Reciprocal regulation between m6 A modifications and non-coding RNAs: emerging roles in cancer therapeutic resistance.

Introduction

Cancer stands as one of the most pressing and widespread public health challenges globally, significantly impacting morbidity, mortality, and quality of life across diverse populations [ 1 ]. Despite significant advancements in treatment protocols, encompassing innovations in radiotherapy, chemotherapy, targeted therapy, and immunotherapy, a subset of patients continues to confront unfavorable prognoses due to therapeutic resistance [ 2 ]. Understanding the molecular mechanisms underlying therapeutic resistance is therefore crucial for improving treatment efficacy. The mechanisms driving tumor resistance are highly diverse and encompass both genetic and non-genetic factors. Among the non-genetic pathways, epigenetic alterations, which entail inheritable modifications in gene expression patterns without any changes in the underlying DNA sequence, play a pivotal role in the emergence and progression of therapeutic resistance [ 3 ]. Epigenetic is regulated by various factors including DNA methylation, histone modifications, non-coding RNA regulation, chromatin remodeling, and nucleosome localization [ 4 ]. A burgeoning field within epigenetic research is the exploration of RNA modifications, a domain that has identified over 100 distinct types to date. These modifications play crucial roles in regulating gene expression, protein synthesis, and cellular function, thereby contributing significantly to the complex landscape of epigenetic regulation [ 5 ].

Among these, N6-methyladenosine (m6 A) is one of the most prevalent and conserved internal modifications in mammalian mRNA, initially identified in 1974 [ 6 ]. m6 A denotes the methylation that occurs at the sixth nitrogen atom of adenine within an RNA molecule, a modification frequently observed in coding sequences and 3′-untranslated regions (3′-UTRs), particularly in proximity to the stop codon. This process is finely tuned by a diverse array of regulatory proteins [ 7 , 8 ]. Recent studies have suggested that m6 A modification stabilizes oncogenes and enhances the expression of drug-resistant genes, enabling cancer cells to evade the effects of commonly used therapies [ 9 ]. As a result, m6 A modification has emerged as a potential biomarker for predicting cancer treatment outcomes. By analyzing m6 A profiles in tumors, clinicians may be able to identify patients who are more likely to respond to specific therapies, such as chemotherapy or targeted treatments. In addition to mRNA, m6 A modifications are also prevalent in non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), PIWI interacting RNAs (piRNAs) and small nuclear RNAs (snRNAs). These modifications exert significant influence on their metabolic processes, encompassing splicing, transcription, translation, and degradation [ 10 ]. Similarly to m6 A, ncRNAs contribute to chemoresistance through various mechanisms. For example, ncRNAs regulate chemotherapeutic drug efflux pumps, apoptosis-related proteins, epithelial-mesenchymal transition (EMT), and miRNA sponging [ 11 – 13 ]. These findings not only improve our understanding of resistance mechanisms but also suggest m6 A modification and ncRNAs as potential biomarkers for predicting chemotherapy response and prognosis. Emerging studies reveal that non-coding RNAs (ncRNAs) and m6 A modifications engage in cross-regulatory interactions, significantly contributing to pathological processes, particularly cancer development [ 14 – 17 ]. This mutual regulation between m6 A and ncRNAs has emerged as a critical factor in cancer therapeutic resistance.

Despite the growing evidence highlighting the interaction between m6 A modifications and ncRNAs in cancer drug resistance, several critical gaps remain. First, the precise mechanisms by which m6 A-ncRNA interactions dynamically modulate key signaling pathways to drive drug resistance are not fully understood. In addition, the potential of targeting m6 A-ncRNA networks to overcome drug resistance has not been comprehensively evaluated, particularly in terms of clinical translation. In this review, we discuss the mechanisms and functions of m6 A modification and ncRNAs, with a particular emphasis on their mutual regulation. Furthermore, we spotlight several canonical signaling pathways, namely MAPK signaling, PI3 K/Akt/mTOR signaling, Wnt/β-catenin signaling, Hippo signaling, and NF-κB signaling, to elucidate the intricate dynamics between m6 A and ncRNAs in the context of cancer therapeutic resistance and provide new insights for clinical translation.

Dynamic regulation of m6 A

The m6 A modification process is dynamic and reversible, involving three key elements: “writers” (m6 A methyltransferases), “erasers” (m6 A demethylases), and “readers” (binding proteins that recognize m6 A modifications and regulate RNA fate). The enzymes known as writers, notably METTL3 and METTL14, facilitate the methylation process [ 18 ]. METTL3, which serves as the catalytic subunit, forms a robust methyltransferase complex with METTL14, the latter acting as an RNA-binding platform. In vivo, the m6 A methyltransferase activity necessitates the presence of WTAP, which functions as a regulatory subunit within the m6 A methyltransferase complex [ 19 ]. Additionally, several other proteins possessing methyltransferase activity, including METTL5, METTL16, RBM15, ZC3H13, and KIAA1429, also play pivotal roles in the modification of m6 A [ 20 – 24 ]. The erasers, in contrast to the writers, are responsible for the removal of m6 A marks. Currently, only two demethylases have been characterized as m6 A erasers: FTO and ALKBH5. FTO has been implicated in the regulation of adipogenesis and tumor development through its modulation of m6 A levels [ 25 ]. Meanwhile, ALKBH5, the second identified m6 A demethylase, plays a crucial role in governing a wide array of biological processes within tumors, encompassing proliferation, invasion, migration, and apoptosis [ 26 ].

