation. Using these techniques, we investigate a broad range of cellular IRES RNA elements including Hox IRESes. We show IRES-dependent translation in circRNAs, as well as the relative expression, localization, and translation of an IRES-containing mRNA isoform in specific embryonic tissues. We thereby provide a new resource of technologies to elucidate the roles of versatile IRES elements in gene regulation and embryonic development.

Purpose: This study aimed to clarify the protective effect of astilbin (AST) on radiation-induced pulmonary fibrosis (RIPF) and explore its underlying molecular mechanism, focusing on non-coding RNAs. Methods: Mouse lung epithelial cells (MLE-12 and TC-1) and C57BL/6J mice were used to establish in vitro radiation injury models and in vivo RIPF models, respectively. Cell viability, apoptosis, the epithelial-to-mesenchymal transition (EMT), and fibrosis-related markers were assessed using cell-counting kit-8 assays, Western blotting, immunohistochemistry, and histological staining. High-throughput sequencing identified differentially expressed circRNAs. The mechanistic studies included RNA-FISH, a dual-luciferase reporter assay, an RNA immunoprecipitation (RIP) assay, and loss-of-function experiments. Results: AST significantly alleviated radiation-induced apoptosis and EMT in vitro, as well as RIPF in vivo. AST treatment reduced collagen deposition, fibrosis-related protein expression, and EMT marker changes. High-throughput sequencing revealed that AST upregulated circPRKCE, a non-coding RNA that functions through a ceRNA mechanism by binding to miR-15b-5p, thereby promoting Smad7 expression and suppressing the TGF-β/Smad7 pathway. Knockdown of circPRKCE abolished AST's protective effects, confirming its pivotal role in mediating AST's anti-fibrotic activity. Conclusions: This study demonstrates that Astilbin alleviates radiation-induced pulmonary fibrosis via circPRKCE targeting the TGF-β/Smad7 pathway to inhibit EMT, suggesting AST as a potential therapeutic agent for managing this severe complication of radiotherapy.

The intramuscular fat (IMF) content of yak beef is critical for determining its quality. Circular RNAs (circRNAs) are a group of endogenous non-coding RNAs that have emerged as important factors in the regulation of IMF deposition. However, the molecular mechanisms through which circRNAs regulate IMF deposition, particularly in yaks, remain unclear. In the present study, a novel circRNA, circCDK14 (originating from the yak's CDK14 gene), was identified by sequencing and RNase R treatment. In our previous study, we successfully established a ceRNA network map and identified miR-4492-z, which interacts with circCDK14. Furthermore, using methylation prediction software, we predicted two genes, SRSF3 and hnRNP A1, that have a strong binding relationship with circCDK14; existing research has confirmed their close association with m6A methylation modifications. On the basis of these findings, we comprehensively evaluated the effects of circCDK14, miR-4492-z, SRSF3 and hnRNP A1 on the proliferation and differentiation of yak intramuscular pre-adipocytes using EdU, CCK-8, BODIPY, Oil Red O and qRT-PCR analyses. Mechanistically, the interaction between circCDK14 and miR-4492-z was validated using a dual-luciferase reporter gene assay and rescue experiments. RIP assays revealed the binding interaction of circCDK14 with SRSF3 and hnRNP A1. The MeRIP experiments showed modification of circCDK14 methylation, with SRSF3 and hnRNP A1 promoting the methylation and translocation of circCDK14 from the nucleus to the cytoplasm. In summary, our results suggest that m6A-modified circCDK14 plays a crucial role as an miR-4492-z sponge in regulating IMF deposition in yaks and that the nuclear export of circCDK14 correlates with the expression levels of SRSF3 and hnRNP A1. This study provides a theoretical basis for the improvement of yak meat quality and promotes the development of molecular yak breeding.

