The circular structure of circRNA is formed through back-splicing of precursor mRNA, which is a process of connecting downstream splicing donors with upstream splice acceptors (16). Unlike linear RNA, circRNAs lack a 5′cap and a 3′polyadenylation [poly(A)] tail, which contributes to their enhanced stability and resistance to exonuclease-mediated degradation compared to their linear counterparts (17). Additionally, circRNAs display high sequence conservation and tissue- or developmental stage-specific expression patterns (18). These unique structural properties confer exceptional long-term cellular stability to circRNAs, enabling their function as efficient microRNA (miRNA) sponges, scaffolds for protein interactions and modulators of gene transcription and splicing (19,20). Recent studies have demonstrated the pivotal role of circRNA in various diseases, particularly in cancer, where it orchestrates critical biological processes such as tumor cell proliferation, migration and invasion (19,21). Dysregulated expression of circRNA in colorectal cancer, gliomas and thyroid cancer has been extensively documented, underscoring their potential as reliable biomarkers for early diagnosis and prognosis evaluation (16,20,22). Additionally, leveraging the unique mechanisms of circRNA, such as their ability to act as miRNA sponges, offers novel therapeutic strategies to enhance the precision and efficacy of targeted cancer therapies (23,24).

In summary, research on circRNA has revealed its significant role in cellular biology and disease progression, particularly in cancer. With a deeper understanding of its biological functions and mechanisms, circRNA holds promise as a versatile molecular biomarker in cancer diagnosis, treatment and prognosis evaluation, paving the way for more personalized and effective therapeutic interventions.

The translation of circRNA relies on cap-independent mechanisms, including internal ribosome entry sites (IRES) and N6-methyladenosine (m6A)-mediated IRES (MIRES), which collectively enhance translational efficiency and specificity (25,26). IRES elements allow translation to occur without the traditional 5′cap structure, while m6A modifications enhance the efficiency and selectivity of this cap-independent translation (27). IRES is a special RNA sequence that can directly bind ribosomes and initiate translation, bypassing the traditional cap-dependent initiation mechanisms (28,29). m6A, a widespread RNA modification, plays a pivotal role in the translational regulation of circRNA by modulating the recruitment of translation initiation factors (30). Studies have shown that m6A-modified circRNA can recruit the translation initiation complex directly via m6A reader proteins like YTH N6-methyladenosine RNA-binding protein family activators, facilitating translation through MIRES, providing an alternative to the traditional cap-dependent translation initiation mechanism (31). Furthermore, specific features, such as open reading frames (ORFs) and structural motifs, enhance the translational potential of circRNAs, allowing a subset to encode functional proteins or peptides (32,33). In certain cases, a rolling translation mechanism enables continuous translation from an ORF even without IRES or MIRES (26,34). The translation mechanism of circRNA is shown in Fig. 1.

Research into circRNA translation not only deepens the current understanding of disease mechanisms but also uncovers new molecular targets for disease diagnosis and therapy (35,36). For instance, circRNA MTCL1 promotes the progression of advanced laryngeal squamous cell carcinoma by inhibiting C1QBP ubiquitin degradation and mediating β-catenin activation (37). Furthermore, circRNA-derived peptides may modulate cellular functions and signaling pathways, indicating their emerging importance in physiological and pathological processes (38). Collectively, current findings suggest that circRNA-encoded peptides represent a promising area of research with potential implications for disease diagnosis and therapeutic development (39,40).

Recent studies analyzing circRNA expression profiles in NPC have revealed their critical potential to regulate tumor progression, offering novel insights into diagnostic and therapeutic strategies (41). Recent studies indicate that circRNA can regulate NPC cell proliferation, migration and invasion by modulating multiple signaling pathways, such as the Wnt/β-catenin pathway (42) and competing endogenous RNA (ceRNA) networks (43).

Studying the expression profiles of circRNA not only helps to reveal their mechanism of action in the development of NPC but may also provide important information for early diagnosis, prognosis assessment and the development of new therapeutic targets. For instance, analysis of the circRNA-miRNA-target gene network revealed that hsa_circ_0002375 (circKITLG) may play a pivotal role in the potential mechanism of NPC by acting as a sponge for miR-3198 and disrupting its downstream targets, and experimental silencing of circKITLG inhibits the proliferation, migration and invasion of NPC cells in vitro (41). In addition, researchers have investigated the spectrum of differentially expressed circRNA in NPC and found that hsa_circ_0007637 may be a biomarker for NPC and play a role in its development (44). It has been shown that hsa_circ_0044569 (circCOL1A1) exerts its oncogenic role in NPC by precisely regulating the miR-370-5p/PTMA signaling axis, thereby promoting tumor growth and progression (45).

