Circular RNAs as a novel class of potential therapeutic and diagnostic biomarkers in reproductive biology/diseases

circRNAs serve primarily to control the function of initial genes and alter the progression of RNA development or gene duplication [ 38 , 51 ]. Recent research has revealed that circRNAs, particularly those found within introns known as ciRNAs and EIciRNAs, possess an exclusive capacity to directly govern the expression of genes inside the nucleus [ 59 ]. Increasing proof suggests that there is an inverse relationship between the proficiency of splicing for certain genes and the level of expression of circRNAs. Studies have observed a rivalry in splicing among the production of linear and circular transcripts [ 60 ]. The mouse formin (Fmn) gene is a recognized example of this occurrence and is scientifically known as “RNAtrap”. A phenomenon closely associated with the production of circular RNAs (circRNAs). In this process, the gene undergoes back splicing, leading to the formation of circRNAs while simultaneously generating a non-coding linear RNA transcript. This back-splicing event effectively “traps” the RNA in a circular form, preventing it from being translated into the Fmn protein. As a consequence, the production of functional Fmn protein is reduced, because the RNA that would normally be translated is diverted into the formation of circRNAs. This regulatory mechanism illustrates how the generation of circRNAs can impact protein expression, acting as a natural “trap” for RNA transcripts. As a result, the expression of the Fmn protein is reduced [ 61 ]. circRNAs function as ceRNAs by serving as competitive “sponges” for miRNAs, affecting multiple biological systems or diseases. A recent investigation found that fully developed ovaries had considerably higher levels of circEGFR compared to developing ovaries. It was also found that circEGFR functioned as a mechanism to bind miR‐125a‐3p and regulate the expression of Fyn [ 62 ]. By utilizing the gene knockout method, researchers successfully illustrated the involvement of circEGFR in facilitating the production of estradiol and the development of granulosa cells. Moreover, the researchers discovered that reducing the amount of circEGFR resulted in a reduction of estrogen production [ 62 ]. The addition of miRNA binding sites within circRNAs suggests that they play a role in regulating a range of miRNA functions. According to the findings of Chen et al., found that circFGFR2 plays a crucial role in the formation and progression of myoblasts by serving as a suppressor of miR-133a-5p and miR-29b-1-5p [ 63 ]. The connection between circRNAs and miRNAs has been linked to the advancement of multiple diseases. According to Chioccarelli and colleagues, out of 148 circRNAs in high-quality sperm, they specifically selected two which displayed a strong presence of circ-RERE and circ-NFIC [ 64 ]. The study revealed that circ-RERE displays a robust association with multiple microRNAs, including has-miR-550a-3p, has-miR-335-3p, has-miR-571, has-miR-377-3p, and has-miR-105-5p. Moreover, the precise management of particular RNA molecules by the circular non-coding RNA circ-RERE plays a vital role in regulating a range of essential biological functions, including embryo implantation and growth, endometrium responsiveness, stem cell renewal, and the development of the central nervous and skeletal systems. This is significant in guaranteeing the correct operation of these procedures. In the same way, circ-NFIC serves as a substance that takes in and counteracts has-miR-612, has-miR-92a-1-5p, has-miR-890, has-miR-181d-3p, and has-miR-92b-5p, with the purpose of aiding spermatogenesis and the maturation of sperm cells. Although circRNAs are commonly believed to be noncoding RNAs, it has been found that certain ones are capable of coding for proteins through processes like ribosome entry sites (IRES), rolling circle amplification (RCA), untranslated regions (UTR), and N 6-methyladenosine (m6 A) driven translation mechanisms [ 65 – 69 ]. The translation of certain circRNA is initiated by IRES, wherein there are particular elements situated prior to the commencement codon. The purpose of these components is to make the translation of circRNA easier [ 66 ]. According to the research conducted by Yang et al. observed that the initiation of IRES resulted in the formation of a 21-kDa protein called FBXW7-185aa [ 67 ]. Research involving cells and animals has shown that FBXW7-185aa effectively hinders the growth of cancerous cells, especially in glioma cases. This finding underscores the significance of FBXW7-185aa as a valuable focus for therapeutic methods. Moreover, RCA has been demonstrated to have an impact on the translation of circRNAs, even those without a stop codon and containing a continuous ORF capable of generating proteins. Abe et al., demonstrated that this phenomenon was confirmed through their research [ 68 ]. They found that DNA sequences containing numerous open reading frames (ORFs) could be converted into proteins using the replicative circularization-aided (RCA) mechanism in both a rabbit reticulocyte lysate and an Escherichia coli cell-free translation system. The UTR-driven process of translation utilizes circRNAs by retaining a portion of the same UTR sequences from pre-mRNA after undergoing back-splicing. The ribosomes responsible for translating genetic information attach to these particular fragments of untranslated regions to produce proteins. It has been proven that the cUTR sequence of CircMBI can effectively initiate protein synthesis in a Drosophila cell-free translation system [ 69 ]. Yang et al., conducted research which revealed that the m6A modification was a key factor in promoting the translation of circRNAs through the m6A-driven mechanism [ 65 ]. They found that this modification directly interacts with YTHDF3, further indicating its importance, a reader protein for m6A, circRNA’s conservative m6A motifs are recognized, and with the help of other translation starting factors, YTHDF3 initiates the translation of circRNAs. The discovery was made that the FTO enzyme specifically inhibited the translation function of circRNA, while the METTL3/MTTL14 enzyme promoted it. The act of converting circRNA into a different form enables it to regulate the quantities of proteins present and impact the progression of illnesses. This offers a novel viewpoint for investigating the potential application of circRNA-based protein engineering as a treatment strategy [ 70 ]. circRNAs act as a particular type of absorbent material that specifically captures proteins, ultimately influencing and controlling the processes in which they are involved. The study conducted by Du et al., has confirmed that circ-Foxo3 plays a vital role as a mediator by interacting with both cyclin-dependent kinase 2 (CDK2) and p21 [ 71 ]. As a result, a complex is formed with circ-Foxo3, p21, and CDK2, which reinforces the inhibitory effect of p21 on the synthesis of cyclin A/CDK2 and cyclin E/CDK2, ultimately leading to the suppression of cell proliferation [ 71 ]. The circular arrangement of Foxo3 contains unique regions that can engage with MDM2 and p53, leading to the facilitation of MDM2-induced ubiquitination and subsequent degradation of p53 [ 72 ]. This implies that the presence of circRNAs may significantly influence the development of illnesses, as they serve as decoys for proteins (Fig.  2 ). Fig. 2 Major function of circRNA is to control gene expression through the manipulation of pre-messenger RNA processing, specifically concerning intronic circRNAs, ciRNAs, and EIciRNAs. Furthermore, it has the ability to sponge and regulate the levels of miRNAs and proteins, acting as a barrier. Moreover, circRNA is also involved in the process of ribosomal RNA maturation, which controls the translation of proteins. This is achieved through the functions of ciRNA, intronic circRNA, circRNAs, EIciRNAs, and mRNAs Major function of circRNA is to control gene expression through the manipulation of pre-messenger RNA processing, specifically concerning intronic circRNAs, ciRNAs, and EIciRNAs. Furthermore, it has the ability to sponge and regulate the levels of miRNAs and proteins, acting as a barrier. Moreover, circRNA is also involved in the process of ribosomal RNA maturation, which controls the translation of proteins. This is achieved through the functions of ciRNA, intronic circRNA, circRNAs, EIciRNAs, and mRNAs