Glioblastoma (GB), the most common and aggressive brain tumor, demonstrates intrinsic resistance to current therapies, resulting in poor clinical outcomes. Cancer progression can be partially attributed to the deregulation of protein translation mechanisms that drive cancer cell growth. In this study, we present the translatome landscape of GB as a valuable data resource. Eight patient-derived GB sphere cultures (GSCs) were analyzed using ribosome profiling and messenger RNA (mRNA) sequencing. We investigated inter-cell-line differences through differential expression analysis at both the translatome and transcriptome levels. Translational changes post-radiotherapy were assessed at 30 and 60 min. The translation of non-coding RNAs (ncRNAs) was validated using in-house and public mass spectrometry (MS) data, whereas RNA expression was confirmed by quantitative PCR (qPCR). Our findings demonstrate that ribosome sequencing provides more detailed information than MS or transcriptional analyses. Transcriptional similarities among GSCs correlate with translational similarities, aligning with previously defined subtypes such as proneural and mesenchymal. Additionally, we identified a broad spectrum of open reading frame types in both coding and non-coding mRNA regions, including long non-coding RNAs (lncRNAs) and pseudogenes undergoing active translation. Translation of ncRNAs into peptides was independently confirmed by in-house data and external MS data. We also observed that translational regulation of histones (downregulated) and splicing factors (upregulated) occurs in response to radiotherapy. These data offer new insights into genome-wide protein synthesis, identifying translationally regulated genes and alternative translation initiation sites in GB under normal and radiotherapeutic conditions, providing a rich resource for GB research. Further functional validation of differentially expressed genes after radiotherapy is needed. Understanding translational control in GB can reveal mechanistic insights and identify currently unknown biomarkers, ultimately enhancing the diagnosis and treatment of this aggressive brain cancer.

Despite multiple diagnostic and therapeutic advances, including surgery, radiation therapy, and chemotherapy, cancer preserved its spot as a global health concern. Prompt cancer diagnosis, treatment, and prognosis depend on the discovery of new biomarkers and therapeutic strategies. Circular RNAs (circRNAs) are considered as a stable, conserved, abundant, and varied group of RNA molecules that perform multiple roles such as gene regulation. There is evidence that circRNAs interact with RNA-binding proteins, especially capturing miRNAs. An extensive amount of research has presented the substantial contribution of circRNAs in various types of cancer. To fully understand the linkage between circRNAs and cancer growth as a consequence of various cell death processes, including autophagy, ferroptosis, and apoptosis, more research is necessary. The expression of circRNAs could be controlled to limit the occurrence and growth of cancer, providing a more encouraging method of cancer treatment. Consequently, it is critical to understand how circRNAs affect various forms of cancer cell death and evaluate whether circRNAs could be used as targets to induce tumor death and increase the efficacy of chemotherapy. The current study aims to review and comprehend the effects that circular RNAs exert on cell apoptosis, autophagy, and ferroptosis in cancer to investigate potential cancer treatment targets.

Sulfatases mediate the sulfation level of cell-surface heparan sulfates to regulate signal transduction, thereby promoting cancer progression. Sulfatase activation requires a sulfatase modifying factor (SUMF) for the modification of its catalytic domain. The role of the SUMF family in urothelial carcinoma (UC) has not been adequately evaluated. In this study, we used an online database and immunohistochemistry to assess genetic changes and the mRNA and protein expression of SUMFs and related candidate targets in UC. We found that SUMF1 and SUMF2 were amplified in UC tissues. High SUMF2 mRNA levels were associated with poor overall survival (OS) and disease-free survival (DFS) in bladder UC (BLCA) from The Cancer Genome Atlas (TCGA) dataset. High SUMF2 protein levels were associated with grade (P < 0.001), T status (P = 0.01), and stage (P = 0.006) in patients with BLCA. We also examined SUMF2 expression levels in upper tract UC (UTUC). SUMF2 expression was associated with stage (P = 0.046), poor OS (P = 0.0022), and DFS (P = 0.019) in patients with UTUC. Knockdown of SUMF2 significantly reduced the migration and invasion abilities of 5637 cells. Furthermore, SUMF2 mRNA levels negatively correlated with FBXW7 mRNA levels in BLCA. The SUMF2high/FBXW7low expression profile predicted the worst survival in BLCA. Taken together, SUMF2 expression is linked to unfavorable clinical outcomes in patients with UC and may serve as a useful prognostic biomarker for UC staging.