Although studies have revealed diverse functions of circRNA in NPC, this field still faces significant challenges and limitations. For instance, a thorough understanding of the complete expression profile of circRNA is still lacking and the connection between circRNA and the pathophysiological characteristics of cancer needs to be further clarified (46). While numerous circRNAs have been identified, the specific roles of many remain to be investigated (44).

In summary, profiling circRNA in NPC offers valuable insight into disease-related molecular changes and may contribute to improved diagnostic and therapeutic approaches. Continued research may help clarify the biological functions of circRNA and facilitate their clinical application.

In NPC, circRNAs interact with miRNAs to form complex ceRNA networks, thereby precisely regulating the expression of downstream genes and driving the progression of NPC (47). A study has found that circFIP1L1 enhances NPC cell radiosensitivity by directly inhibiting the expression of miR-1253, highlighting its potential role in modulating NPC response to radiation therapy (48). Furthermore, circCTDP1 interacts with miR-320b to further regulate the expression of HOXA10 and TGFβ2, promoting NPC cell proliferation and migration, underscoring the complex regulatory role of circRNAs in NPC progression (49). Research indicates that circNRIP1 enhances NPC cell resistance to 5-Fu and cisplatin by modulating the miR-515-5p/IL-25 axis, suggesting its potential as a new target for reversing NPC chemotherapy resistance (50). Similarly, a study by Yin et al (51) showed that circ-0046263 promotes NPC progression by acting as a sponge for miR-133a-5p and upregulating IGFBP3 expression, thereby driving tumor growth. Additionally, circ-ABCB10 has been found to promote NPC cell proliferation and metastasis by upregulating ROCK1 (52), further highlighting the significant role of circRNA in tumor metastasis.

The complex regulatory networks involving circRNA in NPC are being progressively elucidated. Through bioinformatics analysis, researchers have identified key genes associated with NPC and predicted the potential of circRNA to regulate these genes via ceRNA mechanisms (53). Furthermore, Chen et al (53) discovered through bioinformatics analysis that numerous circRNAs may regulate the expression of the key gene FN1, thereby affecting NPC progression. Likewise, Li and Wang (54) reported that hsa_circ_0081534 promotes NPC cell proliferation and invasion by regulating the miR-508-5p/FN1 axis.

In NPC, there are multi-level interactions between circRNA and EBV factors, forming an important mechanistic network for regulating tumor progression. EBV-encoded circBART2.2, a virus-derived circRNA, can upregulate PD-L1 expression, weaken T-cell immune function and help tumors achieve immune escape (55). In addition, EBV indirectly affects the splicing and expression patterns of host circRNA by reshaping the host's epigenetic landscape and enhancing inflammation-related gene expression, providing a basis for NPC molecular typing and treatment response differences (56). EBV-associated glycoproteins can alter the membrane structure and extracellular vesicle secretion of tumor cells, which may affect the transport and function of circRNA between cells (57). EBV also inhibits natural killer cell function by upregulating B7-H3, coupled with circRNA-mediated immune regulation, exacerbating the tumor immune suppressive microenvironment (58). Meanwhile, studies have confirmed that EBV induces GPX4 expression and enhances cellular drug resistance, which may involve the cross action of circRNA regulation of lipid metabolism and antiapoptotic pathways (59). Metabolomics and animal model studies further indicate that EBV can promote sustained activation of circRNA-related pathways and drive malignant progression of NPC by activating glycolysis and lipid metabolism pathways (60,61). In addition, the EGFR signaling pathway is activated in EBV infection and interacts with multiple oncogenic pathways regulated by circRNA, amplifying oncogenic signals (62). It is worth noting that EBV forms systematic reprogramming with host ceRNA networks (including circRNA) through its protein products, and cooperatively promotes NPC generation at multiple levels of chromatin, epigenetics and post-transcriptional regulation (63,64). Furthermore, host genetic variations may regulate responses to different EBV subtypes and the interaction of these genetic virus circRNA forms a complex NPC risk regulatory network (65).

