Gynecological malignancies, encompassing numerous types of cancer of the female reproductive system, represent a notable global health burden. Among these malignancies, ovarian, endometrial and cervical cancer are the most prevalent. According to GLOBOCAN 2020 statistics, ovarian, endometrial and cervical cancer accounted for 313,959, 417,367 and 604,127 new global cases, respectively, and ranked 19, 17 and 9th, in terms of global cancer incidence. In addition, regarding the mortality rates, ovarian cancer, endometrial cancer and cervical cancer were responsible for 207,252, 97,370 and 341,831 deaths respectively, collectively representing 6.5% of all female cancer-related deaths (1).

Despite advances in medical science, the diagnosis and treatment of gynecological malignancies continue to pose notable challenges. Early detection methods remain elusive for a number of patients, and the current therapeutic approaches often fall short in managing advanced or recurrent disease. However, recent research into circular RNAs (circRNAs) has emerged as a promising option for both diagnostic and therapeutic innovations in gynecological oncology (2,3). circRNAs are a class of non-coding RNAs characterized by their covalently closed loop structure, which have gained considerable attention in cancer research due to their stability, tissue-specific expression and diverse regulatory functions (4). In the context of gynecological malignancies, circRNAs have been implicated in various aspects of tumor biology, including cell proliferation, metastasis and drug resistance (5). For example, in ovarian cancer, circWHSC1 has been shown to promote tumor progression by sponging microRNA (miRNA/miR)-145 and miR-1182, ultimately upregulating mucin-1 (MUC1) and human telomerase reverse transcriptase (hTERT) (6). In endometrial cancer, homo sapiens (hsa)_circRNA_079422 has been found to enhance tumor growth and metastasis by modulating the miR-136-5p/high-mobility group AT-hook 2 axis (7). Similarly, in cervical cancer, circRNAs serve a key regulatory role in cervical cancer progression, showing potential as therapeutic agents and novel biomarkers; however, further clinical research is needed to fully understand their therapeutic benefits (8). The unique properties of circRNAs, including their abundance, stability in bodily fluids and tissue-specific expression patterns, make them promising candidates for biomarker development in gynecological cancer (9). Moreover, the diverse regulatory functions of circRNAs offer potential targets for novel therapeutic interventions (10).

The present review aimed to provide a comprehensive overview of recent advances in circRNA research within the context of gynecological malignancies. The biogenesis and functions of circRNAs, their roles in the pathogenesis of ovarian, endometrial and cervical cancer were explored, and as well as potential applications in diagnosis, prognosis and treatment. By summarizing current knowledge and identifying future research directions, the present review highlighted the potential of circRNAs as a novel avenue for improving the management of gynecological malignancies (Table I).

circRNAs represent a unique class of non-coding RNA molecules characterized by their covalently closed loop structure, which distinguishes them from linear RNAs by the absence of 5′-3′ polarity and polyadenylated tails (11). This distinctive structure, first identified in viruses by Sanger et al (12) in 1976, confers properties of enhanced stability, cooperativity and self-complementarity. The presence of circRNAs in eukaryotic cells was subsequently demonstrated by Hsu and Coca-Prados in 1979 (13), marking the beginning of a new era in RNA biology.