Circular RNA (CircRNA)s, a newly discovered type of noncoding RNAs, have been found to play a role in controlling the development and aggressiveness of tumors. Abnormal control of circRNA has been observed in various types of human cancers, including bladder cancer, hepatocellular carcinoma (HCC), breast cancer, and gastric cancer (GC). CircRNAs possess binding sites for microRNAs (miRNAs) and function as miRNA sponges in posttranscriptional regulation. This mechanism has been documented to influence the course of cancer. Significantly, among these putative circRNAs, circular RNA protein tyrosine kinase 2 (circPTK2) exhibited increased expression and displayed a substantial association with adverse clinical characteristics and a negative prognosis. The production of these transcripts occurs via a back-splicing mechanism. The enclosed conformation of circRNAs shields them from destruction and enhances their potential as biomarkers. Gaining insight into the molecular mechanisms involved in these processes would aid in the development of treatment approaches and the discovery of new tumor markers. This article provides a comprehensive assessment of the latest research on the biosynthesis and features of circRNAs. It examines the role of circPTK2 in the diagnosis, treatment, and prognosis evaluation of cancer.

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.

Long non-coding RNAs (lncRNAs), once thought to be mere transcriptional noise, are now revealing a hidden code. Recent advancements like ribosome sequencing have unveiled that many lncRNAs harbor small open reading frames and can potentially encode functional micropeptides. Emerging research suggests these micropeptides, not the lncRNAs themselves, play crucial roles in regulating homeostasis, inflammation, metabolism, and especially in breast cancer progression. This review delves into the rapidly evolving computational tools used to predict and validate lncRNA-encoded micropeptides. We then explore the diverse functions and mechanisms of action of these micropeptides in breast cancer pathogenesis, with a focus on their roles in various species. Ultimately, this review aims to illuminate the functional landscape of lncRNA-encoded micropeptides and their potential as therapeutic targets in cancer.

Brain cancer remains a formidable challenge with limited treatment options. Non-coding RNAs (ncRNAs) have emerged as promising biomarkers due to their dysregulation in tumorigenesis. This review explores the potential of biosensors for early detection of brain cancer by targeting ncRNAs. We discuss the classification and functions of ncRNAs, emphasizing their involvement in key cancer-related processes. Additionally, we delve into recent advancements in biosensor technology, focusing on their ability to accurately detect specific ncRNA biomarkers associated with brain cancer. Our findings underscore the potential of biosensors to revolutionize brain cancer diagnosis, enabling personalized medicine and improving patient outcomes. Future research should focus on refining biosensor technology and expanding their clinical application.

Circular RNAs (circRNAs) are covalently closed RNAs that are present in all eukaryotes tested. Recent RNA sequencing (RNA-seq) analyses indicate that although generally less abundant than messenger RNAs (mRNAs), over 1.8 million circRNA isoforms exist in humans, much more than the number of currently known mRNA isoforms. Most circRNAs are generated through backsplicing that depends on pre-mRNA structures, which are influenced by intronic elements, for example, primate-specific Alu elements, leading to species-specific circRNAs. CircRNAs are mostly cytosolic, stable and some were shown to influence cells by sequestering miRNAs and RNA-binding proteins. We review the increasing evidence that circRNAs are translated into proteins using several cap-independent translational mechanisms, that include internal ribosomal entry sites, N6-methyladenosine RNA modification, adenosine to inosine RNA editing and interaction with the eIF4A3 component of the exon junction complex. CircRNAs are translated under conditions that favor cap-independent translation, notably in cancer and generate proteins that are shorter than mRNA-encoded proteins, which can acquire new functions relevant in diseases.

