Controlling the cell cycle meticulously and precisely is critical during typical cellular responses to environmental cues. More and more circRNAs have been discovered to manage cellular proliferation during cell cycle checkpoint regulators, transcription factors, and signaling pathways. Studies have shown that circRNAs are involved in controlling WNT/β-catenin pathways to increase cellular proliferation. One study found that a decrease in circHIPK3 caused FZD4 receptor and WNT2 ligand expression to diminish. This led to less cell proliferation of hampered retinal endothelial and nuclear β-catenin [63]. Additionally, circRNAs affect both AKT/PI3K and ERK/MAPK. The two most common pathways that monitor the increase of cells are AKT PI3K and ERK/MAPK [8]. Studies have shown that growth factors such as FGF attach to tyrosine kinase’s receptor in MAPK/ERK pathways. The binding causes MAPK to phosphorylate, leading to cell proliferation and ERK activation. PI3K phosphorylates AKT and stimulates cell proliferation when receptor tyrosine kinases ligands attach to each other in AKT/PI3K signaling pathways. In glioblastoma and HCC, CDR1as and circNT5E promoted cell proliferation by increasing PI3K expression [64,65]. In esophageal squamous cell carcinoma and colorectal cancer, EGFR receptor expression was enriched by circHIPK2 and CDR1as [61,66]. The expression of FGF2 ligand has improved by circWDR77 in smooth muscle cells found in vascular tissue [67]. Furthermore, a recent study found that the knockdown of hsa_circ_0064559 expanded apoptosis and reduced proliferation rate in cells found in colorectal cancer [68]. Collectively, this evidence shows that circRNAs have the ability to regulate cell proliferation by regulating various signaling pathways and thus can control important cellular processes.

miRNAs control post-transcriptional repression by combining with protein-coding mRNAs, indicating its crucial role in gene-regulatory roles [69]. Evidence demonstrated that miRNA sponges’ activity is unique to each individual miRNA seed family and just as successful as current antisense technology. Additionally, assay miRNA loss-of-function phenotype and predictions of different targets can be confirmed by using these miRNA sponges [70]. CircRNAs functioning as miRNA sponges have been demonstrated through a multitude of recent research [42]. Table 1 lists the circRNAs that act as microRNA sponges. Studies have found that a transcribed CDR1as/CiRS-7 from the CDR1 antisense strand is extensively found in the brains of humans or mice. While CiRS-7 absorbs miR-7, CiRS-7 boosts target miR-7 expression and blocks its biological functions at the same time. However, circRNA is split by miRNA during miRNA sponging [71]. Additionally, it has been shown that ample amounts of circRNA sponged up miRNAs, similar to what miRNAs do for mRNAs [72]. Another study found that metastatic functions weaken when CDR1as regulates and works with the RNA binding protein known as IGF2BP3 [73]. Further research discovered CDR1 has the ability to prevent gliomagenesis by obstructing the p53/MDM2 complex [74]. Several studies have been published about the interaction between circRNAs and miRNAs, specifically Sry circRNA and CiRS-7 [71]. One study showed that Sry, a gene that decides the sex of mice, can be transcribed into circRNA [75]. Another study demonstrated that Sry circRNA behaved as a miRNA sponge and had 16 sites that can bind miR-138 [16].

Circular RNAs have been found to play important functions in cancer [115]. In cancers such as esophageal squamous cell carcinoma [97] and colorectal cancer [49], evidence consists of dysregulated circRNAs. Colorectal cancer was found to be the third highest cancers in both men and women compared to other cancers [116]. Like most other cancers, colorectal cancer is characterized by two factors: epigenetic as well as genetic modifications. Studies have shown that cancer progression or tumor formation have aberrant miRNA expression [117]. One study analyzed linear and circRNA expression and proliferation in tumor tissues. Researchers proposed that the tumor and typical colon mucosa samples from CRC patients had more than 1800 circRNAs. Tumor samples consistently had a lower circRNA to linear RNA isoforms ratio than colon samples that did not have the tumor. Samples from the colorectal cancer cell lines had an even lower ratio than the tumor samples. Idiopathic pulmonary fibrosis, proliferative diseases that are non-cancerous, and several other typical human tissues supported the correlation between proliferation and abundance of global circRNA [51].

