Dynamic imbalance of the m6A methyltransferase system in cervical cancer is a core epigenetic feature that drives disease progression. In cervical cancer, dysregulated m6A modification enzymes (writers, erasers and readers) act as potential prognostic biomarkers and therapeutic targets, of which the high expression levels of certain ones are associated with reduced overall survival (16). However, reduced m6A mRNA methylation levels have been notably associated with advanced cervical cancer stages, larger tumor size, lower differentiation, lymph node invasion and recurrence. Reduced m6A mRNA methylation has also been associated with the progression and poor prognosis of cervical cancer, suggesting that it may act as a potential therapeutic target (17). For example, WT1 associated protein, RNA binding motif protein 15 (RBM15), Cbl proto-oncogene like 1 and YTHDC2 act as hub genes and potential biomarkers for cervical cancer, with RBM15 being markedly overexpressed and the others downregulated. RBM15 gene knockdown inhibits cancer progression and the JAK-STAT pathway, highlighting its therapeutic potential (18).

METTL3, the core regulatory hub, cooperates with HPV to enhance genome stability. Integrative analyses of HPV-related cancers have revealed that METTL3, an m6A regulator, is associated with poor prognosis, HPV status and an immunosuppressive microenvironment, suggesting that it has potential as a therapeutic target. High METTL3 expression is associated with reduced immune cell infiltration and increased levels of immunosuppressive checkpoint molecules, and its inhibition in combination with anti-programmed cell death protein 1 (PD-1) therapy shows promise for the treatment of cervical squamous cell carcinoma (CSSC) (19). Moreover, a marked association between m6A RNA methylation regulators, the tumor microenvironment, programmed death-ligand 1 (PD-L1) expression and immune infiltration was reported in cervical cancer, identifying a prognostic signature that could mediate PD-L1 expression and immune cell dynamics in the tumor immune microenvironment (20). Furthermore, METTL3 is involved in regulating key signaling pathways involved in the progression of cervical cancer. Disks large homolog 2 (DLG2) expression is downregulated in cervical cancer. Its upregulation inactivates the Hippo/YAP signaling pathway and inhibits the malignant behavior of cancer cells. As shown in Fig. 2A, METTL3 destabilized the DLG2 mRNA by increasing m6A modification levels, thereby negatively regulating DLG2 expression. Moreover, low DLG2 expression counteracted the inhibitory effects of METTL3 silencing in cancer cells. This indicates that DLG2 acts as a tumor suppressor in cervical cancer. Moreover, METTL3 promotes the progression of cervical cancer by downregulating DLG2 expression and activating the Hippo/YAP signaling pathway (21).

The transcription factor, interferon regulatory factor 5 (IRF5), induced by m6A modification, promotes cervical cancer progression by upregulating protein phosphatase 6 catalytic subunit; its activity is regulated by METTL3, suggesting that it could be another potential therapeutic target (22). METTL3 gene knockdown inhibits cervical cancer by disrupting the AKT/mTOR pathway, and its upregulation drives tumor growth through m6 modification of the phosphodiesterase 3A (PDE3A) mRNA, highlighting the METTL3/YTHDF3/PDE3A axis as a potential therapeutic target (23). METTL3 promotes cervical cancer progression via m6A modification-mediated upregulation of NIMA-related kinase 2 (NEK2), which together activate the Wnt/β-catenin pathway and inhibit apoptosis, suggesting that the METTL3-NEK2 axis could be a potential therapeutic target for cervical cancer (24). Previous research indicated that individuals with elevated METTL3 levels exhibited reduced disease-free survival, whereas those with increased MYC expression showed decreased overall survival rates. Thus, METTL3 may promote the occurrence and development of cervical cancer by regulating the translation of the oncogene, MYC, through m6A modification, leading to enhanced cell viability and malignant behavior (25). The study also demonstrated that RNA m6A modification, mediated by upregulated METTL3, downregulated nuclear receptor subfamily 4 group A member 1 (NR4A1) in cervical cancer, facilitating malignancy. This process involves the YTHDF2-DDX6 pathway and the recruitment of the lysine demethylase 1A (LSD1)/histone deacetylase (HDAC)1/CoREST complex to the AKT serine/threonine kinase 1 (AKT1) promoter, highlighting the role of m6A modification in cervical cancer progression (26).