Initially, the importance of circRNAs was underappreciated due to limitations in RNA sequencing technologies and bioinformatics tools. For a number of years, these molecules were dismissed as non-functional by-products of aberrant splicing events (14); however, advances in high-throughput sequencing and computational analysis have led to a paradigm shift in the understanding of circRNAs and their potential roles in cellular processes (15). A key breakthrough in circRNA research came with the discovery that these molecules often harbor numerous miRNA binding sites, enabling them to function as competitive endogenous RNAs (ceRNAs) or ‘miRNA sponges’ (16). This mechanism allows circRNAs to regulate gene expression by modulating the availability of miRNAs, thereby influencing various cellular processes and pathways (17). In the context of gynecological malignancies, this regulatory function has been implicated in key aspects of tumor biology, including cell proliferation, metastasis and drug resistance (3). Beyond their role as miRNA sponges, circRNAs have been shown to interact with RNA-binding proteins (RBPs), potentially modulating protein function and localization (18). In addition, some circRNAs have been reported to encode functional peptides, such as circZNF609 (19) and circFBXW7 (20), adding another layer of complexity to their regulatory potential. These diverse functions underscore the importance of circRNAs in both physiological and pathological processes, including the development and progression of gynecological cancer. As research in this field continues to evolve, circRNAs are emerging as promising biomarkers and potential therapeutic targets in gynecological oncology (21). The unique properties of circRNAs, including tissue-specific expression patterns and stability in bodily fluids, make them attractive candidates for non-invasive diagnostic and prognostic applications (22). Moreover, the ability to manipulate circRNA expression levels or function offers novel options for therapeutic interventions in gynecological malignancies (23).

The diversity of circRNAs is reflected in their classification, which is primarily based on their genomic origin and structure. Understanding these classifications is essential for elucidating their roles in gynecological malignancies. circRNAs can be categorized into three main subclasses based on their genomic origin and structure. Exonic circRNA (EcircRNA) is the most prevalent form, accounting for >80% of known circRNAs (24); these are generated through the process of ‘backsplicing’, where a downstream 5′ splice site (donor) is joined to an upstream 3′ splice site (acceptor). Circular intronic RNA (ciRNA) is derived from intron lariats that evade the typical linear splicing debranching step, retaining a 2′-5′ linkage at the branch point (25). Exon-intron circRNA (EIciRNA) contains both exonic and intronic sequences and has been shown to enhance the expression of their parent genes in cis, suggesting a potential regulatory role (26). Other types of circRNAs include antisense circRNAs, which are derived from antisense transcripts, and intergenic circRNAs, which originate from intergenic regions or other unannotated genomic sequences (27). As research progresses, and new biotechnologies and bioinformatics strategies emerge, the understanding of circRNA classification and function could continue to evolve (28). Future studies may identify additional subtypes or refine the current classification system, providing deeper insights into the diverse roles of these unique RNA molecules in cellular processes and disease mechanisms.

The classification of circRNAs is not merely an academic exercise but has significant implications for understanding their functions in gynecological cancer. For example, EcircRNAs often act as miRNA sponges, modulating gene expression and influencing tumor progression (29). By contrast, ciRNAs and EIciRNAs tend to regulate gene expression through interactions with the transcriptional machinery (30). The ongoing exploration of circRNA classification in gynecological cancer promises to uncover novel biomarkers for early detection and prognosis, as well as potential therapeutic targets. For example, the tissue-specific expression patterns of certain circRNA classes may be exploited in the development of targeted therapies or diagnostic tools specific to ovarian, endometrial or cervical cancer (3).

The biogenesis of circRNAs in gynecological malignancies remains an area of active investigation, with several proposed models offering insights into their formation (4,27,31). A prominent hypothesis posits that during the splicing of mRNA precursors, a process critical in gene expression regulation, non-contiguous exons may be brought into proximity through partial folding of the transcript. This spatial rearrangement can lead to exon skipping, resulting in the formation of a lariat intermediate structure encompassing both exonic and intronic sequences. Subsequently, this lariat undergoes a reverse splicing event, culminating in the generation of a stable circRNA molecule. This mechanism may be particularly relevant in the context of gynecological tumors, where aberrant splicing events are frequently observed and could contribute to the dysregulation of circRNA formation, potentially influencing tumor progression and treatment response (32).

In the context of gynecological malignancies, an alternative model of circRNA biogenesis has gained traction, emphasizing the role of intronic sequences in facilitating circularization. This mechanism, known as intron pair-driven circularization, involves the interaction of specific complementary sequences within flanking introns. These sequences, often found at the termini of exons, engage in reverse complementary base pairing, effectively bridging distant genomic regions. This intronic ‘kissing’ interaction brings downstream splice donor sites into close proximity with upstream splice acceptor sites, thereby promoting the circularization of the intervening exonic sequences. In gynecological tumors, where genomic instability and chromosomal rearrangements are common, this mechanism may be particularly relevant, potentially contributing to the aberrant expression of circRNAs observed in these malignancies. Understanding this process could provide insights into tumor-specific circRNA profiles, and their potential diagnostic or therapeutic implications in gynecological oncology (33).