The utilization of advanced biomarker identification methods is crucial in diagnosing diseases. In recent times, the thorough investigation of circRNAs has been conducted as they possess distinctive characteristics, such as tissue-specific expression, long lifespan, and significant abundance, indicating their promising role as biomarkers in specific illnesses. In the past, scientists have studied miRNAs and various regions of RNA transcripts as potential biomarkers that can remain stable. However, the identification of circRNAs has prompted a significant emphasis on studying this molecule as a potential biomarker through RNA analysis, to assess its level of sensitivity [ 126 ]. As a result of their ability to function in both transcription and post-transcription processes, circRNAs (circRNAs) possess considerable potential as viable biomarkers for a range of conditions including cardiovascular disorders, neurological ailments, and cancer. The main reason for this is their tendency to be let go by cells into the bloodstream, which could create chances to find biomarkers. Furthermore, the detection of circRNAs within exosomes presents a potential opportunity for their use as biomarkers in cancer detection [ 127 ]. In individuals with colorectal cancer (CRC), circulating exosomal circRNAs found in serum serve as an innovative and dependable type of circRNAs [ 127 ]. The investigation of circRNAs in human diseases is currently a widespread and intensive area of research. In various illnesses, distinct circRNAs have been found to have varying levels of expression. These include both increased and decreased expression. As they can control the gene expression, circRNAs have garnered interest as promising agents for therapeutic use. Researchers are focusing on numerous types of circRNAs that possess the ability to be used as treatments. Various circRNAs are currently being utilized as targets for therapy in a wide range of illnesses. In addition, it has been noted that specific circRNAs that suppress tumor growth may have the capability to serve as therapeutic agents for treating cancer [ 128 ]. To fully grasp the therapeutic possibilities of circRNAs, it is imperative to conduct functional trials that alter the levels of circRNAs through methods, such as inhibition or overexpression. Using self-splicing introns or splint ligation methods, circRNAs have the ability to be created and incorporated into cells, enabling researchers to effectively assess their functions [ 70 , 79 , 129 ]. The process of inducing an increased level of circRNA involves the utilization of circRNA overexpression plasmids containing the specific circRNA sequence [ 130 ]. CircRNAs have a completed closed construction, which allows them to be more stable in contrast to many kinds of RNAs. CircRNAs possess a natural durability that may make them a highly suitable option for utilization as biomarkers in upcoming studies and advancements [ 131 – 134 ]. The usefulness of circRNAs extends to the treatment of various ailments, such as neurological issues, heart problems, and cancer, showcasing their potential as therapeutic molecules [ 135 – 138 ]. In recent times, numerous research has been conducted to explore the role of circRNAs in the progression of cancer [ 139 – 141 ]. Several studies have linked circRNAs to a wide range of cancer forms. It has been shown that certain circRNAs derived from the tumor suppressor gene FBXW7 have the ability to produce protein products that can decrease the stability of the c-Myc protein [ 142 ]. There are two distinct categories of circRNAs, namely, circHIPK3 and circDOCK1, which both serve to govern cell proliferation and function as indicators for the presence of cancer [ 143 , 144 ]. To illustrate, in instances of colorectal and ovarian cancer, the level of circRNAs detected, when compared to linear isoforms, is found to be noticeably reduced in tumor tissue [ 145 ]. The ratio showed a clear inverse relationship with the speed at which cancer cells multiplied. Furthermore, when compared to individuals without any health conditions, colon cancer patients exhibited distinct expression profiles of circRNAs in peripheral blood exosomes [ 146 ]. It is not yet fully determined how these circRNAs contribute to cancer; however, they have the potential to be useful indicators for diagnosing EC or monitoring its development. Despite evidence suggesting that circRNAs play a role in the formation and advancement of tumors, their specific impact on EC remains entirely unexplored. Previously, there has been limited investigation on circRNAs in EC. The levels of circRNAs in EC tissue have been observed to differ significantly from those in neighboring healthy tissues [ 74 ]. Likewise, research has validated a notable distinction in the amounts of circRNAs (circRNAs) found in grade 3 endometrial cancer tissue compared to adjacent, non-cancerous endometrium. This discovery provides promising new avenues for identifying and treating grade 3 EC through the use of molecular techniques [ 147 ]. The amount of circRNAs found in EC was considerably lower in comparison to the levels found in normal endometrium. However, there were no discrepancies in the amount of linear RNA transcripts in both types of tissue. Furthermore, there is a significant presence of circRNA-specific genes that may contribute to the disparity in circRNA expression levels between normal and cancerous endometrium tissues [ 74 ]. Based on a study, DNAH14, ESR1, RABGAP1, MT-RNR2, FIP1L1, GFPT1, INADL, and PCNX are the most distinct hotspot genes have been recognized in both regular and EC tissue. These genes were found to be within the top 10 and top 8, respectively, in terms of ranking [ 74 ]. Hotspot genes refer to the generation of a multitude of diverse circRNA variants, surpassing a count of twelve, within a specific tissue or cell [ 148 ]. Research has revealed that fluctuations in circRNA levels in EC are attributed to alterations in particular spliced forms and circular isoforms, wherein isolated exons are produced by a solitary gene site [ 74 ]. Researchers discovered a higher level of circ_0067934 in both cervical cancer tissue and cell lines comparing surrounding healthy tissue [ 149 ]. A considerable amount of circ_0067934, a circRNA variant, was detected in patients suffering from cervical cancer and suffering from lymph node metastasis, indicating its prospective use as a means of identifying the spread of the disease. Ding et al. conducted a research which revealed a notable rise of circ-ATP8A2 in both cervical cancer samples and cellular models. Moreover, this research demonstrated a robust correlation between elevated levels of circ-ATP8A2 and increased FIGO stage, presence of lymph node invasion, and infiltration of the myometrium in patients [ 150 ]. Furthermore, the concentration of has-circ-u0000745 was found to be raised in both the tissues and cell cultures of cervical cancer. This was deemed to be connected with multiple clinicopathological factors, including poorly differentiated tumors and the presence of vascular or lymphatic invasion [ 151 ]. Research has linked another circRNA, circ_0005576, to an elevated pathological level and the presence of lymph node metastases [ 152 ]. On the other hand, different research has shown that decreased levels of circRNA also facilitate the spread of cancer to other parts of the body. According to Jiao et al., the decreased expression of circRNA_101308 is linked to the invasion of cancerous cells into the underlying muscle layer