METTL3-driven m6A modification promotes cancer cell dissemination via β-catenin expression and membrane trafficking. The METTL3/β-catenin axis acts as a potential target for the inhibition of cancer metastasis (27). Additionally, METTL3-mediated m6A modification of the heat shock protein family A9 mRNA in cervical cancer cells led to increased stability and translation efficiency of mortalin, an exosomal protein. Overexpression of exosomal mortalin promotes cancer cell proliferation, migration and invasion, whilst inhibiting cellular senescence by blocking the nuclear transport of p53 and inactivating it. These findings highlight the notable role of METTL3 and exosomal mortalin in cervical cancer progression and suggest their potential as early diagnostic biomarkers and therapeutic targets (28). METTL3 enhances HDAC6 translation by facilitating its m6A modification and subsequent interaction with YTHDF3, thereby modulating cilia dynamics and alpha-tubulin acetylation, which affect cervical cancer cell growth and tumor progression (29). METTL3 upregulates cell cycle progression and proliferation in cervical cancer by enhancing cell division cycle 25B translation via m6A/YTHDF1-dependent mechanisms, revealing a novel role of m6 methylation in regulating the cell cycle (30). Finally, METTL3 participates in metabolic reprogramming of cervical cancer cells. For instance, METTL3 targets the 3′-UTR of the hexokinase 2 (HK2) mRNA and enhances its stability by recruiting YTHDF1 for m6A modification, contributing to cervical cancer progression and the Warburg effect; its upregulation in cancer tissues is associated with poor prognosis, highlighting a potential therapeutic target (31). METTL3-induced m6A methylation of solute carrier 38A1 promotes cervical cancer growth by stabilizing its mRNA, suggesting that targeting this pathway could be a novel therapeutic strategy for cervical cancer treatment (32). Moreover, METTL3 was reported to target thioredoxin domain containing 5 for m6A modification, which promoted cervical cancer progression by alleviating endoplasmic reticulum stress, suggesting the role of METTL3 as a biomarker and therapeutic target (33).

METTL3 regulates ncRNA expression. For example, m6A modification, involving writers METTL3 and METTL14, as well as erasers, FTO and AlkB homolog 5, RNA demethylase (ALKBH5), serves a pivotal role in regulating the stability and translation of the mRNA of the tumor suppressor, DIRAS family GTPase 1, which is markedly downregulated in cervical cancer cells, and contributes to its anti-oncogenic effects (34). LINC00426, an m6A-modulated lncRNA, induces epithelial-mesenchymal transition (EMT) in cervical cancer by binding to ZEB1, which confers resistance to certain chemotherapies and sensitizes cells to imatinib, suggesting its potential as a therapeutic target (35). Aspartyl-tRNA synthetase (DARS)-antisense RNA 1 (DARS-AS1), an oncogenic lncRNA, promotes cytoprotective autophagy in cervical cancer by recruiting METTL3/METTL14 to enhance DARS mRNA m6A modification and translation, forming a hypoxia-induced pathway that could be a potential therapeutic target (36). Circ0000069, upregulated in cervical cancer due to m6A modification, promotes cell proliferation and migration by inhibiting microRNA (miRNA/miR)-4426, indicating a role for this circular (circ)RNA in cervical cancer progression (37). CircRNF13, an m6A-modified circRNA, confers radioresistance to cervical cancer by stabilizing the C-X-C motif chemokine ligand 1 (CXCL1) mRNA, suggesting that the METTL3/YTHDF2/circRNF13/CXCL1 axis is a potential therapeutic target for countering radiotherapy resistance (38). circSTX6, overexpressed in cervical cancer, is associated with poor prognosis and promotes cell survival, proliferation, invasion and migration via its interaction with Spi-1 proto-oncogene (SPI1), leading to IL-6 upregulation and JAK2/STAT3 pathway activation. METTL3-induced m6A modification of circSTX6, recognized by YTHDC1, enhances circSTX6 stability by forming a positive regulatory loop with SPI1. This insight deepens the understanding of cervical cancer pathogenesis and suggests that circSTX6 may be a novel therapeutic target (39). Moreover, METTL3 fosters cervical cancer progression by stabilizing the lncRNA, forkhead box D2-AS1, which recruits LSD1 to the P21 promoter, facilitating H3K4 demethylation and transcriptional silencing of the tumor suppressor, p21, thereby representing a novel therapeutic axis in cervical cancer (40). Another study revealed a pivotal role of METTL3 in CSCC, where it upregulates and stabilizes the m6A-modified lncRNA, METTL4-2, which in turn promotes cell migration, proliferation and tumor growth, suggesting that the METTL3-METTL4-2 axis could be a novel therapeutic target for CSCC (41). ZNFX1 antisense RNA 1 serves an oncogenic role in cervical cancer by suppressing miR-647 via a METLL3-mediated m6A-dependent mechanism, and its upregulation is associated with poor prognosis and aggressive tumor behavior, suggesting its potential as a therapeutic target (42). MiR-30c-5p promotes ferroptosis and inhibits the growth and metastasis of cervical cancer by targeting the METTL3/KRAS axis, revealing a novel molecular mechanism for cervical cancer progression (43). Downregulation of miR-193b by m6A methylation, mediated by METTL3 (Fig. 2A), promotes cervical cancer aggressiveness by targeting Cyclin D1, indicating a novel mechanism for tumor progression (44).