In summary, circRNA not only serves as a regulatory factor within host cells but may also play an important role as a 'signaling node' in virus host interactions, providing a new research perspective for understanding the virus-driven mechanisms of NPC and laying a theoretical foundation for developing virus-related molecular targeting strategies.

CircRNA-encoded peptides have been experimentally validated as regulators of multiple oncogenic pathways in various cancers (66,67). For instance, AXIN1-295aa derived from circAXIN1 activates Wnt/β-catenin signaling by disrupting the adenomatous polyposis coli (APC)-containing destruction complex, promoting gastric cancer progression (68). Similarly, circPDHK1 encodes PDHK1-241aa, which binds PPP1CA and prevents AKT dephosphorylation, thereby promoting AKT/mTOR signaling activation in renal cancer (69). Other examples include TRIM1-269aa from circTRIM1, which enhances PI3K/AKT/mTOR signaling and chemoresistance in breast cancer (70), and MAPK1-109aa from circMAPK1, which inhibits MAPK1 phosphorylation and suppresses gastric tumor cell growth (71).

Although similar peptides have not yet been identified in NPC, circRNA has been shown to play functional roles in this cancer type through non-coding mechanisms. For instance, hsa_circ_0081534 promotes proliferation and invasion in NPC via the miR-508-5p/FN1 axis (54).

These parallels suggest that circRNA-encoded peptides may represent an uncharted but relevant layer of regulation in NPC. Further investigation using proteomics and functional models such as NPC organoids will be essential to determine their presence and roles in this disease context.

CircRNA, as a type of non-coding RNA, plays a crucial role in the initiation and progression of various cancers. CircRNA can directly activate the Wnt/β-catenin signaling pathway by encoding polypeptides. For instance, the AXIN1-295aa polypeptide encoded by circAXIN1 disrupts the Wnt signaling pathway's destruction complex' by competing with the APC gene product, thereby releasing β-catenin into the nucleus and activating the expression of downstream genes, which promotes gastric cancer initiation and progression (68). Studies have shown that circRNA can modulate tumor progression through specific interactions with the PI3K/AKT/mTOR signaling pathway. For instance, the PDHK1-241aa polypeptide encoded by circPDHK1 interacts with PPP1CA, inhibiting AKT dephosphorylation, which subsequently activates the AKT-mTOR signaling pathway and promotes renal cancer progression (69). In addition, the TRIM1-269aa polypeptide encoded by circTRIM1 enhances the interaction between MARCKS and calmodulin and activates the PI3K/AKT/mTOR pathway in triple-negative breast cancer, promoting chemoresistance and metastasis (70). Research also indicates that the SEMA4B-211aa polypeptide encoded by circSEMA4B modulates the PI3K/AKT signaling pathway by inhibiting AKT phosphorylation, thereby suppressing breast cancer progression (72). CircRNA can further modulate the MAPK signaling pathway through various mechanisms. For instance, the MAPK1-109aa polypeptide encoded by circMAPK1 inhibits MAPK1 phosphorylation, blocking its activation, and subsequently suppressing the proliferation and invasion of gastric cancer cells (71).

A study revealed that the SMO-193aa polypeptide encoded by circ-SMO interacts with SMO in glioblastoma, enhancing cholesterol modification of SMO and relieving SMO receptor inhibition, thereby promoting Hedgehog signaling pathway activation (73). Additionally, Song et al (74) identified the critical function of the CAPG-171aa polypeptide encoded by circCAPG in triple-negative breast cancer, which activates the MEKK2-MEK1/2-ERK1/2 pathway by disrupting the interaction between STK38 and SMURF1, thus promoting tumor growth. In fish, the MORC3-84aa polypeptide encoded by circMORC3 interacts with TRIF, facilitating its autophagic degradation, and inhibits TRIF-mediated IRF3 and NF-κB signaling pathways, thus acting as a negative regulator of the antiviral immune response (75).

Studies have suggested that circRNA-encoded peptides may potentially participate in the regulation of key oncogenic signaling pathways in NPC, particularly NF-κB and JAK/STAT, both of which are closely associated with immune modulation and viral pathogenesis. The NF-κB pathway is frequently activated in NPC due to factors such as cancer-associated fibroblasts, inflammatory signals and regulatory proteins, supporting tumor survival and metastasis (76-79). In parallel, the JAK/STAT pathway has been linked to lymph node metastasis and poor prognosis in NPC (80,81). Notably, hsa_circ_0013561 was shown to promote NPC progression via the JAK2/STAT3 axis, implicating circRNA in the activation of this pathway (81). Although direct evidence remains limited, these findings raise the possibility that circRNA-derived peptides may act as functional modulators within these signaling cascades.