of the uterus and the spread to nearby lymph nodes [ 153 ]. Hence, careful examination is necessary when choosing a suitable circRNA marker for a particular disease condition. As circRNAs play a crucial role in determining the traits of sperm, it is expected that alterations in their expression would lead to a connection with changes in sperm characteristics, ultimately impacting sperm functionality. Several research studies have indicated that an unequal distribution of circRNAs is correlated with problems in sperm, including a reduced amount of sperm, impaired sperm function, and a decrease in ability to fertilize [ 107 , 154 , 155 ]. Most studies have proven that circRNAs have a significant effect on azoospermia, oligozoospermia, and asthenozoospermia [ 109 , 154 , 156 – 158 ]. Azoospermia, a type of male infertility, where there is a total absence of sperm in semen, is a major focus due to its high prevalence, representing 10–15% of all male infertility cases [ 159 , 160 ]. This condition can be divided into two categories: obstructive azoospermia (OA) and nonobstructive azoospermia (NOA). According to the findings of Ge and colleagues, individuals with non-obstructive azoospermia (NOA) showed higher levels of hsa_circRNA_0023313 [ 158 ]. This suggests that this specific circRNA may play a role in suppressing sperm production by blocking the function of related miRNAs. Based on the study findings, it has been determined that hsa_circRNA_0023313 acts as a specific enzyme involved in the transfer of ubiquitin proteins and serves important functions in the processes of endocytosis, meiosis, protein breakdown through ubiquitin, and the signaling pathways of FOXO and AMPK. The miRNAs, namely, hsa-miR-373-3p, hsa-miR-372-3p, hsa-miR-520d-3p, hsa-miR-302c-3p, and hsa-miR-130b-5p, are highly probable to be influenced by the presence of hsa_circRNA_0023313 [ 158 ]. Prior studies have demonstrated that hsa-miR-373 and hsa-miR-372 exhibit alterations in the seminal fluid of men presenting with NOA [ 158 , 161 ]. Lv et al.’s study found a large increase in hsa_circ_0000116 levels in testicular biopsies of individuals with non-obstructive azoospermia (NOA) compared to those with obstructive azoospermia (OA). As a result, the experts suggested that hsa_circ_0000116 may function as a controller of the process of spermatogenesis. Moreover, the results of their study also showed that increased levels of hsa_circ_0000116 were linked to a decreased likelihood of successfully obtaining sperm from the testes. It appears that hsa_circ_0000116 is capable of impeding the process of spermatogenesis by suppressing miR-449 [ 162 ]. The research conducted by Bo et al. shows that several circRNAs, namely, hsa_circRNA_402130, hsa_circRNA_072697, hsa_circRNA_030050, hsa_circRNA_100812, and hsa_circRNA_406168, exhibit atypical expression in testicular biopsies from individuals with non-obstructive azoospermia (NOA). This suggests that these circRNAs may play a role in the development of NOA [ 163 ]. There is a large body of evidence indicating that circR-NAs play a crucial role in the advancement of oligozoospermia. A specific instance, Ssc_circ_0345, derived from SLC5A10, has been seen to control the activity of miR-423-5p [ 164 ]. Prior studies have established that individuals with a low sperm count have elevated levels of miR-423-5p in their sperm cells [ 165 , 166 ]. Overall, the disturbance of circRNAs has a significant impact on the occurrence of non-obstructive azoospermia (NOA) and oligozoospermia. A significant number of observed changes in circRNA activity result from their interaction with microRNAs, ultimately affecting spermatogenesis (Fig.  4 ). As a result, identifying the specific patterns and levels of circRNAs could be a highly effective method for diagnosing various forms of male infertility. Recently, Manfrevola and team conducted research to assess the impact of circRNAs on asthenozoospermia. Based on their research, the levels of circMCC, circSLC25A26, circPAPPA2, circCANX, circDYNC1H1, circHDAC3, circDDX17, circSIRT5, and circFABP6 were higher in the sperm samples, while the levels of circ-TADA2A, circUSP54, circPEX1, circCLSPN, circATF, circTRMT2B, circCIT, circPTBP3, and circEPS15 showed a decrease. Furthermore, it has been verified that circUSP54 is associated with a range of miRNAs, such as has-miR-4677-5p, has-miR-1305, has-miR-103a-2-5p, has-miR-3614-3p, and has-miR-4482-3p, which play a role in controlling vital genes responsible for maintaining the integrity and performance of mitochondria. These specific genes, including TRIM4, MYOF, XIAP, VPS13A, VPS13A, and SOD2, all play a role in sperm motility and are significantly influenced by this factor [ 109 ]. The gene SPATA19 notably engage in both the function of mitochondria in sperm and maintaining their overall integrity. According to a recent investigation, the transcript ssc_circ_1532, derived from the SPATA19 gene, may have the ability to impact sperm movement. In particular, it is believed that ssc_circ_1532 can control the levels of miR-99a, which is known to be elevated in individuals with asthenozoospermia [ 107 , 156 ]. Liu et al. conducted separate research which indicated that LRGUK protein contributes to the creation of both and operation of sperm. Hence, Blocking LRGUK in any way can result in a condition called oligoasthenoteratozoospermia (OAT) [ 167 ]. In a study by Gòdia et al., it was discovered that a particular circRNA, known as ssc_circ_0780 and derived from LRGUK, is associated with the ratio of cells that are actively moving [ 107 ]. The PAPOLA gene has been found to produce another type of circRNA, namely, ssc_circ_1321 that showed a significant decrease in levels in ejaculate samples containing sperm with low motility. Its human ortholog, has_circ_0033126, may potentially produce a similar impact [ 156 ]. In contrast, the ssc_circ_1219 molecule, which originates from the OSBPL9 gene, is closely associated with the movement and activity of sperm. This particular gene is involved in the processing of hormones involved in male reproductive functions and is also a possible target for miR-101-3p, a molecule that has been found to be decreased in males with asthenozoospermia [ 107 , 156 ]. Therefore, it can be deduced that fluctuations in the quantities of circRNAs in the testes can notably influence the motility of sperm. The pattern of circRNA expression in individuals with reduced sperm motility, known as asthenozoospermia, differs from that found in other forms of male infertility. Identifying circRNAs involved in flagellum construction or cellular energy provision may uncover novel molecular insights into the link between sperm motility and asthenozoospermia. Fig. 4 CircRNA molecules play crucial roles in the processes of spermatogenesis and sperm motility. These circular entities can influence the expression of genes through the process of miRNA sequestration CircRNA molecules play crucial roles in the processes of spermatogenesis and sperm motility. These circular entities can influence the expression of genes through the process of miRNA sequestration Not only in male reproductive disorders, but also in female reproductive disorders these ncRNAs play a significant role. Polycystic ovary syndrome is the primary factor of female infertility, making it essential to identify and treat it promptly to effectively control its effects. Mounting evidence has strongly indicated the use of circRNAs as highly effective markers for both diagnosing and targeting treatment for PCOS. It has led to in a surge of interest in circRNAs as viable therapeutic targets for this condition in recent times. The rising quantity of circRNAs linked to the development and advancement of PCOS indicates their promising use as targets for treatment. Methods involving RNA interference are commonly used to suppress circRNA activity, while expression plasmids are utilized to boost their expression [ 168 ]. In particular, the compound known as