Emerging evidence has highlighted context-dependent regulation of the m6A methylation machinery under apoptotic stress. A comparative analysis of chemotherapy-induced apoptosis revealed that cisplatin treatment selectively reduces METTL14 and FTO transcript levels in cervical cancer cells, unlike that observed in TNF-α-mediated apoptosis pathways. Notably, cisplatin exposure also markedly diminishes the levels of m6A reader proteins, IGF2BP2 and IGF2BP3, suggesting stress-specific rewiring of the m6A epitranscriptome that may underlie heterogeneous therapeutic responses across cell death inducers (45). Owing to this regulatory plasticity, METTL14 demonstrates multifaceted oncogenic roles. As shown in Fig. 2B, sorafenib promotes ferroptosis by destabilizing the ferritin heavy chain 1 mRNA via m6A methylation, indicating its role in regulating cancer progression via the PI3K/AKT signaling pathway (46). Utilizing m6A-dependent upregulation of homeobox B13, METTL14 activates NF-κB signaling and drives tumor invasion. It is associated with advanced International Federation of Gynecology and Obstetrics (FIGO) stages and is emerging as a potential therapeutic target (47). In collaboration with insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1), METTL14 stabilizes tripartite motif containing 11 transcripts to enhance PH domain and leucine rich repeat protein phosphatase 1 ubiquitination and proteasomal degradation, thereby activating the AKT pathway and enhancing cell proliferation, migration and invasion, indicating that it is a potential therapeutic target for cervical cancer (48). Consistent with these pro-tumorigenic functions, a previous study reported that silencing of METTL14 in cervical cancer cells led to cell cycle arrest and suppression of the PI3K/AKT/mTOR pathway. METTL14 knockdown inhibited the growth, migration and invasion of cervical cancer cells, including both HPV-positive and -negative cell lines, suggesting that METTL14 serves an oncogenic role in cervical cancer progression. This is supported by bioinformatics analysis indicating that METTL14 upregulation is a poor prognostic factor in patients with cervical cancer (49). Notably, the oncogenic activity of METTL14 is modulated by ncRNA crosstalk. piRNA-14633 is highly expressed in cervical cancer tissues and cells, where it promotes cell viability, proliferation, migration and invasion via the METTL14/cytochrome P450 1B1 signaling axis, suggesting a notable role for piRNA-14633 in cervical cancer progression. In vitro and in vivo experiments demonstrated that piRNA-14633 affects m6A RNA methylation and METTL14 mRNA stability, with implications for potential therapeutic targeting in cervical cancer (50).

