Cancer is still a major worldwide health concern, exposing significant life-threatening hazards in both industrialized and poor countries [1]. Despite extensive research into early cancer treatment modalities, there exists an urgent necessity for effective biomarkers facilitating early detection and enhancing survival rates. Circular RNAs (circRNAs) represent a unique category of single-stranded, mechanically closed RNA transcripts that have garnered attention because of their involvement in various physiological mechanisms and diseases. These molecules are primarily formed through exon back-splicing in precursor mRNAs and serve various roles, including acting as microRNA (miRNA) sponges, protein brackets, and regulatory elements in transcription and splicing processes [2], [3]. Recent investigations have offered perspective on the contributions of circRNAs to disease development, specifically in the context of cancer, thyroid cancer (TC), cardiovascular disease (CVD), and myotonic dystrophy. Their involvement in the tumor microenvironment and immune responses in digestive cancers has been recognized, underscoring their significance as potential biomarkers for a range of diseases [4], [5]. The field of circRNA research has been complemented by the development of computational methods and resources for circRNA identification and analysis, providing valuable tools for in-depth investigations. Furthermore, circRNAs have exhibited potential in crop improvement, with observed differential expression during stress responses and developmental programs in cereal crops. In the context of CVDs, circRNAs are establishing themselves as vital gene expression controllers, acting as miRNA sponges and exhibiting promise as potential biomarkers. Collectively, circRNAs have positioned themselves as pivotal players in the intricate network of gene regulation, offering novel avenues for disease diagnosis and therapeutic interventions [6], [7].

The discovery of covalently closed circRNAs has added a layer of complexity to our understanding, as these molecules exhibit unique structures not just inside the tissues, but also throughout the circulation, demonstrating remarkable stability and conservation [8]. This stability renders circRNAs more resilient compared to linear mRNA. Moreover, A growing body of data implies that they perform crucial functions in regulating diverse biological and physiological processes. They function as competing endogenous RNAs (ceRNAs), controlling gene expression and the translation of regulatory proteins. Additionally, circRNAs act as effective miRNA sponges, influencing miRNA-mediated gene regulation and RNA-binding proteins (RBPs) [9], [10]. Despite considerable research on circRNAs and their functional roles in malignancy and other conditions, our understanding of their biological functions remains incomplete. Primarily, existing studies have emphasized the ability of circRNAs to target miRNAs, inhibiting their regulatory influence on target genes. This mechanism prevents miRNAs from exerting their modulatory functions on mRNA expression [11]. As of now, numerous translated circRNAs have been discovered, each exhibiting crucial roles in human cancers. In the parts that proceed, we delineate these circRNAs along with their respective functions in the context of human cancers (Table 1). Further exploration of circRNAs and their intricate functions holds promise for unveiling novel insights into their regulatory roles and potential implications in cancer pathogenesis and other diseases.

Research findings indicate that circRNAs-Disintegrin and Metalloproteinase Domain-Containing Protein 9 (circ-ADAM9) exhibit elevated expression levels in multiple cancers. Notably, in breast cancer (BC) and pancreatic cancers (PAC), circ-ADAM9 has been reported to foster the malignant characteristics of cancerous cells. The exploration of circ-ADAM9 as a therapeutic target, in conjunction with complementary strategies such as radiotherapy, holds promise for cancer treatment. Nonetheless, a thorough knowledge of the basic mechanics and the potential therapeutic implications of circ-ADAM9 targeting across diverse cancer types requires further investigation [12], [13]. Recent investigations have unveiled the association between circ-ADAM9 and various malignancies, particularly BC, PAC, and melanoma. This review aims to elucidate the possible role of circ-ADAM9 in non-invasive and prompt cancer screening. The following discussion gives an in-depth look at the origins and applications of circRNAs, with a specific focus on circ-ADAM9, to offer valuable insights and pave the way for enhanced early cancer detection (Table 1).

CircRNAs originate through a distinctive biogenesis process known as pre-mRNA backwards splitting, distinct from the splicing of linear RNAs. Eukaryotic cells contain abundant circRNAs in the cytoplasm, categorized into exonic circRNA (EcircRNAs) derived from exons, or exon-intron circRNA (EIciRNA) generated from exon-intron regions, and intronic circRNAs. Two primary models, lariat-driven circularization and intron-pairing-driven circularization, are suggested for circRNA origination. While these models differ in the initial steps, subsequent circRNA generation steps are largely similar [21], [22]. According to the information, intron-pairing-driven could be more common than lariat-driven [23].