circ_0043532 has the potential to be used as a means for treatment by affecting the miR-182/SGK3 axis. In research, it was discovered that this compound’s suppression led to the inhibition of cell growth in both GC and KGN cells, as well as disruptions in the cell cycle associated with polycystic ovary syndrome (PCOS) [ 169 ]. Moreover, it has been demonstrated that circ-FURIN, which forms a regulatory pathway in conjunction with the miR-195-5p/BCL2 pathway, can effectively repress the growth of GCs and promote their programmed cell-death in individuals with PCOS through the use of small interfering RNA [ 170 ]. Additional investigation revealed that the absence of circ_0030018 could effectively hinder the advancement of Polycystic Ovary Syndrome (PCOS) by means of the regulation of the miR-136-mediated MIEN1 pathway [ 171 ]. Hence, preventing the production of circRNA may improve the symptoms of PCOS. Introducing high levels of circPSMC3, which play as a sponge for miR-296-3p to regulate PTEN expression, may also alleviate PCOS symptoms in mice. Laboratory tests confirmed that circPSMC3 could hinder cell development and enhance cell death by halting the cell cycle in KGN cells, suggesting that its external introduction could serve as a potential therapeutic method [ 172 ]. Improving insulin sensitivity is crucial for the treatment of PCOS as it is a key factor in reducing insulin resistance, promoting proper glucose utilization, decreasing excessive androgen production, and improving fertility outcomes [ 173 ]. In a prior investigation, the suppression of circANKRD36 effectively hindered insulin resistance by directly affecting miR-145 through the involvement of XBP1 [ 174 ]. CircRNF111 has a crucial role in safeguarding against both ischemia–reperfusion damage and accumulation of lipids by controlling the miR-143-3p/IGF2R pathway [ 175 ]. As a result, circRNAs have the potential to be targeted for therapy in PCOS-associated IR. Nevertheless, additional scientific investigation is required to fully comprehend their viability and underlying mechanisms. The dominant gauge of diagnostic proficiency when utilizing receiver operating curve analysis is the AUC, which represents the area beneath the curve. A number of circRNAs (circRNAs) have been identified as potential biomarkers for polycystic ovary syndrome (PCOS), and their abnormal expression is linked to the pathological features observed in individuals with PCOS. Of all the identified circRNAs, hsa_circ_0097636 displayed decreased expression in CCs and exhibited strong diagnostic value, reflected by its AUC score of 0.738, when tested on a group of 25 patients with PCOS and 25 healthy individuals. The findings from the binary logistic regression analysis highlight the significance of combining hsa_circ_0097636 with serum testosterone level, as it resulted in a considerable increase in the AUC value to 0.893. In addition, both hsa_circ_0043533 and hsa_circ_0043532 showed promising AUC values of 0.709 and 0.718, respectively [ 176 ]. Huang and colleagues discovered that three specific circRNAs (hsa_circ_0085997, hsa_circ_0075692, and hsa_circ_0075691) showed noticeable variations in expression levels among those diagnosed with polycystic ovary syndrome (PCOS). These circRNAs also demonstrated strong discriminatory capabilities, with AUC scores between 0.75 and 0.89 [ 177 ]. These three circRNAs have not been detected in any other medical conditions, indicating that their distinctiveness and efficacy could potentially make them suitable biomarkers for PCOS. Nevertheless, the number of PCOS patients involved in the aforementioned research is quite limited, hence a larger group of individuals should be studied to validate the suitability of these circRNAs as diagnostic indicators for PCOS. Significantly, a number of circRNAs display abnormal levels in both serum and serum-based exosomes, as well as in plasma, making them promising candidates for non-invasive biomarkers for the early detection of disease. Consequently, forthcoming research can center on examining changes in circRNAs in bodily fluids as a means to track the development of PCOS. Detecting cancer in its early stages, prior to it spreading, significantly increases the likelihood of successful treatment. In addition, evaluating the diagnosis of ovarian cancer can extend a patient’s lifespan [ 178 ]. Understanding the origins and development of ovarian cancer is multifaceted, and the existing techniques used for diagnosis, namely, identifying specific molecules associated with the tumor, utilizing ultrasound, computed tomography, magnetic resonance imaging and examining tissue samples, are inadequate. Consequently, there is a pressing need for new measures to accurately diagnose, track the spread, and predict the outcome of this disease. At present, there is a notable focus among researchers on controlling circRNAs in ovarian cancer, in search of new biomarkers that can assist in detecting this disease. Pei and colleagues noted a significant increase in the levels of hsa_circ_0013958 in both ovarian cancer tissues and cell lines. In addition, they observed a notable connection between heightened levels of hsa_circ_0013958 expression and more advanced FIGO stage as well as metastasis to lymph nodes among patients [ 179 ]. After a thorough examination, it was determined that hsa_circ_0013958 is a highly reliable and accurate marker for detecting ovarian cancer. Prior studies have demonstrated that circLARP4 acts as a competitive antagonist of miR-424, regulating the progression of gastric cancer. There has been a recognition of lower levels of circLARP4 in instances of ovarian cancer, and this has been connected to both the FIGO stage and the advancement of cancer to lymph nodes. A more in-depth analysis of survival rates demonstrated that a reduction in circLARP4 was an influential factor in forecasting the outcome of ovarian cancer, suggesting its potential as a marker for predicting prognosis [ 180 ]. In addition, the results of the study revealed that circRNA_MYLK exhibited noticeably increased levels of expression in tissue specimens of ovarian cancer compared to nearby normal tissues. Furthermore, a strong connection was observed between increased levels of circRNA_MYLK expression and the advancement of the condition. The research also revealed that high levels of circRNA_MYLK expression were closely associated with a decreased survival rate among those suffering from ovarian cancer, as shown by the results of Kaplan–Meier survival analysis [ 181 ]. It has been confirmed that there is an excessive amount of CiRS-7 present in ovarian cancer, which is strongly associated with progressed disease stage, spreading to lymph nodes, and an unfavorable prognosis. In addition, Fan et al. revealed that circMAN1A2 was present at increased levels in the blood specimens of individuals with various types of cancer, such as ovarian cancer, indicating its potential as a serum-based diagnostic marker [ 178 ]. Meanwhile, additional examination in a medical setting is necessary to substantiate these results. Liu et al., Assess potential markers and medications that could be used for repeat unexpected termination of pregnancy, and investigate circRNA mechanisms that involve in controlling RSA [ 182 ]. The advanced RNA sequencing technology was utilized to analyze the gene expression patterns of placental villus and decidua samples from females who experienced recurrent spontaneous abortion, as well as those with healthy pregnancies who underwent induced abortion. The employment of real-time quantitative polymerase chain reaction validated the atypical circRNA profiles observed in a larger set of samples. The process of identifying new drugs and determining their fit at the molecular level involved the utilization of digital databases and the Autodock software. The process of identifying new drugs and determining their fit at the molecular level involved the utilization of digital databases and the Autodock