Analogous to METTL14, RBM15 drives cervical carcinogenesis through a multi-layered epitranscriptomic network, demonstrating remarkable pathway heterogeneity. For example, as shown in Fig. 2C, RBM15-mediated m6A modification of enhancer of zeste 2 polycomb repressive complex 2 (EZH2) promotes EMT and the proliferation of cervical cancer cells, suggesting that the RBM15/EZH2/FN1 signaling cascade is a potential therapeutic target (51). During stromal remodeling in cervical cancer tissues, there is an association between elevated RBM15 expression and increased malignancy, whereas RBM15 knockdown reduces the malignancy of cervical cancer by mediating the m6A modification of decorin, leading to increased decorin expression and inhibition of tumor growth both in vitro and in vivo (52). RBM15 promotes cervical cancer cell stemness and progression by stabilizing the oncogenic lncRNA, ‘High Expression In Hepatocellular carcinoma, which competitively adsorbs miR-802, upregulates epithelial growth factor receptor (EGFR) and enhances tumor growth and metastasis (53). Research has also reported that RBM15-mediated m6A modification upregulated OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2), which in turn promoted cervical cancer progression via the AKT/mTOR signaling pathway. Enhanced OTUB2 expression is associated with poor outcomes in patients with CSCC and endocervical adenocarcinoma, and its silencing inhibits cancer cell proliferation and metastasis whilst promoting apoptosis (54). Unlike the role of METTL14 in chemoresponse and ferroptosis regulation, RBM15 predominantly orchestrates tumor plasticity and stromal crosstalk, although both proteins synergistically amplify oncogenic signaling via AKT/mTOR activation. This hierarchical regulatory architecture underscores the therapeutic potential of co-targeting m6A writers and downstream effectors (such as OTUB2 inhibitors combined with EGFR blockade) (53,54).

The methyltransferase, KIAA1429, which complements the roles of METTL3, METTL14 and RBM1, has emerged as a dual-function modulator of viral mimicry and plasticity. As shown in Fig. 2D, KIAA1429 enhances cervical cancer tumorigenesis by modulating the m6A modification and stability of the La ribonucleoprotein 1, translational regulator mRNA in HPV⁺ models (55). KIAA1429 facilitates EMT in cervical cancer by mediating the m6A modification of BTG anti-proliferation factor 2, thereby promoting cancer cell malignancy. Silencing of KIAA1429 inhibits cervical cancer cell proliferation, migration, invasion and EMT, whilst enhancing apoptosis, highlighting its role in tumor progression (56).

Moreover, ZC3H13 cells exemplify metabolic stemness-related crosstalk. Cervical cancer samples exhibited marked upregulation of hsa_circ_0081723, with elevated levels associated with advanced histological grade, increased FIGO stage, reduced cellular differentiation and a worse prognosis. ZC3H13-mediated m6A modification of hsa_circ_0081723 facilitates cervical cancer progression via the AMPK/p53 signaling pathway. These findings suggest that the ZC3H13-hsa_circ_0081723 axis is a novel and potentially tractable therapeutic target for the clinical management of cervical cancer (57). Overexpression of ZC3H13 and cytoskeleton associated protein 2 (CKAP2) in cervical cancer is associated with an unfavorable prognosis, with ZC3H13 contributing to malignancy through the m6A modification of CKAP2, which stimulates cell proliferation, invasion and migration (58). In cervical cancer, copy number variations predominantly result in gene amplification in HR groups and deletions in low-risk groups; ZC3H13 downregulation is associated with increased proliferation and invasion of cancer cells, along with reduced RNA methylation levels. By contrast, rapamycin treatment inversely affects these cellular behaviors by increasing m6A levels, suggesting that m6A mRNA methylation is integral to cervical cancer progression and may act as a prognostic indicator and therapeutic target (59). ZC3H13-mediated m6A modification of the centromere protein K mRNA promotes cervical cancer stemness and chemoresistance (60). Additionally, rs1059288, a genetic variant of TAP binding protein (TAPBP), is associated with m6A-associated hereditary risk: It enhances TAPBP expression to promote lymph node invasion and carboplatin resistance, bridging epigenetic dysregulation with genomic instability (61). These findings highlight the complex interplay between m6A writers and cervical cancer pathogenesis and offer multiple avenues for targeted interventions.

The m6A erasers, FTO and ALKBH5, dynamically regulate cervical cancer progression by modulating distinct molecular targets and signaling networks. Their roles vary depending on the downstream pathways and cellular context, yielding dual oncogenic or tumor-suppressive effects (62–78) (Fig. 3).