Genomic profiling has revealed that NPC frequently harbors mutations in negative regulators of NF-κB signaling, such as TRAF3 (TNF receptor-associated factor 3) and CYLD (cylindromatosis lysine 63 deubiquitinase), whose loss may amplify the impact of NF-κB-related oncogenic pathways (82-85). CYLD not only represses NF-κB but also influences post-translational modification and viral replication, suggesting that its dysfunction may modulate circRNA-mediated or circRNA-derived peptide effects at multiple levels (85,86). Furthermore, EBV infection has been shown to reshape chromatin accessibility and enhancer usage, further activating NF-κB signaling in NPC, a process that may converge with circRNA-mediated regulation (87). The potential role of circRNA-encoded peptides in NPC is shown in Fig. 2

To validate these hypotheses, recent studies have highlighted the utility of NPC organoid models and proteomic platforms, which offer powerful experimental systems to dissect the function of circRNA-encoded peptides and their interaction with key oncogenic pathways in a physiologically relevant context (78,88). Altogether, these studies jointly reveal the value of NPC pathogenesis and potential therapeutic targets.

These findings suggest that circRNA-encoded peptides may influence inflammatory and oncogenic signaling pathways, including NF-κB, which is highly relevant to NPC pathogenesis. Further mechanistic studies using NPC-specific systems, such as patient-derived organoids, will be essential to confirm these associations.

A summary of circRNA-encoded polypeptides regulating multiple signaling pathways is presented in Table I. Overall, circRNA-encoded polypeptides represent an emerging layer of molecular regulation in cancer and inflammatory diseases, with potential implications for therapeutic development.

CircRNAs influence the TME through their encoded peptides, modulating tumor growth, immune evasion and stromal interactions. First, the interaction between circRNAs and tumor-associated macrophages (TAMs) is particularly significant. For instance, circSMARCC1 enhances the interaction between prostate cancer cells and TAMs through the miR-1322/CCL20/CCR6 signaling axis, promoting M2 polarization of TAMs, which accelerates tumor progression (89). Furthermore, hsa_circ_0009092 suppresses colorectal cancer proliferation and TAM recruitment by sponging miR-665 and regulating NLK expression, thereby inhibiting the Wnt/β-catenin signaling pathway (90). Second, circRNAs can modulate immune evasion within the TME. For instance, hsa_circ_0136666 modulates PD-L1 phosphorylation through the miR-375/PRKDC axis, impairing T cell-mediated immunity and facilitating immune evasion in gastric cancer (91). Similarly, circNEIL3 stabilizes the IGF2BP3 protein, promoting the immunosuppressive polarization of macrophages, which in turn accelerates glioma progression (92). EBV-encoded circRNA circBART2.2 interacts with RIG-I, activating transcription factors IRF3 and NF-κB, which promotes PD-L1 expression and inhibits T-cell function, thus facilitating immune evasion in NPC (55).

Research has shown that circRNAs can mediate information exchange between cancer cells and immune cells, fibroblasts and other components of the TME via exosomes, thus regulating key aspects of tumor proliferation, metabolism, immune escape and drug resistance (93). Similarly, cSERPINE2 in breast cancer enhances the secretion of IL-6 by TAMs, promoting cancer cell proliferation and infiltration, which exacerbates tumor progression through a positive feedback loop (94). Another critical function of circRNAs is their modulation of tumor angiogenesis, stromal remodeling and immune suppression. For instance, in esophageal squamous cell carcinoma, circRNAs enhance tumor invasiveness by modulating angiogenesis and epithelial-mesenchymal transition within the TME (95). Additionally, circRNA ZNF609 promotes angiogenesis in NPC via the miR-145/STMN1 axis, driving tumor cell proliferation and migration (96). Meanwhile, circRNA ZNF609 enhances NPC growth and metastasis by sponging miR-150-5p and upregulating Sp1 expression (97). In summary, circRNA appear to contribute to multiple aspects of TME regulation, offering potential insights into tumor biology and therapeutic targeting.