Another circRNA circularization model involves the assistance of RBPs, acting as bridges between flanking introns to facilitate biogenesis. Furthermore, an alternative circRNA circularization pathway akin to alternative splicing, promotes complementary pairing of introns, leading to the generation of multiple circRNAs [24], [25]. Fig. 1 illustrates a schematic representation of circRNA biogenesis. This comprehensive exploration provides a foundation for understanding circ-ADAM9 and its potential implications in cancer diagnosis, particularly in the context of early detection strategies.

CircRNAs play integral roles in diverse biological processes including miRNA sponging, RBPs, and gene transcription regulation [26]. These molecules exert their influence on various disease-related pathways through mechanisms such as the formation of R-loops, miRNA or protein sponging, and even translation into functional proteins, thereby contributing to distinct pathological phenotypes [27], [28]. The formation of circRNAs is intricately linked to specific structures within flanking exons or introns, which serve as essential elements for circRNA generation [29]. Notably, the presence of back-splicing regions plays a pivotal part in the initiation of circRNA generation [30].

CircRNAs have been the subject of an extensive investigation regarding their involvement in cell signalling and regulatory processes [26]. These molecules have been implicated in various human diseases, with a notable focus on their roles in both tumorigenesis and antitumor processes [31]. For instance, the circRNA hsa_circ_0071036 has been reported as a promoter of tumorigenesis in PAC by functioning as a miR-489 sponge, thereby correlating with unfavourable characteristics and prognosis [32].

ADAM9 is a protein that has been identified for its function in the progression and spread of diverse cancers. Its involvement in cancer is demonstrated across different types (Table 2). A study revealed that the long non-coding RNA RUNDC3A-AS1 participates in lung cancer (LC) spread in TC by regulating the miR-182-5p/ADAM9 cascade. The potential therapeutic targeting of the RUNDC3A-AS1/miR-182-5p/ADAM9 axis is suggested for the treatment of TC metastasis [33], [34]. Research indicates that USP39 increases glioma cell motility and infiltration by promoting the development of ADAM9 mRNA. Depletion of USP39 resulted in inhibited In vitro growth and spread of glioma cells and reduced invasiveness in vivo. Targeting USP39 is proposed as a possible treatment strategy [35]. According to one study, circADAM9 may be an indicator of colorectal cancer. Additionally, the miR-1298/ADAM9 axis was implicated in the malignant behaviours of BC cells [36], [37]. Research uncovered that tetraspanin CD9 enhances α-secretase's oncogenic function in PAC. CD9 activity was correlated with α-secretase functioning and its knockdown suppressed α-secretase in PAC. Targeting CD9-ADAM interactions is proposed as a potential therapeutic strategy for PAC [38]. ADAM9 has been linked to the development and spread of many malignancies, encompassing TC, glioma, colorectal, and PAC. The exploration of therapeutic interventions targeting ADAM9 and its related pathways holds promise for advancing cancer treatment (Table 2).

ADAM9 undergoes intensive regulation by various miRNAs, and their expression profiles exhibit an inverse correlation. MiR-126 exemplifies a tumour-suppressive microRNA that modulates ADAM9 expression across multiple cancers, including melanoma, osteosarcoma, pancreas, bladder, TC, and BC [57], [58]. Additionally, several other tumor-suppressive miRNAs, such as miR-1, miR-20b, miR-1274a, miR-154, miR-203, miR-488, and miR-543, have been identified to regulate ADAM9 expression in diverse solid tumors, including hepatocellular carcinoma, colon cancer (CC), glioblastoma (GBM) multiform, BC, LC, and PAC [59], [60]. Oxidative stress (OS) emerges as a significant regulatory factor influencing ADAM9 and participates in cancer spread. Investigations across various malignancies, including gastric, prostate, and LC, establish an association between OS and ADAM9 [55], [61].