FTO, the most extensively studied m6A eraser in cervical cancer, is commonly upregulated in cervical cancer tissues and is strongly associated with cervical carcinoma (62). Moreover, FTO expression is elevated in patients with HPV-positive cervical cancer, is associated with advanced FIGO stages, and is higher in cancerous tissues than in paracancerous tissues, with FTO knockdown increasing PIK3R3 m6A levels and affecting FoxO pathway activation (63). FTO is a multidimensional oncogenic driver that promotes tumorigenesis via several mechanisms. As shown in Fig. 3, the E6 and E7 oncogenes activate the transcription of GSK3B for metabolic reprogramming; glycogen synthase kinase 3β (GSK3β) can promote the ubiquitination-mediated proteasomal degradation of FTO and reduce the level of FTO protein; and FTO inhibits the maturation and translation of the HK2 mRNA by retaining the HK2 pre-mRNA in the nucleus. Therefore, E6/E7 regulates HK2 expression in cervical cancer via GSK3β/FTO signaling (64). FTO facilitates adipogenesis by regulating adipogenic pathways and inducing pre-adipocyte differentiation (65). FTO knockdown markedly suppressed xenograft tumor growth and reduced the bone morphogenetic protein 4 (BMP4) level in vivo. Collectively, the results demonstrate that FTO promotes cervical cancer progression in vitro and in vivo by regulating the BMP4/Hippo/Yes1 associated transcriptional regulator (YAP1)/WW domain containing transcription regulator 1 (TAZ) pathway, suggesting that FTO acts as an oncogenic molecule and that the FTO/BMP4 Hippo/YAP1/TAZ axis may act as a valuable target for cervical cancer treatment (66).

Furthermore, in transcriptional and post-transcriptional networks, FTO stabilizes the lncRNA, HOXC13 antisense RNA (HOXC13-AS), which recruits CBP/p300 to acetylate the frizzled class receptor 6 (FZD6) promoter, thereby epigenetically upregulating FZD6 and activating the Wnt/β-catenin signaling to drive cervical cancer proliferation, invasion and EMT. This suggests that HOXC13-AS is a potential target for cervical cancer treatment (67). Moreover, FTO demethylates E2F1, MYC and ZEB1 mRNAs, promoting the cell cycle and invasion (62,68).

ALKBH5 exhibits dual regulatory functions depending on the HPV status and target specificity in cervical carcinogenesis. Emerging evidence has revealed an oncogenic role in distinct m6A-dependent networks. In HPV-positive tumors, ALKBH5 is upregulated by E7-mediated E2F1 activation and histone H3K27Ac/H3K4Me3 modifications, leading to erasure of the m6A mark on the P21 (RAC1) activated kinase 5 (PAK5) mRNA. This demethylation stabilizes PAK5 transcripts via YTHDF2 recognition and activates RAC1/CDC42 signaling to potentiate metastasis (69). ALKBH5 further stabilizes oncogenic circCCDC134 by removing m6A marks, enabling dual pro-metastatic functions: Nuclear recruitment of p65 to enhance transcription and cytoplasmic sponging of miR-503-5p to derepress MYB expression (70). Silencing of metastasis associated lung adenocarcinoma transcript 1 decreases ALKBH5 expression via miR-141-3p, leading to reduced matrix metallopeptidase (MMP)2 and MMP9 expression and suppression of cell migration and invasion, suggesting that the MALAT-ALKBH5 axis may promote HPV-positive cervical cancer cell proliferation and metastasis (71). These findings suggest that ALKBH5 can act as a molecular rheostat tuned to viral status, with its downstream effectors (PAK5 and hypoxia inducible factor-1α) being targets for precise therapeutic intervention.

Emerging evidence have also delineated the context-dependent tumor-suppressive functions of ALKBH5 through metabolic and epigenetic regulation. In CSSC, ALKBH5 destabilizes sirtuin 3 mRNA via m6A-IGF2BP1 recognition and suppresses acetyl-CoA carboxylase α deacetylation and lipid accumulation to inhibit tumor growth, a mechanism that is inversely associated with clinical prognosis (72). Concurrently, the growth arrest specific 5 (GAS5)-AS1 lncRNA inhibits cervical cancer growth and metastasis by stabilizing GAS5 via interaction with ALKBH5 and reduction of GAS5 m6A modification, which is crucial for epigenetic regulation in cervical carcinogenesis (73). These mechanisms, including metabolic suppression and RNA stabilization, exemplify the pivotal role of ALKBH5 as a safeguard against the advancement of carcinogenesis.