Another emerging model of circRNA formation highlights the pivotal role of RBPs in the landscape of gynecological malignancies. These versatile proteins exhibit a marked capacity to influence circRNA biogenesis through specific interactions with both exonic and intronic sequences. RBPs can selectively bind to motifs located at the termini of exons and introns, subsequently forming dimeric complexes. These RBP dimers serve as molecular bridges, effectively reducing the spatial distance between distal intronic regions. This RBP-mediated proximity facilitates the circular connection of exons, promoting circRNA formation. In the context of gynecological tumors, where the aberrant expression and function of RBPs is frequently observed, this mechanism may contribute to the dysregulation of circRNA profiles. Understanding the interplay between RBPs and circRNA biogenesis in these malignancies may indicate novel diagnostic biomarkers and potential therapeutic targets, thereby advancing the understanding of tumor biology and treatment strategies in gynecological oncology (34).

circRNAs have emerged as key regulators of gene expression and are implicated in the pathogenesis of various human diseases, including gynecological malignancies. These versatile molecules exhibit multiple functional modalities that contribute to cellular processes and disease progression. Current research has elucidated several key functions of circRNAs: i) They can modulate transcriptional activity; ii) act as ceRNAs by sequestering miRNAs; iii) serve as scaffolds for protein complexes; and iv) possess protein-coding potential under specific cellular conditions (35). These diverse functions highlight the significance of circRNAs in the complex landscape of gynecological tumor biology and present potential avenues for diagnostic and therapeutic interventions.

The intricate interplay between circRNA biogenesis and transcriptional regulation has emerged as a notable area of interest in gynecological oncology (36,37). This complex relationship indicates novel mechanisms of gene expression modulation that may be key in the development and progression of gynecological cancer. In a pioneering study, Ashwal-Fluss et al (38) reported a competitive relationship between circRNA splicing and pre-mRNA processing. This competition was shown to occur at the 5′ and 3′ splice sites, suggesting that circRNA formation may serve as a regulatory checkpoint in the gene expression cascade. In the context of gynecological tumors, where aberrant gene expression is a hallmark feature, this circRNA-mediated regulation of linear transcript levels could represent a novel layer of transcriptional control. Further elucidating this concept, research has demonstrated that optimized circRNA expression systems can markedly enhance backsplicing efficiency (39). This process effectively sequesters exons into circular structures, consequently attenuating the production of linear mRNA transcripts. For example, in ovarian cancer, the formation of circ-mucin 16 (MUC16) has been shown to reduce the expression of its linear counterpart, CA125, a well-known biomarker for ovarian cancer (40). This finding highlights the potential impact of circRNA biogenesis on the expression of clinically relevant genes in gynecological malignancies. In endometrial cancer the circRNA, circ-rho GTPase activating protein 12 (ARHGAP12), has been shown to regulate the expression of its parental gene ARHGAP12, a tumor suppressor, by competing for splicing machinery (41). This regulatory mechanism can influence cell proliferation and invasion, underscoring the functional significance of circRNA-mediated transcriptional control in gynecological cancer.

Moreover, some circRNAs have been shown to interact directly with RNA polymerase II or other components of the transcriptional machinery. For example, the ciRNA ci-ankyrin repeat domain 52 has been reported to accumulate at its sites of transcription and modulate the elongation of its parent gene by associating with RNA polymerase II (42). While this specific circRNA has not been studied in gynecological cancer, similar mechanisms could occur, potentially influencing the expression of key oncogenes or tumor suppressors. The ability of circRNAs to influence linear mRNA production through competitive splicing mechanisms may have notable implications for tumor biology, potentially affecting key oncogenic or tumor-suppressive pathways. These findings underscore the potential of circRNAs as key modulators of gene expression in gynecological malignancies. The complex interplay between circRNA biogenesis and transcriptional regulation offers new perspectives on the molecular mechanisms underlying these types of cancer. Further investigation into this regulatory axis could identify new targets for therapeutic intervention and contribute to the understanding of the complex transcriptional landscape in gynecological cancer. As research in this field progresses, it will be necessary to elucidate the tissue-specific and cancer-specific aspects of circRNA-mediated transcriptional regulation. This knowledge may lead to the development of novel diagnostic tools and therapeutic strategies tailored to specific gynecological malignancies, potentially improving patient outcomes.