Circ-ADAM9 has been implicated in diverse cellular processes and diseases, and its expression and regulation have been investigated in different scenarios. Liang et al. investigated that Circ-ADAM9 exhibits elevated expression in diabetic retinopathy (DR) individuals and increased glucose-induced retinal pigment epithelial cells (ARPE-19). Its involvement in promoting ARPE-19 cell injury suggests a potential role in the progression of DR. Circ-ADAM9 is proposed to regulate the miR-338-3p/CARM1 axis in this context [62], [63], [64]. In vestibular schwannoma (VS) primary cells, ADAM9 expression is not regulated by Merlin. Silencing ADAM9 in these cells results in reduced cell numbers, indicating a potential role in tumor growth and invasiveness [65], [66]. According to Song et al., Circ-ADAM9 is increased in BC cells in comparison to normal. Circ-ADAM9 suppression reduces development, movement, and penetration while increasing radiosensitivity and death in BC cells. The combination of radiation and circ-ADAM9 inhibition inhibits tumor development significantly [67]. According to Song et al., Circ-ADAM9 is increased in BC cells in comparison to normal. Circ-ADAM9 suppression reduces development, movement, and penetration while increasing radiosensitivity and death in BC cells. The combination of radiation and circ-ADAM9 inhibition inhibits tumor development significantly. According to Tian et al., Circ-ADAM9 sponging miR-20a-5p addresses PTEN and ATG7, causing autophagy and death of diabetic endothelial progenitor cells (EPCs). This process is suggested to suppress the angiogenic activity of EPCs under elevated sugar conditions [68]. Huang et al. studied that Circ-0107593 facilitates the osteogenic progression of human adipose-derived stem cells (hADSCs) through the miR-20a-5p/SMAD6 signalling pathway [69], [70]. These findings illustrate the several functions of circ-ADAM9 in various cellular processes and diseases. Its expression and regulation are influenced by different factors and pathways, emphasizing the need for further research to comprehensively understand the mechanisms and identify potential therapeutic targets of circ-ADAM9 in diverse contexts [71].

Twenty-three distinct Circ-ADAM9 isoforms originate from the ADAM9 and play crucial roles in diverse physiological mechanisms, encompassing cell-cell and cell-matrix linkage, fertilization, muscle growth, neurogenesis, and homeostasis. Alterations in ADAM9 expression are implicated in various pathologies, notably cancer, where ADAM9 is consistently overexpressed. In mouse models, ADAM9 has been associated with tumorigenesis and angiogenesis. Notably, ADAM9 can release several molecules pivotal in carcinogenesis and angiogenesis (CD40, EGF, EphB4, Flk-1, Tie-2, VCAM-1, and VE-cadherin), positioning it as a possible target for therapy in cancers characterized by its high expression.

Circ-ADAM9 has also appeared as a noteworthy factor in the development of various cancers and disorders, including PAC, BC, malignant melanoma, and Diabetes mellitus, as reported in several studies [72], [73], [74]. This comprehensive overview highlights the intricate connections between ADAM9 and Circ-ADAM9, shedding light on their roles in both physiological and pathological contexts, particularly in the realm of cancer and associated disorders.

The intricate interactions between circRNAs-miRNAs-mRNA targets have been the focus of extensive research, playing pivotal roles in diverse biological functions and disease processes. Numerous studies have delved into the biological functions of circRNAs across numerous conditions, such as age-related macular degeneration (AMD), atherosclerosis (AS), and systemic lupus erythematosus (SLE) [75], [76]. To explore ceRNA modulation in AS and pinpoint AS-linked circRNAs, Zhang et al. employed the miRanda software to identify potential interactions between differentially expressed miRNAs (DEmiRNAs), DEcircRNAs, and DEmRNAs. This computational analysis yielded a total of 345 DEmiRNA-DEcircRNA and 2,874 DEmiRNA-DEmRNA encounters. Subsequently, the authors focused on miRNAs that exhibited pairing with both circRNAs and mRNAs, enabling the construction of a comprehensive DEcircRNA-DEmiRNA-DEmRNA triple system. This intricate system comprised miRNAs, circRNAs, and mRNAs, having 81, 115, and 399, respectively and a total of 3,007 interaction pairs (Fig. 2) [77], [78].

Experimental techniques, including high-throughput sequencing and bioinformatic analyses, have been pivotal in identifying dysregulated circRNAs, miRNAs, and mRNAs. These approaches have enabled the construction of circRNA-miRNA-mRNA networks [79], [80], [81], shedding light on the regulatory roles of circRNAs, identifying key genes and pathways, and screening potential therapeutic agents for conditions such as SLE and AMD [82]. The extensive studies on the interactions of circRNAs-miRNAs-mRNA targets have provided valuable insights into their regulatory roles across various diseases and biological processes. The research has spanned biological functions, disease associations, and experimental methodologies, contributing significantly to our understanding of circRNA-mediated regulatory mechanisms.