The YTHDF family of proteins (YTHDF1, YTHDF2 and YTHDF3) regulate mRNA stability and translation by recognizing the m6A mark. Moreover, YTHDF1 was reported to predict unfavorable clinical outcomes in cervical cancer, which were negatively associated with CD8⁺ T-cell infiltration (74). As shown in Fig. 4, YTHDF1 drives immune evasion by stabilizing monocarboxylate transporter 1 (MCT1) mRNA to enhance lactate accumulation and upregulates RAN binding protein 2 translation to accelerate tumor growth and invasion (74,75). Its synergy with IGF2BP3 via pyruvate dehydrogenase kinase 4 (PDK4) stabilization amplifies glycolysis, establishing a metabolic vulnerability targeted by dual YTHDF1/PDK4 inhibition (76). Additionally, YTHDF2 collaborates with METTL3 to degrade the tumor suppressor NR4A1 mRNA, relieving its repression of AKT1 transcription, thereby driving malignant progression (26). YTHDF2 also mediates the METTL3-dependent degradation of circRNF13, indirectly stabilizing the pro-metastatic CXCL1 mRNA, revealing its dual role in radioresistance (38). YTHDF3 promotes lymph node metastasis via the LDL receptor related protein 6-YAP-VEGF-C axis and confers radioresistance by enhancing RAD51 paralog D translation, and its overexpression was reported to predict a poor radiotherapy response (77,78). YTHDC2 has emerged as a pan-cancer immune modulator, and its hypomethylation is associated with cytotoxic T cell exhaustion in CSSC (79). These findings suggest that reader-specific inhibitors (such as YTHDF3 antisense oligonucleotides) and reader-immune checkpoint combinations (such as the IGF2BP3/PD-L1 blockade) are precise strategies for dismantling the m6A-regulated oncogenic network.

The IGF2BP family exhibits context-dependent oncogenicity. The lncRNA interactome diversifies reader functions, in which IGF2BP1 partners with leucine rich repeat containing 75A-AS to destabilize synoviolin 1, activating NLR family pyrin domain containing 3/IL-1β/SMAD2/3 signaling. By contrast, YTHDF2 degrades the tumor suppressor lncRNA, cardiac mesoderm enhancer-associated non-coding RNA, in concert with miR-21-5p (80,81). IGF2BP2 stabilizes MYC and forkhead box M1 (FOXM1) mRNAs to drive HPV-mediated aerobic glycolysis and Rho GTPase activating protein 12-dependent metastasis (82,83), whilst IGF2BP3 hijacks lipid metabolism via stearoyl-CoA desaturase upregulation and activates glutaminolysis through glutaminase/glutamate dehydrogenase 1 stabilization, fostering the Treg-mediated immune escape (84,85). Paradoxically, Parkin-mediated ubiquitination of IGF2BP3 at K213 suppresses PI3K/MAPK signaling, underscoring its regulatory complexity (86).

HNRNP readers sculpt tumor spatial heterogeneity. HNRNPA2B1 accelerates glycolysis via lactate dehydrogenase A stabilization, whilst HNRNPC induces FOXM1 exon skipping to promote lymphatic metastasis (10,87). Clinically, EIF3A-mediated stabilization of hypoxia up-regulated 1 has been reported to be associated with cisplatin resistance, whereas the TAPBP rs1059288 risk allele (G) enhances m6A modification via METTL14/YTHDF2, which drives TAPBP overexpression and activates the JAK/STAT/major histocompatibility complex class I polypeptide-related sequence B pathway to confer multidrug resistance (61).

The m6A regulatory system exhibits context-dependent duality in function cervical cancer. For instance, YTHDF1 presents a particularly challenging paradox, highlighting the need for nuanced interpretation of the evidence. Evidence supporting a pro-tumorigenic role comes from preclinical studies, such as cell line and xenograft models, where YTHDF1 promotes tumor growth by enhancing the translational efficiency of cyclins, and its deficiency markedly suppresses tumor progression (93). However, contradictory evidence arises from clinical data analyses, which paradoxically associate elevated YTHDF1 expression with improved patient prognosis. Furthermore, whilst the preclinical evidence suggests YTHDF1 depletion attenuates tumor development (93), it unexpectedly increases cancer cell resistance to cisplatin-based chemotherapy in these models, adding another layer of complexity. This contradictory ‘pro-tumorigenic yet therapy-sensitizing’ duality observed across different experimental systems (cell lines compared with clinical cohorts) suggests phase-dependent regulatory roles of YTHDF1 across distinct stages of tumor evolution; however, further robust clinical evidence is needed to fully resolve this paradox and understand the contextual factors driving these opposing effects.