software. The overall number of circRNAs identified in both the villi and decidual tissue types was 4263, with 22 of these circRNAs, along with 58 miRNAs and 393 mRNAs, showing notable variations in expression levels. Out of these, five circRNAs were confirmed to be present and the expression of hsa_circ_0088485 was notably increased in the group with recurrent spontaneous abortions (RSA) with a significant P value of 0.041. This particular circRNA also had a high area under the curve value, sensitivity rate was recorded at 76.5%, while the specificity rate was 64.7%. Further analysis through GO and KEGG revealed that the genes showing differential expression were linked to processes, such as angiogenesis and cell adhesion. In addition, the network of competing endogenous RNAs (ceRNA) was examined, with a focus on 93 differentially expressed messenger RNAs, for drug discovery and molecular docking purposes. Totally, 36 compounds were recognized as potential bioactive substances for RSA, and a single compound was chosen for binding analysis with six proteins. These discoveries offer new perspectives on the circRNA mechanism of RSA regulation and its potential impact on clinical detection and management [ 182 ].

The process of thoroughly examining alterations in genetic activity throughout time is crucial in understanding how molecular mechanisms control the development of early human embryos. After conducting a thorough analysis of the transcriptome patterns of individual cells in pre-implantation embryos, we have acquired significant knowledge and understanding [ 73 ]. The oligo-d(T) primers during our past study were limited in their ability to identify mRNAs without a polyA tail, therefore, leaving a significant amount of knowledge about polyA–RNAs unavailable. Cells that have a clearly defined nucleus contain a specific form of RNA called circRNAs, which is characterized by a string of adenine bases at its end. This type of RNA has been identified as a notable category that does not have a role in protein coding [ 44 , 74 , 75 ]. Transcripts with a circular shape can consist of exons that are arranged in the opposite sequence, circRNAs that serve as introns, or a mixture of exons and introns referred to as EIciRNAs [ 48 , 49 , 76 ]. circRNA molecules, also known as circRNAs, have the capacity to have a significant impact by functioning as microRNA decoys, competing with traditional splicing methods, or binding with U1 small nuclear ribonucleoprotein to regulate gene expression across various biological functions [ 47 , 49 , 51 , 77 ]. A significant amount of research has been conducted to investigate the genetic characteristics associated with the formation of circRNAs, including the identification of inverted repeats, longer adjacent introns, and traditional splicing sites in both controlled laboratory settings and real-life situations [ 51 , 78 , 79 ]. circRNAs have been identified in various tissues of various species. A recent study of circRNAs, which are circRNA molecules, in the mammalian brain found that their expression patterns and sequences are closely conserved [ 55 , 80 ]. To gain a comprehensive comprehension of the distinct transcriptome of an embryo and include recently discovered circRNAs, it is essential to possess a technique that is capable of detecting both polyA + mRNAs and polyA–RNAs simultaneously in a singular human embryo at the pre-implantation stage. On the other hand, conventional RNA sequencing techniques require a considerable amount of starting material, making them unsuitable for scarce and precious samples. In addition, at the moment, the methods used for single-cell RNA sequencing are unable to identify polyA–RNA variations, since they heavily depend on using oligo dT as the primers for reverse transcription [ 81 – 83 ]. In recent times, a fresh approach known as SUPeR-seq has emerged, facilitating the concurrent identification of both polyA + mRNAs and polyA–RNAs in individual mammalian cells. This innovative approach has proven to be highly efficient in examining polyA–RNAs, such as circRNAs, in the pre-implantation stage of mouse development [ 84 ]. In their study, Dang et al. performed a comprehensive analysis of both mRNAs with a polyA + tail and RNAs lacking a polyA tail in individual human oocytes and embryos during the pre-implantation stage, utilizing the methodology known as SUPeR-seq [ 85 ]. In a new and original approach, they have discovered a total of 10,032 circRNA molecules, which are derived from 2974 genes. Most of these circRNAs are unique to specific stages of development and exhibit continuous variations in their expression levels. A significant number of them are produced by the mother, suggesting their potential role in regulating oogenesis and the creation of fully potent zygotes. A thorough investigation of human and mouse embryos uncovers significant levels of similarity, as well as notable differences, highlighting the coexistence of strong resemblance and distinct characteristics within these two species. During the pre-implantation stage, the embryos of humans produce a greater variety of circRNA molecules in comparison to those of mice. This difference is attributed to a significant elongation of the introns surrounding the circRNA in humans. Scientists also perform a procedure for producing new RNA and identifying transcript units that were not previously known, some of which may be long non-coding RNAs. This research is the first examination to comprehensively examine all transcribed genetic material during the stages of human pre-implantation development, comprising both polyA + mRNAs and polyA–RNAs like circRNAs. The resource is a valuable tool for understanding exactly how circRNAs operate and their complex regulatory mechanisms during this significant period [ 85 ]. Qiao and colleagues’ groundbreaking discoveries have shed light on the role of circRNA in the growth of human oocytes and early stage embryos, highlighting its importance in this process. They were the first to unveil the distinctive circRNA profile present in these critical stages. Their findings emphasize the significance of circRNA in this developmental process [ 85 ]. The exact function of circRNAs in the maturation of oocytes has yet to be extensively investigated. To optimize the use of assisted reproductive technology, there is a need to improve ovulation induction protocols to obtain high-quality oocytes. In a 2019 study, Shen, Li, and colleagues found that circRNAs played a role in regulating various reproductive functions, such as oocyte development, GnRH signaling, and the maturation of oocytes via progesterone, by acting as decoys for miRNAs. Are circRNAs involved in the process of oocyte genesis and how exactly do they impact the quality of oocytes? To thoroughly investigate the circRNA expression patterns in both granulosa and theca cells collected from those undergoing in vitro fertilization (IVF), the researchers utilized a technique known as chromatin immunoprecipitation (CHIP). Upon completion of their study, the researchers found that circ_103827 and circ_104816 were considerably more expressed in older individuals. In addition, a clear inverse correlation was noted between the abundance of these circRNAs and the levels of anti-Müllerian hormone in the blood, the number of sinus follicles, and the quality of oocytes. The existence of Circ_103827 and circ_104816 had a significant influence on the reaction of GnRH, and this impact varied according to the age, indicating that the quantities of circRNAs could be indicative of dysfunction in the follicular environment [ 86 ]. In a different study, Cao and colleagues made a discovery that a combined 7067 circRNAs were identified in cumulus cells of pigs, with a separate 637 being observed in oocytes [ 87 ]. This was accomplished by utilizing gene knockout techniques, researchers discovered that the elimination of circARMC4 led to significant impairments in the advancement and maturation of