CircRNA-derived peptides have been found to affect signaling pathways relevant to the TME in various tumor types. Studies have shown that the peptide C-HGF encoded by circHGF activates the c-MET signaling pathway, promoting glioblastoma growth (98). Additionally, the SEMA4B-211aa protein encoded by circSEMA4B inhibits the progression of breast cancer. Its mechanism involves binding to p85, inhibiting AKT phosphorylation, thereby regulating the PI3K/AKT signaling pathway (72). In colorectal cancer, the circMAPK14-175aa peptide encoded by circMAPK14 competes with MKK6, inhibiting cancer progression and metastasis (99). Zhang et al (100) found that the 198-aa peptide encoded by hsa_circ_0006401 promotes colorectal cancer proliferation and metastasis by stabilizing mRNA of its host gene COL6A3. Furthermore, the circPPP1R12A-73aa peptide encoded by circPPP1R12A activates the Hippo-YAP signaling pathway, promoting the growth and metastasis of colon cancer (101).

Research on chronic obstructive pulmonary disease has revealed that the circ-0008833-57aa peptide encoded by has-circ-0008833 induces apoptosis in bronchial epithelial cells, promoting the progression of chronic obstructive pulmonary disease (102). Li et al (103) found that the CORO1C-47aa peptide encoded by circ-0000437 inhibits angiogenesis, suppressing the progression of endometrial cancer. In addition, the β-TrCP-343aa peptide encoded by circ-β-TrCP competes with NRF2, blocking SCF β-TrCP-mediated proteasomal degradation of NRF2, thereby upregulating antioxidant genes and conferring resistance to trastuzumab (104). These findings collectively indicate that circRNA-derived peptides can modulate immune responses, angiogenesis, metabolism and drug sensitivity within the TME. Continued research is needed to further define their mechanistic roles and therapeutic relevance.

Peptides are molecular chains formed by connecting two or more amino acids through peptide bonds. Each peptide bond is formed through the dehydration condensation reaction of the amino group of one amino acid and the carboxyl group of another amino acid (105). Peptides serve various biological functions in the body, such as acting as hormones, enzymes and antibodies, and play key roles in regulating physiological processes (106). Furthermore, peptides hold promise for diagnosing and treating diseases, with specific peptides acting as biomarkers for cancers and neurodegenerative diseases, thereby aiding in early diagnosis and prognostic evaluation (107,108). For instance, a peptide known as MDANP has been shown to protect mice from necrotizing enterocolitis by modulating the PERK-eIF2α-QRICH1 signaling pathway (107). Similarly, Zhong et al (109) developed a peptide drug delivered via specific nanotechnology carriers, which targets and treats triple-negative breast cancer with high anti-tumor efficacy and low toxicity. These studies underscore the extensive biological functions and application potential of peptides, which can influence disease progression through various mechanisms and occupy a significant position in the development of novel therapies (110).

CircRNA is a class of non-coding RNA molecules with a closed-loop structure, characterized by high stability and tissue specificity. Studies suggested that circRNAs, besides acting as miRNA sponges or interacting with RNA-binding proteins to regulate gene expression, can also translate peptides through their ORF, thereby participating in the regulation of diseases such as cancer (32,67,111). These circRNA-encoded peptides possess diverse functions, including promoting or inhibiting the occurrence and development of tumors. For instance, certain circRNAs are translated independently of the canonical 5′ cap and 3′ poly(A) tail through mechanisms such as IRES and m6A modifications. The peptides encoded by these circRNAs regulate tumor progression by modulating pathways such as Yap-Hippo and Wnt/β-catenin, or through phosphorylation and ubiquitination of specific molecules (29,112). Furthermore, these peptides have been identified as novel tumor biomarkers and prognostic factors, useful for early tumor screening and personalized treatment strategies (113).

Notably, circRNA-encoded peptides have emerged as promising candidates for anti-tumor drug development, owing to their regulatory roles in key signaling pathways. For instance, in digestive system cancers, they influence key processes such as tumor cell proliferation, migration and apoptosis through the regulation of signaling pathways (113,114). Overall, circRNA-encoded peptides play crucial roles in tumor pathology but also show immense potential as novel biomarkers for diagnosis, therapy and prognosis assessment (14,115). Future research should focus on elucidating the precise mechanisms of circRNA-encoded peptides, facilitating their translation into clinical applications such as precision oncology.