Radiotherapy (RT) is an integral part of treatment management in cancer patients. However, one of the limitations of this treatment method is the resistance of cancer cells to radiotherapy. These restrictions necessitate the introduction of modalities for the radiosensitization of cancer cells. It has been shown that Noncoding RNAs (ncRNAs), along with modifiers, can act as radiosensitivity and radioresistant regulators in a variety of cancers by affecting double strand break (DSB), wnt signaling, glycolysis, irradiation induced apoptosis, ferroptosis and cell autophagy. This review will provide an overview of the latest research on the roles and regulatory mechanisms of ncRNA after RT in in vitro and preclinical researches.

The mRNA vaccine has emerged as a powerful tool against viral infection during the coronavirus disease 2019 (COVID-19) pandemic. In the post-COVID-19 era, the applications of mRNA-based therapy continue to expand and evolve. Circular RNA (circRNA), long assumed to be a noncoding RNA, has been proven to be translatable and subsequently developed as a next-generation mRNA modality due to its higher stability and wider therapeutic window. Nonetheless, the studies of circRNA translation and its application in diseases still present numerous technical features and challenges. In this chapter, we provide a summary and discussion on the mechanisms of circRNA translation and its applications in medicine development, aiming to serve as a reference and inspiration for readers interested in circRNA-based therapy.

Infertility is a prevalent problem among 10% of people within their reproductive years. Sometimes, even advanced treatment options like assisted reproduction technology have the potential to result in failed implantation. Because of the expected changes in gene expression during both in vitro and in vivo fertilization processes, these methods of assisting fertility have also been associated with undesirable pregnancy outcomes related to infertility. In this aspect, Circular RNAs (circRNAs) play a crucial role as epigenetic modifiers in a wide range of biological and pathological activities, including problems with fertility. CircRNAs are integral pieces in multiple cellular functions, including moving substances within the nucleus, silencing one X chromosome, cell death, the ability of stem cells to differentiate into different cell types, and the process of gene expression inherited from parental genes. Due to the progress made in high-speed gene sequencing, a large amount of circRNA molecules have been detected, revealing their significant functions in diverse biological functions like enhancing testicular development, preserving the differentiation and renewal of spermatogonial cells, and controlling spermatocyte meiosis. Moreover, these non-coding RNAs contribute in different aspects of female reproductive system including pregnancy-related diseases, gynecologic cancers, and endometriosis. In conclusion, there is no denying that circRNAs have immense potential to be used as biomarkers and treatments for reproductive disorders in males and females. In this research, we provide a comprehensive analysis of the multiple circRNAs associated with women's infertility.

Circular RNAs (circRNAs) have emerged as a large class of stable and conserved RNAs that are derived primarily from back-splicing of pre-mRNAs and expressed in a cell- and tissue-specific fashion. Recent studies have indicated that a subset of circRNAs may undergo translation through cap-independent pathways mediated by internal ribosome entry sites (IRESs), m6A modifications, or IRES-like short elements. Considering the stability and low immunogenicity of circRNAs, in vitro transcribed circRNAs hold great promise in biomedical applications. In this review, we briefly discuss the noncoding and coding functions of circRNAs in cells, as well as the methods for the in vitro synthesis of circRNAs and current advances in the applications of circRNAs in biomedicine.

The critical role of circular RNAs as non-coding RNAs in glioma has been extensively investigated. Therefore, we aimed to explore the role and potential molecular mechanisms of circRNA-mind bomb homolog 1 (circMIB1) in gliomas.

RNA sequencing was used to analyze the expression profiles of circRNAs in glioma tissues and normal brain tissues. Quantitative real-time polymerase chain reaction was implemented to examine the levels of circMIB1 in glioma cells and tissues. The circMIB1 was identified as a cyclic RNA molecule by DNA nucleic acid electrophoresis and ribonuclease R assay. The relationship between circMIB1 expression and the prognosis of glioma patients and its potential as a biomarker were analysed using Kaplan-Meier, Receiver operating characteristic curves, and Principal component analysis. Bioinformatics analysis predicted the miRNAs that bind to circMIB1 and their downstream targets, and analysed the functions of these genes.