embryonic pigs. The crucial role of circARMC4 in the process of meiosis and the movement of the first polar body was also revealed, specifically in its capability to facilitate the maturation of porcine oocytes by assisting in chromosome arrangement. PCOS, also known as Polycystic Ovary Syndrome, is a common medical condition that impacts the endocrine and metabolic systems of women who are in their reproductive years. Its defining features include the presence of polycystic ovaries, elevated levels of male hormones (hyperandrogenemia), and persistent lack of ovulation (chronic anovulation) [ 88 ]. Despite the shared characteristics, PCOS poses even more serious and widespread health hazards, with indications that persist beyond the reproductive stage and even into menopause [ 89 ]. Furthermore, individuals with PCOS are more susceptible to developing conditions related to metabolism as they get older, including but not limited to obesity and cardiovascular disease [ 90 , 91 ]. Despite advances in medical care, addressing PCOS remains a complex task. As a result, it is crucial to investigate its underlying causes and investigate improved biomarkers and treatments. The existence of follicular fluid is crucial for the growth and maturation process of ovarian follicles and oocytes. This process serves an important function in comprehending the interaction between oocytes and the cumulus cells that surround them [ 92 ]. The intricate FF system is composed of a multitude of highly intricate elements, which encompass proteins, RNAs, and metabolites, all of which originate from theca cells, granulosa cells, and oocytes [ 93 – 97 ]. New studies have illustrated the significant function of circRNAs present in follicular fluid (FF) in the growth and advancement of polycystic ovary syndrome (PCOS) [ 98 ]. In their study, Huang and colleagues documented that the elimination of exosomal circLDLR from the fluid surrounding the ovarian follicles triggered an increase in miR-1294 expression. This in turn inhibited the function of CYP19A1 and ultimately caused a reduction in estradiol levels in individuals diagnosed with PCOS [ 88 ]. To elaborate, it is possible that circDDX10, which is present in granulosa cells originating from human follicular fluid, may serve as a determining factor in regulating ovarian function. This is achieved by its impact on the maturation and demise of GCs, along with the synthesis of steroid hormones [ 99 ]. Many circRNAs, such as circASPH, circLDLR, and circPUM1, have been confirmed to significantly impact the regulation of PCOS [ 88 , 100 , 101 ]. Currently, we do not have a complete understanding of how many other circRNAs contribute to the development of PCOS. Despite its potential as a diagnostic method for PCOS due to its durability and ability to withstand degradation, the presence of circRNA in the ovaries further supports its viability [ 102 , 103 ]. Around two decades ago, the identification of the cyclical transcriptional sequence in the sex determining region SRY was made [ 104 ]. The SRY gene consists of a solitary component and generates a sequential transcription that acts as a guide for protein synthesis in the early stages of growth. In developed testes, circ‐SRY is primarily located in the cytoplasm and does not contribute to the production of proteins. Ascertaining the standard of spermatozoa is highly important in the context of implementing intra-cytoplasmic sperm injection (ICSI). circRNAs were believed to have the potential to serve as indicators of sperm vitality, encompassing factors, such as the integrity of SPZ DNA, sperm quantity, appearance, and motility [ 64 ]. The testicles of cattle contained a total of 4248 circRNA molecules that exhibited varying levels of expression depending on the animal’s age. These RNA molecules had an impact on regulating the process of sperm production [ 105 ]. A team of researchers who were among the initial pioneers to investigate this region unveiled a grand total of 15,996 circRNAs originating from the human testis. Upon conducting a gene ontology analysis, they determined that these circRNAs were associated with important processes, such as spermatogenesis, sperm motility, and fertilization. Furthermore, the researchers observed that these circRNAs remained stable in seminal plasma and were not vulnerable to degradation when stored at room temperature [ 106 ]. The presence of particular circRNA molecules in both SPZ (spermatozoa) and seminal plasma is highly noteworthy in evaluating the quality of sperm. An extensive research analysis determined that there is a total of 1598 co-expressed circRNAs found in boar sperm samples. Out of these, 148 are exonic circRNAs that displayed a significant relationship with sperm motility. Among them, two specifics circRNAs, ssc_circ_1458 and ssc_circ_1132, stood out as potential markers for predicting sperm movement based on their varying levels of expression in sperms with high and low motility [ 107 ]. Moreover, circRNAs demonstrated the ability to forecast the amelioration of sperm motility in the process of addressing asthenospermia [ 108 , 109 ]. Roughly 10 to 15% of couples in their childbearing years around the globe experience the impact of infertility [ 110 ]. IVF, a commonly employed method to assist those who struggle with infertility, has seen significant advancements in success rates through assisted reproductive technologies in recent years. However, despite these improvements, there remains a significant number of infertile women with high-quality embryos who face repeated inability to successfully implant, potentially due to factors linked to the endometrium [ 111 , 112 ]. The current process of assessing endometrial receptivity based on visual markers may require the addition or substitution of non-invasive biomarkers to improve the detection of unsuccessful embryo implantation. Despite being presented evidence of their crucial role in the progression and growth of endometrial cancer and endometriosis, research has concretely shown how significant LincRNA and miRNA truly are. There is a lack of extensive investigation into the connection between non-coding RNA and the readiness of the endometrium for implantation in individuals who have had repeated unsuccessful implantations [ 113 – 116 ]. Therefore, in the future, the potential application of circRNAs as effective therapeutic methods or valuable indicators in diagnoses is highly encouraging. However, even though there is potential, there is still a lack of comprehension about the governing factors that control circRNAs in cases of repeated failed implantation. Liu et al., Evaluated the circRNAs that were expressed at varying levels in individuals with recurrent failure of implantation [ 117 ]. A thorough analysis of circRNA expression profiles was carried out on endometrial biopsies collected from six individuals with a history of unsuccessful implantation, as well as a control group, utilizing a circRNA microarray. Furthermore, bioinformatic methodologies were utilized to examine the dissimilarly expressed circRNAs. In addition, the researcher’s utilized qRT-PCR to validate and verify the findings mentioned above. The data gathered from circRNA microarrays presented convincing proof that 856 unique circRNAs experienced significant alterations, with a level of significance of p  < 0.05. The quantitative real-time polymerase chain reaction (qRT-PCR) confirmed the increased quantities of hsa_circRNA_070616, hsa_circRNA_104001, hsa_circRNA_103716, and hsa_circRNA_104854, as well as the decreased levels of hsa_circRNA_044353, hsa_circRNA_004183, and hsa_circRNA_404686. The research demonstrated a notable contrast in the levels of various circRNAs between individuals experiencing repeated implantation failure and those with normal outcomes. This finding proposes that these circRNAs have potential as cutting-edge indicators for identifying and treating embryo implantation failures [ 117 ]. The process of implantation