CircRNAs, closed-loop non-coding single-stranded RNAs, are increasingly recognized for their diverse biological functions in human diseases (116). Studies revealed that certain circRNAs, apart from serving as miRNA sponges or templates for protein translation, can encode biologically active peptides through unique mechanisms such as IRES or m6A modifications (117-119). These circRNA-encoded peptides are involved in regulating cellular growth, migration, apoptosis and drug resistance. For instance, the peptide Aβ175 encoded by circAβ-a is implicated in the pathogenesis of Alzheimer's disease (AD), highlighting these peptides as promising therapeutic targets (117). Additionally, circMRPS35-168aa expression is upregulated in response to chemotherapy drugs, contributing to hepatocellular carcinoma resistance (120). In colorectal cancer, the peptide circMAPK14-175aa, by competitively binding MKK6, inhibits cancer progression and metastasis (99). Studies have also shown that the peptide SHPRH-146aa encoded by circ-SHPRH induces apoptosis in neuroblastoma cells, demonstrating its potential as a therapeutic agent for neurodegenerative diseases (121).

The high disease relevance and regulatory complexity of circRNA-encoded peptides provide possibilities for developing new biomarkers and therapeutic approaches. However, the current understanding of these peptides' functions and mechanisms of action remains relatively limited, necessitating further research to explore their precise roles in disease onset and how to effectively utilize these findings clinically (118). Such research not only aids in a deeper understanding of circRNA functions but may also advance translational medicine, offering new strategies for disease diagnosis and treatment.

In recent years, circRNAs have become a focal point in drug development and therapeutic strategies due to their unique structure and function. The closed-loop structure of circRNAs imparts higher stability and resistance to degradation in vivo, offering substantial potential for pharmaceutical applications (122). Research has shown that the peptide circFBXW7-185aa, encoded by circFBXW7, interacts with β-catenin, reducing its stability and promoting its ubiquitination, thereby inhibiting Wnt signaling pathway activation. This mechanism aids in enhancing the sensitivity to tyrosine kinase inhibitors in lung adenocarcinoma and reversing resistance (123). Another example is the peptide β-TrCP-343aa, encoded by circ-β-TrCP, which modulates the NRF2-mediated antioxidative pathway, promoting resistance to trastuzumab in HER2-positive breast cancer (104). In addition, the CAPG-171aa peptide encoded by circCAPG plays a crucial role in the pathogenesis of triple-negative breast cancer by activating the MEKK2-MEK1/2-ERK1/2 signaling pathway, enhancing tumor proliferation and metastasis (74).

CircRNA-encoded peptides also facilitate the development of novel diagnostic and prognostic markers. For instance, a peptide encoded by circβ-catenin can regulate the expression of β-catenin, thereby influencing the malignant phenotype of non-small cell lung cancer (124). In AD, circRNA-encoded amyloid β peptides provide new mechanisms for understanding the disease's pathogenesis (117). Furthermore, circRNA-encoded peptides show potential in treating metabolic diseases. For instance, the SLC9A6-126aa peptide encoded by circ-SLC9A6 modulates H4K16ac-mediated CD36 transcription, influencing lipid metabolism and offering a novel target for treating non-alcoholic fatty liver disease (125).

Overall, the prospects for circRNA-encoded peptides in overcoming cancer and anti-cancer drug resistance are broad. With deeper research into the functions and mechanisms of circRNA-encoded peptides, these molecules are expected to become important tools in the next generation of drug development, bringing innovative strategies for disease treatment.

Research has shown that EBV circBART2.2 can promote tumor immune escape by upregulating PD-L1 (55), while EBV circRPMS1 drives tumor progression in EBV-associated gastric cancer through Sam68-dependent METTL3 activation (47). These findings suggest that targeting EBV-encoded circRNAs, such as through antisense oligonucleotides or small molecule inhibitors, may become an effective strategy for intervening in NPC. In addition, LMP1 can regulate the expression of host circRNA through the NF-κB pathway (126), but the direct interaction mechanism between circRNA and LMP1 still needs further validation.

High-frequency mutated genes in NPC, such as TRAF3 and CYLD, may affect the biological function of circRNA. CYLD deficiency can inhibit cell apoptosis through NDRG1-dependent pathways (86) and enhance PFKFB3-mediated metabolic reprogramming (83). In addition, TRAF3 deficiency is associated with abnormal activation of the NF-κB pathway (127), but whether it regulates circRNA translation efficiency through m6A modification remains to be clarified. The correlation between TRAF3/CYLD mutations and circRNA peptide expression in patients with NPC can provide molecular evidence for targeted interventions through sequencing analysis.