Firstly, a novel circRNA molecule termed circMIB1 was identified and validated by RNA sequencing. The expression of circMIB1 was significantly downregulated in glioma cells and tissues, and was closely associated with the tumor grade and survival prognosis of patients with glioma. Hence, it may be useful as a biomarker for glioma. Secondly, it was predicted that circMIB1 binds to hsa-miR-1290 based on bioinformatics analysis, which was significantly upregulated in glioma cells and tissues, and correlated with the tumor grade and overall survival of patients. Thirdly, through a series of bioinformatics analyses identified six genes downstream of hsa-miR-1290 that were significantly associated with glioma expression and prognosis, these genes are associated with cell cycle, cell necrosis and cell circadian rhythms.

CircMIB1 may play a role in inhibiting glioma development through the hsa-miR-1290 competitive endogenous RNA interaction network, these findings provide new ideas and directions for the diagnosis and treatment of glioma.

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.

Glioblastoma (GBM) is an aggressive type IV brain tumor that originates from astrocytes and has a poor prognosis. Despite intensive research, survival rates have not significantly improved. Noncoding RNAs (ncRNAs) are emerging as critical regulators of carcinogenesis, progression, and increased treatment resistance in GBM cells. They influence angiogenesis, migration, epithelial-to-mesenchymal transition, and invasion in GBM cells. ncRNAs, such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are commonly dysregulated in GBM. miRNAs, such as miR-21, miR-133a, and miR-27a-3p, are oncogenes that increase cell proliferation, metastasis, and migration by targeting TGFBR1 and BTG2. In contrast, lncRNAs, such as HOXD-AS2 and LINC00511, are oncogenes that increase the migration, invasion, and proliferation of cells. CircRNAs, such as circ0001730, circENTPD7, and circFOXO3, are oncogenes responsible for cell growth, angiogenesis, and viability. Developing novel therapeutic strategies targeting ncRNAs, cell migration, and angiogenesis is a promising approach for GBM. By targeting these dysregulated ncRNAs, we can potentially restore a healthy balance in gene expression and influence disease progression. ncRNAs abound within GBM, demonstrating significant roles in governing the growth and behavior of these tumors. They may also be useful as biomarkers or targets for therapy. The use of morpholino oligonucleotides (MOs) suppressing the oncogene expression of HOTAIR, BCYRN1, and cyrano, antisense oligonucleotides (ASOs) suppressing the expression of ncRNAs such as MALAT1 and miR-10b, locked nucleic acids (LNAs) suppressing miR-21, and peptide nucleic acids (PNAs) suppressing the expression of miR-155 inhibited the PI3K pathway, tumor growth, angiogenesis, proliferation, migration, and invasion. Targeting oncogenic ncRNAs with RNA-interfering strategies such as MOs, ASOs, LNAs, CRISPR-Cas9 gene editing, and PNA approaches may represent a promising therapeutic strategy for GBM. This review emphasizes the critical role of ncRNAs in GBM pathogenesis, as well as the potential for new therapeutic strategies targeting these pathways to improve the prognosis and quality of life for GBM patients.

Short open reading frames (sORFs) are frequently overlooked because of their historical classification as non-coding elements or dismissed as "transcriptional noise". However, advanced genomic and proteomic technologies have allowed for screening and validating sORFs-encoded peptides, revealing their fundamental regulatory roles in cellular processes and sparking a growing interest in microprotein biology. In neuroscience, microproteins serve as neurotransmitters in signal transmission and regulate metabolism and emotions, exerting pivotal effects on neurological conditions such as nerve injury, neurogenic tumors, inflammation, and neurodegenerative diseases. This review summarizes the origins, characteristics, classifications, and functions of microproteins, focusing on their molecular mechanisms in neurological disorders. Potential applications, future perspectives, and challenges are discussed.