is crucial for the proper development of an embryo and for the attainment of a successful pregnancy. According to the results of the study, the levels of mmu_circRNAs_39505 and mmu_circRNAs_39503 were significantly elevated at the site of implantation, while the levels of mmu_circRNAs_44122 and mmu_circRNAs_44123 were notably lower in comparison to areas between implantation sites. The circRNAs that showed different levels of expression were found to have genes that were involved in processes, such as modification of phosphates, removal of acetyl groups from histones, binding with proteins and ATP molecules, and the ability to catalyze protein phosphorylation. After examining the KEGG pathway analysis, it was discovered that the genes responsible for the development of a hospitable environment for implantation may have a strong correlation with cancer pathways. The reason for this may be due to the common characteristics seen in both embryo implantation and tumor invasion. This implies that there could potentially be a correlation between various cancer-related genes and the signaling pathways that play a role in the process of embryonic implantation [ 118 ] (Fig.  3 ). Fig. 3 CircRNAs have a strong connection to embryogenesis and embryo implantation, as they have a major influence on the development of granulosa cells and sperm production CircRNAs have a strong connection to embryogenesis and embryo implantation, as they have a major influence on the development of granulosa cells and sperm production Recurrent spontaneous abortion (RSA) is a medical condition characterized by the occurrence of multiple consecutive miscarriages, typically before the 24th week of pregnancy while conceiving with the same sexual partner. The prevalence of recurrent spontaneous abortion (RSA) among women of childbearing age is a significant issue in the field of public health. However, the underlying factors behind RSA remain unknown in approximately half of all cases [ 119 – 121 ]. Between 15 and 25% of pregnancies experience spontaneous abortion, as seen in clinical settings. The onset of RSA can be attributed to intricate mechanisms involving both inherited traits and external influences. Abnormal gene expression plays a crucial role in this multifaceted condition, while epigenetic alterations, namely, RNA methylation, DNA methylation, and histone modification, along with noncoding RNA, may also contribute to the onset and progression of RSA [ 122 , 123 ]. In reproductive biology, a substantial amount of data suggests that circRNAs have a vital impact on the procedure of embryonic development and implantation, potentially providing insight into the underlying mechanisms and reasons behind Recurrent Spontaneous Abortion (RSA) [ 85 , 121 ]. Qian et al. and Li et al. thoroughly examined the circRNA profiles in the chorionic villi and decidua of women with Recurrent Spontaneous Abortion (RSA) and those with normal pregnancies, discovering that these circRNAs may have significant roles in the trigger of RSA by acting as “miRNA sponges” [ 124 , 125 ]. Moreover, particular circRNAs, namely, circPUM1, circZUFSP, and circFOXP1, were identified as playing a role in regulating the functioning of trophoblast cells through the miRNA-30a-5p/JUNB axis, miR-203/STOX1 axis, and miR-143-3p/S100A11 axis, respectively, ultimately influencing the occurrence and progression of RSA. These discoveries expose possible focal points that can be used to create strategies for identifying and handling RSA at an early stage.

An ideal biomarker should have certain qualities including strength, comprehensiveness, specificity, and effortless detectability. CircRNAs possess all of these traits, making them promising biomarkers for human illnesses. One of the main strengths of these covalently closed loop structures is their capacity to remain stable. Unlike linear RNAs, they are not as vulnerable to degradation by exonuclease RNase R due to their distinct molecular makeup. Furthermore, circRNAs (circRNAs) have a significantly longer lifespan in the bloodstream, lasting for at least 48 h, compared to mRNA. This longer lifespan is due to the circular structure of these RNAs which makes them resistance to enzymes and reduces their instability [ 183 ]. These molecules are extremely well-preserved across various species, making them well-suited for use in medical settings. Moreover, circRNAs (circRNAs) can be found in numerous types of human tissues and cells, and in certain cases, their quantity surpasses that of linear messenger RNA (mRNA). This is particularly evident in reproductive tissues and cells, where a large number of circRNAs have been observed. Ultimately, a large number of circRNAs that are highly present in bodily fluids and can be accurately identified in autonomously polarized cells and extracellular vesicles that circulate throughout the body’s fluid systems. Like other non-coding RNAs, determining the levels of circRNAs relies heavily on utilizing reverse-transcription polymerase chain reaction methods with complementary primers. As a result, circRNAs show promise as detectable biomarkers in bodily fluids, circulating cells, and extracellular vesicles, making them viable candidates for use as indicators of disease. The significant protection found among species, the distinct interpretation, and the diversity of their functions indicate that circRNAs play a significant role in the physiological processes of cells. This article highlights the influential role of circRNAs in the pathogenesis of reproductive system disorders as a result of dysregulated gene expression. We showed that circRNAs are potential biomarkers for early diagnosis of several diseases including cancers and infertility problems. Moreover, we showed a high potential capabilities of these molecules to be used as promising therapeutic targets. However, the study of circRNAs is not without challenges. Studying these molecules faces several methodological limitations that can impact the accuracy of their identification and functional analysis. One major challenge is the incomplete annotation of circRNAs in genomic databases, making it difficult to detect novel circRNAs reliably. In addition, linear RNA contamination during experiments can obscure results, as methods like RT-PCR and RNA-seq may inadvertently amplify linear RNA instead of circRNA. Another issue is the generation of false positives due to back-splicing artifacts during RNA library preparation, leading to misidentification. Quantification can also be problematic, as standard tools may lack the sensitivity or specificity to distinguish circRNAs from their linear counterparts. Furthermore, functional studies are complicated by the lack of targeted methods to selectively inhibit or overexpress circRNAs without affecting their linear RNA forms, which share the same genetic locus. These limitations highlight the need for improved bioinformatics tools, experimental protocols, and targeted methodologies for circRNA research which showed the future research perspective and directions. Studying about the abilities of circRNAs and their probable side effects as therapeutic factor could also be considered in future researches. As we continue to explore and comprehend the genetic elements contributing to cancer, the significance of circRNAs is becoming more and more apparent, and their roles are being further illuminated. There is a substantial body of compelling evidence indicating that circRNAs will play a crucial role in the treatment of individuals suffering from reproductive system disorders in the years to come, through diagnostic and therapeutic methods. If the involvement of circRNAs is still uncertain, circular transcripts may become a groundbreaking target for therapies. This could involve targeting overexpressed circRNAs or restoring down-regulated ones. The increasing availability of circRNA databases will aid scientists in accessing well-established studies and advancing their research in this area.