The NPC organoid model has been successfully used to simulate the TME, such as CD70-CD27 interaction-mediated regulatory T-cell activation (128). In addition, EBV circLMP2A promotes angiogenesis through the KHSRP/VHL/HIF1α axis under hypoxic conditions (129), suggesting that organoid or patient-derived xenograft models can be used to validate the regulatory effect of circRNA peptides on the NF-κB/JAK-STAT pathway. For instance, the function of circARHGAP35 in NPC remains to be clarified and further research using gene editing models is needed.

The detection of circRNA-encoded peptides may become a new strategy for NPC diagnosis. For instance, circRNF13 inhibits NPC metastasis through SUMO2 (130), and its peptide segment may serve as a serum biomarker. In terms of treatment, monoclonal antibodies targeting circBART2.2 or vaccines that bind to EBV antigen epitopes may enhance the efficacy of immunotherapy (55). In addition, circIPO7 mediates cisplatin resistance by promoting YBX1 nuclear translocation (131), suggesting that its peptide segments can serve as targets for combination therapy.

Existing research has clarified the oncogenic role of EBV circRNA in NPC, but the specific mechanisms and translational application of circRNA peptides still require to be further explored. Future research needs to combine organoid models, high-frequency mutation gene analysis and clinical sample validation to promote the application of circRNA peptides in the diagnosis and treatment of NPC.

The field of circRNA-encoded peptides has garnered widespread attention due to its technical challenges and research advancements. For instance, studies have shown that the peptide circMAP3K4-455aa, translated from circMAP3K4 via m6A modification, interacts with AIF, inhibiting apoptosis in hepatocellular carcinoma, highlighting its potential in the context of RNA-based therapeutic development (132). Additionally, Lu et al (133) reviewed the role of circRNAs in translation, emphasizing the importance of IRES and m6A modifications in cap-independent translation, and showcased how modern high-throughput sequencing technologies and bioinformatics tools can explore the coding potential of circRNAs.

Despite these advancements, several key challenges remain in the study of circRNAs' coding functions. First, identifying and validating circRNAs with coding potential is particularly challenging, requiring advanced bioinformatics analysis and experimental validation (134). Furthermore, elucidating the biological functions and mechanisms of action of these peptides involves complex biochemical and molecular biology techniques (135). Lastly, translating these findings into clinical applications, such as developing targeted cancer therapies based on circRNA-encoded peptides, remains a significant research challenge (69,136).

In conclusion, although this is an emerging research area, the potential for circRNA-encoded peptides to bridge basic biology and translational medicine is gradually being recognized. Continued efforts are needed to elucidate their biological relevance and therapeutic value (137).

NPC is a malignant tumor with unique epidemiological and pathological features, including a close association with EBV infection and significant immune infiltration (138). Although advances in radiotherapy and chemotherapy have improved patient prognosis (139,140), challenges such as distant metastasis, recurrence, and drug resistance still exist (141). The study of circRNAs encoding peptides is becoming a promising frontier with potential relevance to these issues (137). However, research directly linking circRNA encoded peptides with NPC is still limited, which points to a clear direction for future research.

Recent advances have shown that certain circRNAs can produce bioactive peptides with tumor regulatory functions in other cancers. For instance, circFBXW7 and circGSPT1 encode peptides that inhibit cancer and gastric cancer tumor growth, respectively (142,143). These findings emphasize the importance of identifying and characterizing circRNAs in NPC that may also have coding potential, potentially revealing new tumor inhibitors or oncogenes specific to this cancer type.

In addition, technology platforms such as ribosome profiling and mass spectrometry have been proven to effectively detect circRNA translation events (137). Applying these techniques to NPC tissue and cell models may uncover novel circular RNA-encoded peptides that are uniquely expressed or dysregulated in NPC, thereby expanding the current molecular landscape of the disease.

Meanwhile, circRNA-based methods have been explored for therapeutic applications in other diseases. For example, it has been reported that circMIB2 exerts therapeutic effects by encoding a new protein in infectious diseases (136). Although not in the context of cancer, it provides a methodological basis for exploring the therapeutic delivery of circRNA-encoded peptides in preclinical NPC models in future research.

Finally, considering the different geographical distribution and region-dependent susceptibility of NPC (138), future research should explore the differences in circRNA expression and translation in patient populations, which may lead to changes in tumor biology and treatment response. Such studies may support the development of geographic region-dependent biomarkers or therapeutic strategies in NPC.