circRNAs have emerged as key regulators of gene expression in gynecological malignancies, primarily through their function as miRNA sponges. This mechanism is characterized by the presence of multiple miRNA binding sites within circRNA molecules, enabling them to competitively sequester miRNAs (43). By preventing miRNAs from binding to their target mRNAs, circRNAs effectively reduce the inhibitory effect of miRNAs on translation, leading to the increased expression of target genes (44). This competitive binding phenomenon, known as the ‘miRNA sponge’ effect, represents an important paradigm in post-transcriptional gene regulation (45). An example of this regulatory mechanism is circ-cerebellar degeneration-related protein 1 antisense (CDR1as, also known as ciRS-7), which has been extensively studied due to its marked capacity to bind miR-7 (46). While initially identified in neurological contexts, recent research has begun to elucidate its potential roles in various types of cancer, including gynecological tumors (47). For example, in ovarian cancer, circ_CDR1 has been shown to sponge miR-1270, leading to the upregulation of suppressor of cancer cell invasion and subsequent inhibition of tumor progression (48). In the context of gynecological oncology, the miRNA sponge function of circRNAs has been implicated in various aspects of tumor biology. For example, in cervical cancer, circRNA_0000745 may act as a sponge for miR-3178, upregulating the expression levels of FOXO4 and inhibiting tumor growth (49). Similarly, in endometrial cancer, circ_0002577 has been demonstrated to sponge miR-625-5p, thereby regulating the insulin-like growth factor 1 signaling pathway and influencing tumor progression (50). Understanding these circRNA-miRNA-mRNA regulatory axes in gynecological malignancies offers new insights into the molecular mechanisms underlying tumor development and progression. Moreover, it presents potential opportunities for the development of novel diagnostic biomarkers and therapeutic targets in gynecological oncology (51).

In addition to their role as miRNA sponges, circRNAs have emerged as important regulators of protein function in various types of cancer, including gynecological malignancies. This function is primarily achieved through their ability to act as protein scaffolds or sponges, facilitating or inhibiting protein-protein interactions and modulating protein activity (36). A well-characterized example of this mechanism is circFOXO3, which has been shown to form a ternary complex with CDK2 and the CDK inhibitor 1, p21. This interaction effectively inhibits CDK2 function, leading to cell cycle arrest (52). While initially studied in cardiac senescence, a research has begun to elucidate the potential roles of circFOXO3 in gynecological cancer (53). For example, in ovarian cancer, circFOXO3 has been shown to drive ovarian cancer progression by orchestrating exosome-mediated intercellular communication targeting the miR-422a/proteolipid protein 2 axis, potentially serving as a valuable biomarker for early detection and treatment monitoring in this aggressive malignancy (54).

Another notable example is circACC1, which forms a ternary complex with the β and γ regulatory subunits of AMP-activated protein kinase (AMPK); this interaction promotes AMPK holoenzyme activity, enabling cancer cells to adapt to metabolic stress and grow under nutrient-limited conditions (55). While the specific role of circ-acetyl-CoA carboxylase 1 (ACC1) in gynecological tumors remains to be fully elucidated, its function in modulating cellular metabolism suggests potential implications for tumor progression and therapeutic resistance in these types of cancer (56). In addition, circPUM1 has been shown to interact with the nuclear receptor binding protein and the androgen receptor, forming a protein complex that promotes ovarian cancer cell proliferation and invasion (57). This example highlights the diverse mechanisms by which circRNAs can influence protein function and cellular processes in gynecological malignancies. The ability of circRNAs to act as protein scaffolds or sponges adds another layer of complexity to their regulatory functions in cancer biology. By modulating protein-protein interactions and enzyme activities, circRNAs can influence various cellular processes, including cell cycle progression, metabolism and signal transduction (58). Understanding these interactions in the context of gynecological tumors may provide novel insights into disease mechanisms and therapeutic targets (59).