Reproductive biology is a vital branch of biology that studies the structures, functions, and processes involved in reproduction across diverse organisms. In humans, it encompasses the study of male and female reproductive systems, hormonal regulation, gametogenesis, fertilization, embryonic development, and childbirth [ 1 , 2 ]. This field plays a crucial role in understanding fertility, conception, and the genetic inheritance of traits [ 1 ]. Diseases and disorders affecting the reproductive system can have significant physical, emotional, and societal impacts [ 3 , 4 ]. Common conditions include polycystic ovary syndrome (PCOS), endometriosis, infertility, sexually transmitted infections (STIs), and cancers of the reproductive organs, such as ovarian, cervical, and prostate cancer [ 5 – 7 ]. Reproductive diseases can result from genetic abnormalities, hormonal imbalances, infections, lifestyle factors, and environmental exposures [ 8 , 9 ]. Genetic issues, such as chromosomal disorders or mutations, may lead to infertility or organ malformations [ 10 , 11 ]. Hormonal disruptions, like in polycystic ovary syndrome (PCOS) or thyroid disorders, often affect fertility and menstrual cycles [ 12 , 13 ]. Infections, particularly sexually transmitted infections (STIs) like chlamydia, gonorrhea, or human papillomavirus (HPV), can cause inflammation and damage reproductive organs [ 8 , 9 ]. In addition, unhealthy lifestyles, including poor diet, stress, or substance abuse, along with environmental toxins, contribute significantly to reproductive health issues [ 14 , 15 ]. Symptoms of reproductive diseases vary widely and may include menstrual irregularities, such as heavy, painful, or irregular periods, or absence of menstruation [ 16 , 17 ]. Pelvic pain, pain during intercourse, and unusual vaginal or penile discharge are common signs [ 16 , 18 ]. Fertility issues, including difficulty conceiving or recurrent pregnancy loss, can also indicate underlying conditions [ 19 – 21 ]. Abnormal bleeding, such as spotting between periods or blood in urine or semen, may occur [ 22 , 23 ]. Other symptoms include swelling or lumps in the pelvic or genital area, urinary or bowel difficulties, and signs of infections like sores, itching, or rashes [ 24 , 25 ]. Hormonal imbalances may cause acne, excessive hair growth, hair loss, or changes in libido [ 12 ]. An overwhelming amount of RNA, precisely 95%, consists of non-coding RNA [ 26 ]. These RNAs could not be translated to the protein as their name indicates. Most non-coding RNAs are considered to belong to transcribed regions that are highly preserved and do not play a role in protein production. Non-coding RNA involves in regulating genes and can also contribute to the evolution of numerous human illnesses. These RNAs could interfere with protein synthesis through the inhibition of the translation of mRNA and further induce related changes in the phenotype [ 27 ]. On the other hand, they could induce the production of other proteins through induction of changes on the transcription factors and further gene expression enhancement [ 28 – 30 ] along with small nuclear RNA (snRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), small interfering RNA (siRNA), MicroRNA (miRNA), long non-coding RNA (lncRNA). The group of non-coding RNA has been enlarged to incorporate a novel member by the name of circular RNA, also referred to as circRNA. Unlike linear RNA structures, circRNA is a circular molecule that has a closed loop form and does not possess a 5′–3′ polarity or a polyadenylated tail [ 31 ]. A circRNA is a specific type of molecule that possesses a closed circular structure, providing it with enhanced protection against the RNAse enzyme, distinguishing it from linear RNAs [ 32 ]. In the field of RNA, circRNAs have become a topic of great interest due to their novel roles in various cellular processes. Their most important function is to act as a blocker of miRNA, preventing it from binding to specific genes and thus decreasing its ability to impede the production of targeted proteins [ 33 , 34 ]. One example of this is the circRNA known as Sry, which is specifically located in the testis and contains a total of 16 sites that can bind to miR-138 [ 35 , 36 ]. The latest discovery has greatly altered our comprehension of the ways in which miRNA manages its regulatory functions and adds to the intricacy of the competing endogenous RNA networks. However, more thorough research is essential to fully comprehend the specific function of circRNA in regulating this network to successfully fulfill its functions. In addition to modulating the activity of circRNAs, miRNA, also have the ability to regulate the mobility of RNA-binding proteins (RBPs) within cellular environments [ 37 , 38 ]. In particular, certain circRNAs have been found to possess the ability to generate active peptides. This has been demonstrated by both laboratory experiments as well as observations in live organisms [ 39 – 41 ]. Moreover, circRNAs have a critical role in various reproductive disorders that affect both males and females, including endometriosis, multiple pregnancy loss, and recurrent difficulties with embryo implantation. As an example, a circRNA molecule could act as a sponge of a specific miRNA and further regulates a specific protein which leads to the modulation of a disease development. Ding and colleagues found that circ_0072995 contributes in the miR-147a/CDK6 axis through sponging miR-147a and further promotes epithelial ovarian cancer [ 30 ]. Therefore, investigating circRNAs is crucial for understanding and predicting the progression of these conditions. They hold potential as diagnostic indicators for reproductive system diseases and can assist in guiding treatment decisions in clinical settings. These RNAs could act as a sponge of a specific miRNA and overexpression or suppression of their expression could further change the expression level of that miRNA and further its downstream target which leads to the modification of a specific disease [ 42 ].