It was previously thought that ncRNA could not encode polypeptides, but recent reports have challenged this notion. As research into ncRNA progresses, it is increasingly clear that it serves roles beyond traditional mechanisms, playing significant regulatory roles in various diseases, notably cancer, which is responsible for 70% of human deaths. Numerous studies have highlighted the diverse regulatory mechanisms of ncRNA that are pivotal in cancer initiation and progression. The role of ncRNA-encoded polypeptides in cancer regulation has gained prominence. This article explores the newly identified regulatory functions of these polypeptides in three types of ncRNA-lncRNA, pri-miRNA, and circRNA. These polypeptides can interact with proteins, influence signaling pathways, enhance miRNA stability, and regulate cancer progression, malignancy, resistance, and other clinical challenges. Furthermore, we discuss the evolutionary significance of these polypeptides in the transition from RNA to protein, examining their emergence and conservation throughout evolution.

Around the world, oral cancer (OC) is a major public health problem, resulting in a significant number of deaths each year. Early detection and treatment are crucial for improving patient outcomes. Recent progress in DNA sequencing and transcriptome profiling has revealed extensive non-coding RNAs (ncRNAs) transcription, underscoring their regulatory importance. NcRNAs influence genomic transcription and translation and molecular signaling pathways, making them valuable for various clinical applications. Combining spatial transcriptomics (ST) and spatial metabolomics (SM) with single-cell RNA sequencing provides deeper insights into tumor microenvironments, enhancing diagnostic and therapeutic precision for OC. Additionally, the exploration of salivary biomarkers offers a non-invasive diagnostic avenue. This article explores the potential of ncRNAs as diagnostic and therapeutic tools for OC.

Hepatocellular carcinoma (HCC) represents a major public health concern and ranks among the leading cancer-related mortalities globally. Due to the frequent late-stage diagnosis of HCC, therapeutic options remain limited. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) in the regulation of Aurora kinase A (AURKA), one of the key hub genes involved in several key cancer pathways. Indeed, the dysregulated interaction between ncRNAs and AURKA contributes to tumor development, progression, and therapeutic resistance. This review delves into the interplay between ncRNAs and AURKA and their role in hepatocarcinogenesis. Recent findings underscore the involvement of the ncRNAs and AURKA axis in tumor development and progression. Furthermore, this review also discusses the clinical significance of targeting ncRNA-AURKA axes, offering new perspectives that could lead to innovative therapeutic strategies aimed at improving outcomes for HCC patients.

Non-coding RNAs (ncRNAs) have key roles in the etiology of many illnesses, including heart failure, myocardial infarction, stroke, and in physiological processes like angiogenesis. In transcriptional regulatory circuits that control heart growth, signaling, and stress response, as well as remodeling in cardiac disease, ncRNAs have become important players. Studies on ncRNAs and cardiovascular disease have made great progress recently. Here, we go through the functions of non-coding RNAs (ncRNAs) like circular RNAs (circRNAs), and microRNAs (miRNAs) as well as long non-coding RNAs (lncRNAs) in modulating cardiovascular disorders.

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

Glioblastoma multiforme (GBM) is the most common harmful high-grade brain tumor with high mortality and low survival rate. Importantly, besides routine diagnostic and therapeutic methods, modern and useful practical techniques are urgently needed for this serious malignancy. Correspondingly, the translational medicine focusing on genetic and epigenetic profiles of glioblastoma, as well as the immune framework and brain microenvironment, based on these challenging findings, indicates that key clinical interventions include immunotherapy, such as immunoassay, oncolytic viral therapy, and chimeric antigen receptor T (CAR T) cell therapy, which are of great importance in both diagnosis and therapy. Relatively, vaccine therapy reflects the untapped confidence to enhance GBM outcomes. Ongoing advances in immunotherapy, which utilizes different methods to regenerate or modify the resistant body for cancer therapy, have revealed serious results with many different problems and difficulties for patients. Safe checkpoint inhibitors, adoptive cellular treatment, cellular and peptide antibodies, and other innovations give researchers an endless cluster of instruments to plan profoundly in personalized medicine and the potential for combination techniques. In this way, antibodies that block immune checkpoints, particularly those that target the program death 1 (PD-1)/PD-1 (PD-L1) ligand pathway, have improved prognosis in a wide range of diseases. However, its use in combination with chemotherapy, radiation therapy, or monotherapy is ineffective in treating GBM. The purpose of this review is to provide an up-to-date overview of the translational elements concentrating on the immunotherapeutic field of GBM alongside describing the molecular mechanism involved in GBM and related signaling pathways, presenting both historical perspectives and future directions underlying basic and clinical practice.