In the realm of DR, another investigation focused on the functioning of circADAM9 in ARPE-19. The study uncovered that circ-ADAM9 participates as a sponge for miR-338-3p (Fig. 3), leading to the upregulation of coactivator-associated arginine methyltransferase 1 (CARM1) and consequently promoting cell injury in DR [62]. Exploring intervertebral disc degeneration (IDD), a bioinformatics analysis discovered that has-circ-0040039 is an indicator for IDD. Through the formation of a circRNA–miRNA–mRNA system, the study proposed that has-circ-0040039, along with the associated network, holds promise as a potential biomarker for IDD. Experimental techniques, including quantitative real-time polymerase chain reaction (RT-qPCR), dual-luciferase reporter (DLR) technique, and RNA sequencing, were employed to evaluate the expression levels of circ-ADAM9, miRNAs, and target genes, shedding light on the intricate regulatory relationships among circRNAs, miRNAs, and mRNAs [62], [83], [84].

Presently, there has been a surge in evidence highlighting the differential expression of circ-ADAM9 in various cancers. A comprehensive overview of its roles in the growth of distinct cancers is presented. BC, with its high morbidity and mortality rates among women, has been a focal point of investigation. Notably, circ-ADAM9 exhibits significant upregulation in BC tissues compared to adjacent samples, showing a correlation with ER receptors [72]. In a separate investigation, circ-ADAM9 was found to diminish the suppression effect of miR-217, leading to an elevation in PRSS3 expression through the stimulation of the ERK/VEGF cascade. This modulation, in turn, influences the growth and metastasis of PAC [12]. In melanoma, circ-ADAM9 (has-circ-0084043) takes centre stage, acting as an oncogene that significantly upregulates melanoma tissue. Its binding to miR-153-3p encourages the growth, spread, and movement of melanoma cells, suggesting its potential as a target [27], [85]. A further investigation on has-circ-0084043 on melanoma shows that it may engage MiR-31, boosting cell growth and glycolysis while inhibiting apoptosis. Silencing Circ_0084043 was associated with cell growth suppression, apoptosis promotion, and glycolysis restriction [86]. This summary provides a consolidated view of the recent findings on the multifaceted roles of circ-ADAM9 in various cancers, shedding light on its possibility as a diagnostic, prognostic, and treatment marker in cancer research.

In BC, ADAM9 exhibits elevated expression levels compared to normal tissue [41], [84]. Its involvement in disease progression is associated with the promotion of tumor extravasation and migration capabilities [42]. Micocci et al. postulated that ADAM9 plays an upstream function in the trans-endothelial migratory route. Micocci et al. found that ADAM9 suppression exclusively reduces the mRNA generated by ADAM15 and MMP2, without altering ADAM10, ADAM17, or MMP9 [87].

Triple-negative BC (TNBC), known for its aggressiveness, exhibits subtype-specific methylation deregulation leading to EGFR overexpression and enhancing cell proliferation and survival. Chromatin precipitation assays have indicated that ADAM9 shares EGFR's methyltransferase. The nuclear receptor-binding SET domain protein 2 increases both ADAM9 and EGFR, which contributes to TNBC cells becoming resistant to EGFR antagonists [43]. MiR-33a, miRNA-126, and miR-154 expression patterns and target locations on ADAM9 have all been examined in BC. These miRNAs address the 3'-UTR of ADAM9, and their decreased expression leads to ADAM9 amplification, which promotes cancerous cell motility and infiltration in vitro [88], [89], [90].

Glioma is a significant contributor to cancer-related mortality, with GBM being particularly aggressive, characterized by a low 5-year survival rate of 10%. Analysis of RNA-seq information from 303 glioma individuals reveals a correlation between elevated ADAM9 mRNA expression and poor progression-free survival as well as overall survival (OS) [91]. In GBM patients, both ADAM9 mRNA and protein expressions are elevated, and this upregulation correlates with shorter OS across various investigations. Tumor invasion in GBM is closely linked to the association between the extracellular matrix (ECM) and cancerous cells. Tenascin-C (TNC), a significant ECM component, stimulates the JNK system, promoting infiltration in GBM. Studies demonstrate that ADAM9 mRNA and protein expressions are increased in TNC-infected GBM cells. TNC-induced ADAM9 expression is inhibited by the JNK antagonist SP600125, and inhibiting ADAM9 in TNC-treated GBM cells decreases movement and penetration (Fig. 4). MiRNAs have been shown to regulate ADAM9 in GBM. MIR-543 and miR-140 are reduced in GBM cells. These miRNAs' binding regions are found in the 3′-UTR of ADAM9. ADAM9 upregulation reverses the negative impact of miR-543 and miR-140 on GBM growth, movement, and penetration in vitro [39].