The m6 A reader proteins are responsible for recognizing and binding to m6 A-modified transcripts, thereby regulating the fate of mRNA. These readers can be classified into three distinct groups: (1) YTH domain-containing proteins, which include YTHDF1-3 and YTHDC1-2 [ 27 ]. Among these, YTHDF2 is the most extensively studied and plays a crucial role in the development of various human diseases. Dysregulation of YTHDF2 can either promote or inhibit cancer, as well as lead to abnormalities in hematopoietic stem cell renewal, differentiation, and reproductive capacity [ 24 ]. YTHDF1 is important in the tumor microenvironment (TME) and participates in immune regulation [ 28 ]. YTHDF3 enhances the stability and translational efficiency of target gene transcripts [ 29 ]. YTHDC1 modulates mRNA splicing and nuclear export, thereby influencing cell proliferation and activation [ 30 ]. (2) Heterogeneous nuclear ribonucleoproteins (HNRNPs), which encompass HNRNPC, HNRNPG, and HNRNPA2B1. The HNRNP family is involved in disease development by modulating target biogenesis. In breast cancer cells, HNRNPC controls the translation of its 3′ UTR-bound regulon, further impacting the metastatic capacity of these cells [ 31 ]. HNRNPG interacts with m6 A-modified nascent pre-mRNA and the phosphorylated C-terminal domain of RNA polymerase II to regulate alternative splicing [ 32 ]. Recent studies have also shown that HNRNPA2B1 selectively mediates the nuclear export of m6 A-tagged mRNAs, facilitating breast cancer development [ 33 ]. (3) Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs), including IGF2BP1, IGF2BP2, and IGF2BP3. These proteins enhance the stability of m6 A-modified mRNA, contributing to cancer progression, heart diseases, and hematopoiesis [ 34 – 36 ] (Fig. 1 ).

Mutual regulation between m6 A modification and ncRNAs

Mutual regulation of miRNAs and m 6 A modification

microRNAs are a class of small endogenous RNAs, typically ranging from 20 to 24 nucleotides in length. Most microRNAs require precise processing steps to become mature fragments with functions in regulating gene expression. Initially, the primary miRNA (pri-miRNA) transcripts are recognized and cleaved in the nucleus by the microprocessor complex, which is composed of RNase III-Drosha and its obligatory partner protein DGCR8, resulting in the formation of precursor miRNA (pre-miRNA) [ 37 ]. Afterwards, the pre-miRNA is transported from the nucleus to the cytoplasm by the nuclear export protein exportin-5. In the cytoplasm, it undergoes further processing by the RNase III enzyme Dicer, resulting in the formation of RNA double-stranded intermediates. Subsequently, one of the strands of the double-stranded mature miRNA is rapidly degraded, while the other strand is incorporated into the AGO2 protein to form the RNA-induced silencing complex (RISC). This process ultimately yields a mature, functional single-stranded miRNA [ 38 ]. Functionally, miRNAs are believed to regulate gene expression by controlling the cleavage of target mRNAs or suppressing the translation of target genes post-transcription, exerting crucial regulatory effects on various biological processes, including cellular aging and disease development [ 39 ]. Recent research has shown that miRNAs are also susceptible to m6 A modification, with m6 A writers, readers, and erasers involved in the regulation of miRNA maturation, export, stabilization, and degradation.

In 2015, m6 A was identified as a novel regulator of miRNA processing, where it functions to recognize pri-miRNA sequences and designate the initiating steps in miRNA biogenesis, thereby facilitating the progression of miRNA maturation [ 40 , 41 ] (Fig. 2 ). As previously reported, the m6 A writer METTL3 facilitates DGCR8's recognition of pri-miRNA and promotes subsequent m6 A-dependent processing of mature miRNAs, including miR-BART3-3p, miRNA-126, miRNA-193a, miRNA-196b, miR-126-5p, and miRNA-221/222 [ 42 – 47 ]. In addition to its interaction with DGCR8 to facilitate pri-miRNA processing, METTL3 has also been proven to promote miRNA biogenesis by enhancing the Dicer splicing of pre-miRNA [ 48 ]. Similarly, METTL14 also promotes DGCR8-mediated pri-miRNA processing and maturation in an m6 A-dependent manner. A recent study, for instance, revealed that m6 A modification mediated by METTL14 orchestrates the conversion of pri-miR-146a-5p into miR-146a-5p. Mechanistically, METTL4 elevates the m6 A modification on pri-miR-146a-5p, thereby enhancing DGCR8 recognition and subsequently promoting the maturation of pri-miR-146a-5p [ 49 ].