Marek's disease (MD), an immunosuppressive disease induced by the Marek's disease virus (MDV), is regarded as an ideal model for lymphoma research to elucidate oncogenic and anti-oncogene genes. Using this model, we found that circRUNX2.2, derived from exon 6 of RUNX2, was significantly upregulated in MDV-infected tumorous spleens. In this study, we deeply analyzed the potential role of circRUNX2.2 in lymphoma cells. An open reading frame (ORF) in circRUNX2.2 with no stop codon was predicted, and small peptides (named circRUNX2.2-rt) presenting multiple ladder-like bands with different molecular weights encoded by circRUNX2.2 were detected via Western blotting assay. The polysome fraction assay reconfirmed the translation ability of circRUNX2.2, which could be detected in polysome fractions. Subsequent analysis verified that it translated in a rolling circle manner, rather than being assisted by the internal ribosome entry site (IRES) or m6A-mediated mechanism. Furthermore, we found that circRUNX2.2-rt was potently induced in MSB1 cells treated with sodium butyrate (NaB), which reactivated MDV and forced the MDV transition from the latent to reactivation phase. During this phase, MDV particles were clearly observed by electron microscopy, and the viral gene pp38 was also significantly upregulated. A biological function study showed that circRUNX2.2-rt promoted cell proliferation and cell cycle transition from the S to G2 phase and inhibited the apoptosis of MSB1. Further immunoprecipitation and mass spectrometry assays showed that 168 proteins potentially interacting with circRUNX2.2-rt were involved in multiple pathways related to cell cycle regulation, which proved that circRUNX2.2-rt could bind or recruit proteins to mediate the cell cycle.

Circular RNAs (circRNAs) are covalently closed, single-stranded RNAs that play critical roles in various biological processes and diseases, including cancers. However, the functions and mechanisms of circRNAs in hepatocellular carcinoma (HCC) need further clarification. Here, we identified and confirmed that circATF6 is downregulated in HCC tissues and negatively associated with the overall survival of HCC patients. Ectopic overexpression of circATF6 inhibits malignant phenotypes of HCC cells in vitro and in vivo, while knockdown of circATF6 had opposite effects. Mechanistically, we found that circATF6 bound to calreticulin (CALR) protein and acted as a scaffold to enhance the interaction of CALR with calpain2 (CAPN2), which promoted the degradation of CALR by its enzymatic activity. Moreover, we found that circATF6 inhibited HCC cells by suppressing CALR-mediated wnt/β-catenin signaling pathway. Taken together, our findings suggest that circATF6 is a potential prognostic biomarker and therapeutic target for HCC.

Metformin, a widely used oral hypoglycemic drug, has emerged as a potential therapeutic agent for cancer treatment. While initially known for its role in managing diabetes, accumulating evidence suggests that metformin exhibits anticancer properties through various mechanisms. Several cellular or animal experiments have attempted to elucidate the role of non-coding RNA molecules, including microRNAs and long non-coding RNAs, in mediating the anticancer effects of metformin. The present review summarized the current understanding of the mechanisms by which non-coding RNAs modulate the response to metformin in cancer cells. The regulatory roles of non-coding RNAs, particularly miRNAs, in key cellular processes such as cell proliferation, cell death, angiogenesis, metabolism and epigenetics, and how metformin affects these processes are discussed. This review also highlights the role of lncRNAs in cancer types such as lung adenocarcinoma, breast cancer, and renal cancer, and points out the need for further exploration of the mechanisms by which metformin regulates lncRNAs. In addition, the present review explores the potential advantages of metformin-based therapies over direct delivery of ncRNAs, and this review highlights the mechanisms of non-coding RNA regulation when metformin is combined with other therapies. Overall, the present review provides insights into the molecular mechanisms underlying the anticancer effects of metformin mediated by non-coding RNAs, offering novel opportunities for the development of personalized treatment strategies in cancer patients.