The best methods for characterizing and identifying circRNAs are based on RIbo-Zero and RNase R treatment [118]. CircRNA being a new cancer biomarker needs more research, thus Vo et al. created MiOncoCirc as a resource for further research. More importantly, MiOncoCirc identified circ-ACPP and circ-CPNE4 in prostate cancer. Studies have shown that circRNAs are also found in urine samples [42]. A variety of tumor tissues have displayed downregulation of circRNAs, supporting the possibility that several circRNAs have a role in suppressing tumors. However, it can also be interpreted as the dilution of accumulated circRNA when cell division occurs. Further analysis showed that cancer tissues produced more circRNA abundance compared to normal tissues due to several upregulated genes in cancer. Furthermore, researchers noticed a downregulation of circRNA in cells that proliferated across diverse types of tumors. This implies that a few circRNAs could have roles in suppressing tumors [51]. Additionally, determining the type of cancer could be possible if certain circRNAs that are upregulated in tissue can act as surrogate markers such as circ-AURKA in NEPC or circ-AR in CRPC [119].

Studies have demonstrated that immune responses and diseases related to the immune system change expression of circRNA [120]. Regulating the immune cells’ function and differentiation is another role of circRNAs. Widespread circRNA expression was found in lymphoid differentiation, myeloid cells, and hematopoietic progenitors. Various enucleated blood cells aggregate additional circRNAs [121]. It has been found that dysregulation of circRNAs could be involved in the mechanisms that pathogens use to avoid immune response linked with relapse of amyloid leukemia (AML) and relapse blasts [122]. It was found that patients who had a relapse in acute myeloid leukemia (AML) had a specific circRNA profile compared to patients who were healthy or in complete remission. A recent study found that PKR is inhibited by cellular circRNAs. As previously mentioned, an innate immune response occurs when cellular circRNAs are degraded by endonuclease RNase L release PKR [120]. Several targeted DE-mRs signaling pathways found in the ceRNA network are involved in the evolvement of Wilms tumors (WT) because these pathways are linked with immune response and cell cycle [123].

In recent years, accumulating evidence suggests that circRNAs, microRNA, and some proteins that bind with RNA play an essential role in gene function modulation that is connected to the development of various diseases [124]. CircRNAs modulate gene expression through their effect on RBPs and miRNAs [125]. Development of breast cancer in vivo and in vitro was found to be suppressed when introducing CREBZF mRNA nanoparticles. This contributes to new understandings of therapeutic approaches for breast cancer [126]. The mRNA translation and stability could be modulated by miRNAs binding to target mRNAs creating a complex with a protein known as Argonaute (AGO) protein [127]. Migration and proliferation of cells in prostate cancer were found to be caused by the interaction between RNA-binding protein FUS and circ0005276, which was formed through the backsplicing of the XIAP [128]. Another study found that circRNAs originating from exons in neuroepithelial stem cells (NES) in humans have a higher chance of having a genetic variation. Studies have shown that some circRNAs had increased in SFPQ ribonucleoprotein complexes and decreased expression due to SFPQ knockdown [129].

As previously mentioned, circRNAs are capable of regulating the transcription of parent genes. It has been found that interaction between circURI1 and heterogenous nuclear ribonucleoprotein M (hnRNPM) caused alternative splicing genes to be regulated, leading to the inhibition of gastric cancer metastasis [130]. Another study has shown that EIciRNA-U1 snRNP and Pol II transcription complex interact with each other more at parental gene promoters, causing gene expression to increase [14]. The amount of cognate exon-6-skipped variant is raised when the host DNA locus and circSEP3 bind, thus creating an R-loop or RNA-DNA hybrid. This causes the recruitment of the splicing factor and pausing of the transcription [131]. A recent study has shown that circRNA: DNA associations have been found throughout the genome and are majorly present in MLL regions [132]. circMLL (9,10) is highly expressed in infants with leukemia and found to be associated with cluster regions of MLL breakpoints. circMLL (9,10) induces translocation and DNA breaks [132]. Interestingly, the circRNA circSMARCA5 was found to inhibit DNA damage repair by interacting with genes in the host. circSMARCA5 interacts with its host gene locus, which causes transcriptional pausing of its parent gene SMARC5 [133]. Additionally, circular intron RNAs (cirRNAs) can grow in human cells when they fail to debranch at the branchpoint of a 5′ splice site. This causes the expression of parental genes to increase by regulating the activity of elongation Pol II [15]. All this evidence suggests that circRNAs can regulate gene transcription and splicing of parental genes.