Multiple pieces of research suggest that increased ADAM9 activity is linked to negative health outcomes and decreased response to immune checkpoint antagonist treatment [92]. MICA was discovered as a new target of ADAM9 in LvC by Kohga et al. ADAM9 breaks down membrane-bound MICA (mMICA) to liberate soluble MICA (sMICA), which functions as an immunological distraction to obstruct immune monitoring. In vitro, ADAM9 suppression enhances mMICA transcription on the cell membrane while lowering sMICA in culture supernatant [44]. In LvC therapy, metastasis is a significant concern. In vitro, IL-6, a significant modulator of LvC growth and dissemination, has been found to increase ADAM9 activity by triggering the JNK network. Blocking ADAM9 lowers basic cancer size and inhibits lung spread, whereas overexpression of ADAM9 increases main tumor development and lung migration [45], [93], [94].

Several studies have identified miRNAs that negatively regulate ADAM9 in LvC. MiR-126, miR-203, and miR-488 target the 3'-UTR of ADAM9, reducing its expression and suppressing cell migration and invasion in vitro [95], [96], [97].

In LC, the dysregulation of ADAM9 has been extensively reported, with multiple investigations establishing its crucial role in disease advancement and spread [46], [47]. Elevated ADAM9 has consistently been linked to shortened OS in different cohorts [49], [98]. High protein expression of ADAM9, determined through immunohistochemical staining, correlates with poor 5-year survival rates in both Asian and resected stage I l LC cohorts [50], [99], [100].

Metastasis, a leading cause of LC-related deaths, particularly due to brain metastasis in late-stage patients, involves ADAM9 in several critical steps. Shintani et al. highlighted ADAM9's role in promoting cancerous cell adhesion to vascular ECs, emphasizing its importance in metastasis. ADAM9 also increases movement and anoikis tolerance, contributing to spread. Suppressing ADAM9 reduces the RNA expression of CUB domain-containing protein 1 (CDCP1) and tissue-type plasminogen activator (tPA) while up-regulating PA inhibitor-1 (PAI-1). ADAM9 boosts tPA functioning, leading to CDCP1 stimulation and promoting movement and anoikis tolerance. The ADAM9-CDCP1 axis's role in LC metastasis has been validated in multiple reports, emphasizing its necessity for cell migration and survival in vitro and in vivo [101]. ADAM9 inhibits the activity of miR-1 and miR-218, targeting the CDCP1 to block its function, contributing to elevated CDCP1 protein levels. ADAM9 is also involved in disrupting the blood–brain barrier for cancerous cell entry by elevating angiopoietins 2 and tPA. Knockdown of ADAM9 enhances VE-cadherin expression, maintaining the restrictive barrier between endothelial cells (ECs), and reducing involves chemical stimulation by various angiogenic proteins. The conditioned medium from ADAM9-silenced cells suppresses tube formation in the human umbilical vein and involves chemical stimulation by various angiogenic proteins. The conditioned medium from ADAM9-silenced cells suppresses tube formation in human umbilical vein ECs permeability in vitro. These outcomes underscore the multifaceted role of ADAM9 in LC metastasis [46], [47], [102].

Angiogenesis, a well-defined process in tumor progression, involves chemical stimulation by various angiogenic proteins. In human umbilical vein ECs, conditioned media from ADAM9-suppressed cells inhibits tube development, inhibiting angiogenesis in vivo. ADAM9 is implicated in mediating the expression of IL-8, a known angiogenesis factor. IL-8 activates its high-affinity receptor, C-X-C Motif Chemokine Receptor 2 (CXCR-2), and the neutralizing antibody of CXCR-2 reverses ADAM9-mediated HUVAC tube development. Another study reveals that vascular endothelial growth factor is reduced in ADAM9-suppressed cell-conditioned medium. The results presented imply that ADAM9 contributes to cancer angiogenesis by increasing the transcription of several angiogenic factors in LC [49]. miR-425, miR-488, and miR-590 have been identified as modulators of ADAM9 in LC. Through prediction tools and luciferase reporter assays, these miRNAs target ADAM9, resulting in the reduction of ADAM9 mRNA expression [103], [104], [105].