Most studies on m6A in cervical cancer are confined to preclinical models (such as cell lines and mice), representing a marked evidence gap for clinical translation. The strength of evidence supporting the predictive efficacy of m6A biomarkers is currently limited, as large-scale, multicenter cohort validations are largely lacking. Whilst several m6A regulators show promise as potential biomarkers in preliminary studies, the evidence often comes from single-center analyses or small patient cohorts, which may not be generalizable. Existing m6A-targeted inhibitors (such as STM2457 and FB23-2) have low selectivity, off-target effects and pharmacokinetic limitations, as evidenced by preclinical and early-phase studies (94). This highlights the urgent need for further preclinical development and, critically, robust clinical evidence from well-designed trials to support tissue-specific or functionally reversible intervention strategies.

The high molecular heterogeneity of cervical cancer (such as existence of HPV subtypes and immune microenvironment variations) presents a challenge for interpreting existing evidence and may dilute the predictive power of m6A biomarkers for specific subgroups. Evidence derived from bulk sequencing analyses, which are common in the field, may obscure subtype-specific or cell-type-specific m6A patterns. Integrating single-cell sequencing and spatial omics is essential for resolving cell type-specific regulatory patterns and generating more precise, context-dependent evidence for the role of m6A in cervical cancer heterogeneity.

Mao et al (95) discussed the functions, molecular mechanisms and clinical applications of m6A modification in cervical cancer. The authors particularly highlighted its regulatory role in non-coding RNAs, including circRNA, lncRNA and miRNA. Moreover, Hu et al (96) summarized the detailed mechanisms of the m6A regulatory factors on tumor cell proliferation, migration, invasion, cell cycle, apoptosis, chemotherapy resistance and sensitivity to chemotherapy. The novelty of the present review compared with previous works shows in the following ways: Firstly, it systematically dissects the cross-regulatory mechanisms between HPV oncoproteins and m6A modification networks. Secondly, in the present review, bioinformatics tools were used to performed a detailed analysis of 24 immune cell subtypes, revealing the systematic associations between m6A modification-related regulators and the characteristics of the immune microenvironment. Furthermore, the present study brings together several m6A regulators (METTL3/FTO/YTHDF1) within key signaling pathways, including the NEK2-Wnt, BMP4-Hippo and MCT1-lactate axes, to elucidate their synergistic cascade effects in driving therapeutic resistance. Concurrently, it proposes precision strategies such as METTL3 inhibition combined with PD-1 blockade, thereby establishing a distinctive systemic perspective and interventional paradigm for cervical cancer research.

m6A modification dynamically orchestrates cervical cancer progression through core regulators, such as METTL3/FTO/YTHDF1-mediated NEK2-Wnt, BMP4-Hippo and MCT1-lactate signaling networks, driving tumor proliferation, metastasis and therapy resistance. Future investigations should prioritize the development of cervical tissue-specific delivery systems for m6A inhibitors and advance the clinical validation of multi-omics biomarkers (such as m6A-circRNA/PD-L1 composite signatures). Systems pharmacology models that integrate epigenetic regulation with immunometabolic pathways may synergize METTL3-targeted agents with PD-1 blockade, potentially overcoming current therapeutic resistance mechanisms. The prognostic value of multidimensional biomarker panels and the therapeutic potential of combination strategies (such as anti-METTL3 + PD-1 inhibitors) offer novel paradigms for clinical translation. In particular, future research should focus on the following: i) Spatiotemporal mapping of the HPV-host m6A interplay; ii) the development of precision tools targeting m6A-dependent networks (subtype-specific proteolysis targeting chimeras and CRISPR-dCas9-based epitranscriptome editing) (97). By integrating these advancements, an epigenetic, metabolic and immune therapeutic framework could redefine precision oncology in cervical cancer. CRISPR-based epitranscriptome editing enables precise m6A modulation of HPV-derived oncogenic transcripts, whereas third-generation liquid biopsy platforms facilitate dynamic monitoring of m6A-modified circRNAs to optimize personalized therapeutic strategies (98); and iii) advancements in liquid biopsy techniques and biomarker-driven clinical trials are revolutionizing cancer diagnostics and therapeutic monitoring. Liquid biopsy platforms for m6A-circRNAs directly decode methylation patterns in biofluids, facilitating dynamic monitoring of therapy and early detection of resistance (70,98–100). The integration of these technologies would provide a closed-loop precision medicine framework that combines targeted epitranscriptomic manipulation with real-time molecular surveillance.