Researchers have found that circRNAs can be used as therapeutic targets or pathological biomarkers in various neurological diseases and manifestations [1]. A deteriorating nervous system can cause neuropathic pain [134]. It is one of the most common diabetic complications with a prevalence of about 30% of type II diabetic patients [135]. Both circRNAs and long-coding RNAs (lncRNAs) have demonstrated involvement in the neuropathic pain [136]. CircHIPK3, a type of circRNA and tumor suppressor, has been found to sponge numerous miRNAs, thus regulating the growth of cancer cells [105,108,109,137,138]. Targeting miR-124 to silence circHIPK3 diminished neuropathic pain in diabetic rate, indicating that a change to the circHIPK3/miR-124 axis contributes to the reduction of diabetic neuropathic pain progression [139]. An abundance of circHIPK3 was found in two places: (1) the root ganglion from diabetic rats that were STZ-induced and (2) serums from diabetic patients who go through neuropathic pain.

Dendrites and neuropils in the brain consist of enriched circRNAs that aid in controlling neural plasticity and synaptic function. This suggests that circRNAs could have a crucial role in diseases such as Alzheimer’s diseases (AD), Parkinson’s diseases (PD), and epilepsy that affect the nervous system [140]. In PD, a study revealed that α-synuclein expression is downregulated by miR-7. High expression of α-synuclein in the brain is greatly entangled in pathogenesis of PD. Additionally, cells are shielded against oxidative stress because miR-7 induces the downregulation of the α-synuclein protein that is induced [141]. MiRNA-7 specifically targets the nuclear factor (NF)-κΒ signaling pathway, thus sheltering against cell death that is caused by 1-methyl-4-phenylpridinium [142]. Furthermore, studies have provided evidence that miR-138 controls acyl protein thioesterase 1, which affects the brain’s ability to memorize and learn [143,144]. In brains with AD, miR-7 expression is upregulated by the functional deficiency of CDR1as and causes ubiquitin-protein ligase A, an AD-relevant target, to downregulate [145]. Ubiquitin-protein ligase is reduced in the AD brain and is critical for clearing amyloid peptides [146], thus suggesting that CDR1as may be important in the pathogenesis of AD [145].

The lack of immune tolerance to self-antigens and an impaired immune system are defining characteristics of autoimmune diseases. CircRNAs working as non-invasive biomarkers in diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) have been demonstrated in recent studies [147]. It was demonstrated that patients with RA have upregulated expression of ciRS-7. Additionally, miR-7 roles were stopped by ciRS-7, causing reduced effects of miR_7 suppressing mammalian target of rapamycin (mTOR) [148]. Studies found levels of hsa_circ_0092285 and hsa_circ_0058794 increased while hsa_circ_0088088 and hsa_circ_0088088 levels diminished in peripheral blood mononuclear cells (PBMCs) of RA patients [149]. In MS patients who relapsed and remitted, it was found that MS pathogenesis was associated with aberrant RNA metabolism because PBMCs displayed dysregulated circRNA and alternative splicing isoforms [150]. The lncRNA known for controlling alternative splicing, more formally known as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), was upregulated in patients with MS [151,152]. Furthermore, thousands of alternative splicing events were found to be regulated. MALT1-knockdown Jurkat T cells also consisted of many differentially expressed circRNAs. Results from various studies suggested that MALAT1 dysregulation could result in the development of MS because it affects backsplicing (BSJ) and splicing events [153].

Approximately, 127 differentially expressed circRNAs were identified in patients with SLE [154]. It has been found that the three following circRNAs were expressed in SLE patients’ plasma: hsa_circ_100226, hsa_circ_102584, and hsa_circ_400011 [154]. Among the several miRNA response elements that were found in hsa_circ_100226, it was found that in chondrocytes, the suppression of p65 expression by miR-138 improved NF-κB activation. Osteoarthritis (OA) progression was found to be influenced by miR-138-5p, controlling inflammation and extracellular matrix catabolism [155]. Moreover, it was also found that CD4⁺ T cells in patients with SLE consisted of several downregulated and upregulated cricRNAs. DNA methyltransferase 1 expression improved, while CD70 and CD11 expression on CD4⁺ T cells in active and inactive SLE patients was reduced due to the downregulation of circRNA. Autoantibody production in SLE was stimulated because of CD70 and CD11a overexpression. [156]. In PBMCs, circlBTK is downregulated, while miR-29b is upregulated in SLE patients. CirclBTK binding together with miR-29b may prevent DNA demethylation and protein kinase from activating in SLE [157]. Much research has revealed that functions of immune cells can be controlled by protein kinase signaling pathway. Dysregulation of the pathway prompts SLE to advance quickly [158]. With a myriad of supporting evidence, it is thought that circRNAs have the capability to act as a non-invasive biomarker of SLE [159].