Numerous current investigations have found that increased mRNA activity for ADAM9 is related to a shorter OS in PAC individuals, a finding substantiated by immunohistochemistry, and it is also linked to a greater level of cancer and recurrence [51], [52]. Maintaining tumorigenesis in PAC requires KRAS signalling. According to Yuan et al., abnormal KRAS activation increases ADAM9 expression via the NF-kB pathway. Furthermore, ADAM9 suppression inhibits the downstream network of the KRAS-MEK-ERK cascade, implying a feedback cycle involving ADAM9 and KRAS [53], [106], [107].

CircRNA adopts a covalently closed form in the cytoplasm and regulates biological functions by acting as a microRNA or protein inhibitor [108]. Investigations have reported the upregulation of circ-ADAM9 in PAC, correlating with negative outcomes. Circ-ADAM9 acts as a sponge for miR-127. Overexpression of circ-ADAM9 enhances the ERK network, promoting growth and movement in vitro while suppressing circ-ADAM9 delays PAC development in vivo [12]. Various miRNAs also regulate ADAM9 in PAC. MiR-489, miR-126, and miR-502f directly target ADAM9, down-regulating ADAM9 and suppressing spread in vitro [52], [91].

Fritzsche et al. reported a correlation between elevated mRNA and protein expression of ADAM9 and poor relapse-free survival in PCa [109]. Using immunohistochemistry, it was observed that over 60% of recurrent PCa exhibited increased protein expression of ADAM9 [54].

PCa progression is reliant on androgens, making androgen deprivation through castration or targeted therapy the primary treatment for advanced PCa. However, this often leads to the development of a more aggressive and castration-resistant type known as androgen-independent PCa (AIPC). Lin et al. discovered the process that keeps the ADAM9 stable in AIPC. The oncoprotein N-α-Acetyltransferase 10 protein (Naa10p) has been proven to be a key player in this procedure. Suppressing Naa10p reduces ADAM9 expression, which inhibits cancer development and spread in vitro and in vivo. Blocking out Naa10p increases ADAM9 degradation, and co-immunoprecipitation has established its direct connection. This Naa10p-mediated stabilization of ADAM9 may potentially be used to induce carcinogenesis in various other kinds of cancer [55].

ADAM9 influences PCa progression through additional mechanisms. Silencing ADAM9 disrupts integrin β1 endocytosis, increasing its membrane expression, thereby enhancing integrin-mediated cell adhesion and suppressing cell migration in vitro. Notably, metalloproteinase antagonists did not influence integrin 1 expression or integrin-mediated movement, showing that ADAM9 proteolytic function is not required for this process to occur. On the other hand, co-immunoprecipitation of ADAM9 and integrin 1 implies that ADAM9 maintains integrin 1 in a non-catalytic way [56].

MiRNAs, particularly miR-126, also contribute to the regulation of ADAM9 in PCa. Hua et al. used a luciferase reporter experiment to identify the binding location and suppressive impact of miR-126 on ADAM9 transcription. In vitro, suppressing ADAM9 with miRNA had the same detrimental impact on cell growth, migration, and penetration as miR-126 overexpression [54].

In patients with advanced tumors, chemotherapy (CT) is a common and often final treatment option, even for cancer types traditionally considered non-responsive to CT. Recent studies underscore the role of ADAM9 in CT resistance across various cancer types. Josson et al. conducted pioneering research, demonstrating that inhibiting ADAM9 enhances sensitivity to common CT drugs in PCa cells. This implies that ADAM9 actively contributes to CT resistance during tumor progression [110]. Ueno et al. observed that silencing ADAM9 induces apoptosis in cisplatin-resistant ovarian cancer cells by impairing EGFR signalling. Notably, treatment with a neutralizing antibody targeting ADAM9 produces a similar inhibitory effect on cisplatin-resistant ovarian cancer cells [111]. Fu et al. identified increased protein expression of ADAM9 and EGFR in 5-FU-resistant CC cell lines. Silencing ADAM9 through microRNA resensitized the CC cells to 5-FU. These findings collectively suggest that ADAM9 may play a crucial role in mediating CT resistance during advanced tumor stages. Consequently, combination therapies involving ADAM9 inhibition alongside CT may represent a viable approach in clinical treatment [112].