Traditionally, circRNAs were considered to be non-coding RNAs; however, a recent study demonstrated that, under specific conditions, some circRNAs can be translated into functional peptides, adding a new dimension to their role in cellular processes and disease pathogenesis, including gynecological malignancies (39). In a seminal study from 2017, Yang et al (60) provided the first comprehensive evidence that circRNAs could undergo protein translation following N6-methyladenosine (m6A) modification. These findings demonstrated that m6A-driven circRNA translation is a widespread phenomenon, with hundreds of endogenous circRNAs possessing translation potential. This discovery not only expanded the understanding of the coding capacity of the human transcriptome but also opened novel avenues for exploring circRNA functions in various diseases, including gynecological cancer. In the context of gynecological oncology, the potential for circRNAs to be translated into functional peptides has significant implications. For example, in breast cancer, circ-F-box and WD repeat domain containing 7 (FBXW7) has been shown to encode a novel 21-kDa protein, FBXW7-185aa, which acts as a tumor suppressor by inhibiting the proliferation and migration of cancer cells (61). Similarly, in cervical cancer, circE7 derived from high-risk human papillomavirus (HPV) has been shown to encode the E7 oncoprotein, contributing to the transforming properties of HPV (62). The ability of circRNAs to produce functional peptides adds another layer of complexity to their regulatory roles in gynecological malignancies. These peptides may interact with other cellular components, modulate signaling pathways or directly influence tumor progression. For example, in ovarian cancer, the circRNA-encoded peptide SNF2 histone linker PHD RING helicase (SHPRH)-146aa has been reported to suppress tumor growth by protecting full-length SHPRH from degradation (63). As research in this field progresses, elucidating the specific functions of circRNA-encoded peptides in various types of gynecological cancer will be crucial. Understanding these novel mechanisms may provide insights into tumor-specific molecular signatures and identify new options to develop innovative diagnostic and therapeutic strategies in gynecological oncology (64).

Ovarian cancer is currently the most lethal type of gynecological malignancy, with a markedly high mortality rate. Globally, ovarian cancer is responsible for >200,000 deaths annually (65). The standard treatment protocol typically involves surgical resection followed by platinum-based chemotherapy in combination with paclitaxel (PTX) (66). Despite these interventions, the prognosis for patients with advanced-stage ovarian cancer remains poor, with a 5-year survival rate of ~30% (67). This poor outcome is largely attributed to late-stage diagnosis and the development of chemoresistance (68). The mechanisms underlying chemoresistance in ovarian cancer are multifaceted, involving both tumor microenvironment factors and intrinsic cellular resistance pathways (69). Given these challenges, there is an urgent need to develop novel therapeutic strategies and enhance treatment efficacy to improve patient outcomes. In recent years, circRNAs have emerged as potential biomarkers and therapeutic targets in various types of cancer, including ovarian cancer (70). These unique non-coding RNAs have been implicated in diverse biological processes, and have shown promise in modulating chemoresistance and tumor progression (71). Understanding the role of circRNAs in ovarian cancer could potentially lead to innovative diagnostic tools and targeted therapies, addressing the critical need for improved management of this disease (72).