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, which affects 3-8% of pregnant individuals worldwide each year. Prevention, diagnosis and treatment of PE are some of the most important problems faced by obstetrics. There is growing evidence that circular RNAs (circRNAs) are involved in the pathogenesis of PE. The present review summarizes the research progress of circRNAs and then describes the expression patterns of circRNAs in PE and their functional mechanisms affecting PE development. The role of circRNAs as biomarkers for the diagnosis of PE, and the research status of circRNAs in PE are summarized in the hope of finding novel strategies for the prevention and treatment of PE.

Non-coding RNAs (ncRNAs), including circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), are unique RNA molecules widely identified in the eukaryotic genome. Their dysregulation has been discovered and played key roles in the pathogenesis of numerous diseases, including various cancers. Previously considered devoid of protein-coding ability, recent research has revealed that a small number of open reading frames (ORFs) within these ncRNAs endow them with the potential for protein coding. These ncRNAs-derived peptides or proteins have been proven to regulate various physiological and pathological processes through diverse mechanisms. Their emerging roles in disease diagnosis and targeted therapy underscore their potential utility in clinical settings. This comprehensive review aims to provide a systematic overview of proteins or peptides encoded by lncRNAs and circRNAs, elucidate their production and functional mechanisms, and explore their promising applications in cancer diagnosis, disease prediction, and targeted therapy.

Translation is a decoding process that synthesizes proteins from RNA, typically mRNA. The conventional translation process consists of four stages: initiation, elongation, termination, and ribosome recycling. Precise control over the translation mechanism is crucial, as dysregulation in this process is often linked to human diseases such as cancer. Recent discoveries have unveiled translation mechanisms that extend beyond typical well-characterized components like the m7G cap, poly(A)-tail, or translation factors like eIFs. These mechanisms instead utilize atypical elements, such as non-canonical ORF, m6A-modification, and circular RNA, as key components for protein synthesis. Collectively, these mechanisms are classified as non-canonical translations. It is increasingly clear that non-canonical translation mechanisms significantly impact the various regulatory pathways of cancer, including proliferation, tumorigenicity, and the behavior of cancer stem cells. This review explores the involvement of a variety of non-canonical translation mechanisms in cancer biology and provides insights into potential therapeutic strategies for cancer treatment.

Circular RNAs (circRNAs) have been shown to be pivotal regulators in various human diseases by participating in gene splicing, acting as microRNA (miRNA) sponges, interacting with RNA-binding proteins (RBPs), and translating into short peptides. As the back-splicing products of pre-mRNAs, many circRNAs can modulate the expression of their host genes through transcriptional, post-transcriptional, translational, and post-translational control via interaction with other molecules. This review provides a detailed summary of these regulatory mechanisms based on the class of molecules that they interact with, which encompass DNA, mRNA, miRNA, and RBPs. The co-expression of circRNAs with their parental gene productions (including linear counterparts and proteins) provides potential diagnostic biomarkers for multiple diseases. Meanwhile, the different regulatory mechanisms by which circRNAs act on their host genes via interaction with other molecules constitute complex regulatory networks, which also provide noticeable clues for therapeutic strategies against diseases. Future research should explore whether these proven mechanisms can play a similar role in other types of disease and clarify further details about the cross-talk between circRNAs and host genes. In addition, the regulatory relationship between circRNAs and their host genes in circRNA circularization, degradation, and cellular localization should receive further attention.

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that have emerged as pivotal players in gene regulation. Our understanding of circRNAs has greatly expanded over the last decade, with studies elucidating their biology and exploring their therapeutic applications. In this review, we provide an overview of the current understanding of circRNA biogenesis, outline their mechanisms of action in cancer, and assess their clinical potential as biomarkers. Furthermore, we discuss circRNAs as a potential therapeutic strategy, including recent advances in circRNA production and translation, along with proof-of-concept preclinical studies of cancer vaccines.