Targeted therapy, renowned for its remarkable efficacy, has become a cornerstone in clinical practice by suppressing cancerous cell growth, differentiation, and movement [113], [114]. The RNA interference (RNAi) technique, utilizing small interfering RNAs (siRNAs), represents a straightforward approach to specifically suppress circRNA translation without influencing the host gene expression. The unique ability of circRNAs to control genetic expression positions them as a therapeutic approach, offering the means to control circRNA expression through upregulation or silencing strategies in various cancers [115], [116].

CRISPR/Cas9 genome editing emerges as another technique to inhibit circRNA expression. However, achieving a silencing of circRNA through gene editing presents challenges, as the deletion of circRNA-involved exons may impact linear mRNA transcription and host gene expression [117]. An illustrative example involves the use of CRISPR/Cas9 to remove the CDR1as locus in mice. In recent advancements, CRISPR-Cas13 has been introduced as a novel tool for RNA modulation, showcasing higher knockdown efficiency and improved specificity compared to RNAi. This system holds promise for RNA-knockdown studies, including circRNA silencing achieved through the guidance of CRISPR-Cas13 guide RNA. However, the therapeutic potential of the cas13 protein and guide RNA remains under consideration, as their delivery into the organism may introduce unknown side effects [117], [118].

The overexpression of circRNA is typically achieved through vector constructs containing the circRNA sequence. These constructs can be delivered using various vectors such as plasmid transfection or viral vector systems like adenovirus vectors [118], [119]. The overall manipulation of circRNA, exemplified by circADAM9, is poised to become a valuable tool for unravelling the functional aspects of circRNA in different diseases shortly.

CircRNA-based therapeutics pose both challenges and opportunities in the cancer landscape, particularly in gastric cancer (GC). CircRNAs, characterized by their covalently closed circular structure lacking a 5′‐cap and a 3′‐tail, have been implicated in various malignancies, functioning through mechanisms such as miRNA sponging, interaction with RBPs, and even encoding functional proteins or peptides [120], [121]. Recent research has unveiled the translation potential of circRNAs, leading to the synthesis of functional proteins that play crucial roles in cancer pathology. This opens avenues for identifying novel drug targets in diseases, including cancer. Despite these prospects, the therapeutic application and associated challenges of synthetic translatable circRNAs are still under exploration [122], [123]. Moreover, advancements in antibody-based drug modalities, encompassing angiogenesis inhibitors, immune checkpoint inhibitors, antibody−drug conjugates, immunoconjugates, T cell-redirecting bispecific antibodies, and CAR-T cells, have emerged as promising approaches for targeted immunotherapy in TNBC [124]. These strides in research present promising opportunities to enhance the management of this aggressive disease. In essence, the realms of circRNA-based therapeutics and antibody-based drug modalities represent active areas of investigation, holding potential for groundbreaking innovations in cancer treatment.

While circRNAs were initially classified as non-coding due to site restrictions, they have emerged as crucial regulators in various cellular processes. Although the understanding of circRNAs in human cancers is still in its early stages, recent research has highlighted their significant roles. The translation of circRNAs is expected to unveil a concealed human proteome, providing insights into the poorly explored landscape of circRNAs in human cancer.

Circ-ADAM9 has been identified as a noteworthy molecular entity associated with cancer. Various studies have reported a substantial upregulation of Circ-ADAM9 in multiple cancer types. Its emergence as a significant player in the complex landscape of cancer biology opens avenues for comprehensive exploration. Circ-ADAM9 holds great promise as a focal point for advancements in cancer diagnostics, prognostics, and therapeutics. The aberrant expression patterns and regulatory roles of Circ-ADAM9 within cancer-related pathways present opportunities for the development of novel biomarkers, facilitating early detection and precise classification of cancer types. The potential impact of Circ-ADAM9 extends to its involvement in intricate networks of molecular interactions within cancer cells. Unravelling these interactions through future research endeavours may pave the way for targeted therapies tailored to specific subtypes of cancer. Moreover, ongoing advancements in RNA-based technologies and delivery systems offer promise in utilizing Circ-ADAM9 as a therapeutic tool. This opens up possibilities for personalized cancer treatments, marking a significant stride toward more effective and targeted interventions in the battle against cancer.