Endometrial cancer is a significant health concern, ranking as the second most prevalent gynecological malignancy in China and the foremost in developed nations. In 2022, China reported ~84,520 new cases of endometrial cancer (93). Various risk factors have been associated with this type of cancer, including obesity, diabetes, polycystic ovary syndrome, infertility, early menarche and late menopause (94). Current screening methods for endometrial cancer primarily rely on transvaginal ultrasound, hysteroscopy and endometrial biopsy (95). However, these techniques have the following limitations: Transvaginal ultrasound results can be subjective, whereas hysteroscopy and endometrial biopsy are invasive procedures, restricting their widespread use in clinical screening (96). The standard treatment approach for endometrial cancer typically involves surgery followed by chemotherapy, often using a combination of carboplatin and PTX (97). Despite these interventions, challenges persist, including poor prognosis and drug resistance in some cases (98). Given these challenges, there is a pressing need to explore novel diagnostic and therapeutic strategies to enhance survival rates for patients with endometrial cancer. circRNAs have emerged as promising candidates in this regard. These unique RNA molecules, characterized by their covalently closed loop structure, have shown potential in both the diagnosis and treatment of various types of cancer, including endometrial cancer (99). A previous study demonstrated that circRNAs serve key roles in endometrial cancer pathogenesis, influencing cell proliferation, invasion and metastasis (100). Moreover, certain circRNAs have been identified as potential biomarkers for early detection and prognostic prediction in endometrial cancer (101). The exploration of circRNA-based therapeutic approaches, such as circRNA-mediated gene therapy or circRNA-targeted drug delivery systems, represents a notable option in endometrial cancer research (102).

Cervical cancer remains a notable health issue for women worldwide, ranking as the second most common malignancy after breast cancer. It is also associated with a high mortality rate, being a leading cause of global cancer-related mortality. Persistent infection with HPV is the primary driver of cervical cancer progression. In China, cervical cancer mortality is slightly higher in rural areas than in urban regions, with midwestern areas exhibiting mortality rates about twice those in eastern regions (118). Additionally, recent trends have indicated a decreasing average age of onset for cervical cancer, suggesting a rise in incidence among younger women (119,120). Current treatments for cervical cancer typically involve a combination of surgery, chemotherapy and radiotherapy. However, poor prognosis and low survival rates due to distant metastasis and lymphatic spread continue to challenge patient outcomes (121). Thus, there is an urgent need to identify new therapeutic approaches and early diagnostic biomarkers to improve survival rates. circRNAs have garnered significant attention in cancer research due to their unique properties, including high stability and resistance to exonuclease-mediated degradation (122). These characteristics make circRNAs promising candidates for developing novel therapeutic strategies and diagnostic tools for cervical cancer (123). Studies have suggested that circRNAs can serve as effective biomarkers for early detection and may offer new opportunities for targeted therapies (5,124). For example, some circRNAs (including circ_0010235 and circCCDC66) have been shown to interact with miRNAs and proteins involved in cancer pathways, influencing tumor growth and metastasis (125). The potential application of circRNA-based therapies could lead to more effective treatment options for cervical cancer, addressing the current limitations of conventional therapies. Research into the role of circRNAs in cervical cancer is still in its early stages but holds promise. Advances in circRNA studies may identify breakthrough therapies, improving prognosis and survival rates for patients with cervical cancer (Table II).

The emerging field of circRNA research offers promising options for advancing the understanding and management of gynecological malignancies. The present review has highlighted the diverse roles of circRNAs in ovarian, endometrial and cervical cancer, from their involvement in tumor progression to their potential as diagnostic and prognostic biomarkers. The unique properties of circRNAs, including their stability, tissue-specific expression and diverse regulatory functions, position them as valuable tools in gynecological oncology. The roles of circRNAs as miRNA sponges, protein scaffolds and even potential peptide encoders underscore their complex involvement in cancer pathogenesis. While notable progress has been made in elucidating the functions of circRNAs in gynecological cancer, much remains to be explored. Future research should focus on validating circRNA-based biomarkers, investigating tissue-specific and cancer-specific circRNA-mediated transcriptional regulation, exploring the therapeutic potential of targeting circRNAs and elucidating the functional significance of circRNA-encoded peptides in gynecological cancer. As the understanding of circRNAs in gynecological malignancies improves, the development of novel diagnostic tools, prognostic markers and targeted therapies is anticipated. These advances hold the potential to markedly improve patient outcomes and to reshape the landscape of gynecological cancer management.