m6 A erasers are also involved in regulating miRNA maturation processing. Zhou et al. demonstrated that FTO regulates the maturation of miR-576 in an m6 A-dependent manner, which in turn drives bladder cancer proliferation through the FTO/miR-576/CDK6 pathway [ 50 ]. Additionally, in breast cancer, FTO recruits DGCR in an HNRNPA2B1-dependent manner to regulate the maturation process of pri-miR-17 in triple-negative breast cancer cells, leading to depletion of zinc finger and BTB domain-containing protein 4 (ZBTB4) [ 51 ]. Another m6 A eraser, ALKBH5, negatively orchestrate the m6 A modification of miR-193a-3p, blocking primary miR-193a-3p processing and affecting the proliferation, migration and invasion ability of esophageal squamous cell carcinoma (ESCC) cells [ 52 ].

m6 A readers likewise exert crucial functions in the regulation of miRNA maturation processes. YTHDF2 is aberrantly expressed in acute myeloid leukemia (AML) and targets miR-126 in an m6 A-dependent manner, promoting its expression, and consequently AML progression [ 53 ]. Furthermore, YTHDC1 facilitates the degradation of pri-miR-30 d and its subsequent processing into mature miRNA, ultimately suppressing pancreatic tumorigenesis through the miR-30 d/RUNX1/SLC2 A1/HK1 axis [ 54 ]. HNRNP family members are also involved in regulating miRNA maturation processing. For instance, HNRNPA2B1 facilitates pri-miR-93 maturation by recruiting DGCR8 in prostate cancer, while HNRNPA1 interacts with the terminal loop of pri-miR-18a to enhance Drosha activity, promoting its processing and maturation [ 55 , 56 ]. AALKBH5 recognizes m6 A-methylated pre-miR-181a and promotes its degradation, thereby impairing miR-181b-1 maturation and subsequently suppressing osteosarcoma progression [ 57 ]. In addition to regulating miRNA maturation, m6 A regulators have also been implicated in modulating miRNA degradation. METTL3-mediated m6 A modification stabilizes microRNA-675, accelerating gastrointestinal stromal tumor (GIST) progression [ 58 ]. Conversely, METTL14-mediated m6 A modification promotes the stability of pri-miR-17 mRNA in a YTHDC2-recognized manner, enhancing its expression [ 59 ].

Interestingly, miRNAs play a pivotal role in the proliferation, migration, and invasion of various cancers by targeting m6 A regulatory components. Specifically, METTL3 is implicated in the proliferation, migration, and infiltration of numerous tumors, and miRNAs regulate tumor progression by targeting METTL3. For example, in prostate cancer, miR-320 d targets METTL3, reducing its expression and limiting malignant behaviors like proliferation and invasion [ 60 ]. Similarly, in cervical cancer, miR-30c-5p inhibits METTL3, reducing the m6 A level of the apoptosis-related gene KRAS and subsequently decreasing KRAS expression to inhibit tumor growth and metastasis [ 61 ]. In pancreatic cancer, miR-33a-3p regulates the stability of AREG mRNA by directly targeting the 3′-UTR of METTL3 and downregulating its expression, thus suppressing cancer invasion and metastasis [ 62 ]. In hepatoblastoma, miR-186 directly targets METTL3 and negatively regulates its expression to modulate cancer progression via the Wnt/β-catenin signaling pathway [ 63 ]. Additionally, other m6 A writers, such as METTL14, are also regulated by miRNAs. MiR-26a-5p directly degrades METTL14, inhibiting METTL14-induced apoptosis via the METTL14/NLRP3 pathway in the nucleus pulposus [ 64 ]. ZC3H13, which is associated with poor prognosis and immune infiltration in hepatocellular carcinoma, is negatively regulated by miR-362-3p and miR-425-5p, which target the 3′-UTR of ZC3H13 [ 65 ].

miRNAs also play a critical role in regulating m6 A erasers. For instance, miR-96 inhibits colorectal cancer (CRC) by targeting FTO and blocking its m6 A-mediated modification of MYC [ 66 ]. In prostate cancer (PC), miR-141-3p promotes cancer progression by downregulating ALKBH5, leading to elevated PRMT6 levels [ 67 ]. Intriguingly, miRNAs have been shown to regulate m6 A readers, such as YTHDF2 and YTHDF1, affecting tumor development and various cellular functions. For example, miR-6125 enhances the stability of GSK3β mRNA by targeting and downregulating YTHDF2, inhibiting CRC growth via the Wnt/β-catenin pathway [ 68 ]. Similarly, miR-145 directly targets 3′-UTR of YTHDF2 mRNA and downregulates YTHDF2 in HepG2 cells, suppressing proliferation of HCC cells [ 69 ]. Additionally, miR-145 inhibits YTHDF2 expression, which promotes the proliferation and migration of ovarian cancer cells [ 70 ]. In glioma, hsa-miR-346 binds to the 3'UTR of YTHDF1 and negatively regulates its expression, impacting patient prognosis [ 71 ]. Moreover, miR-16-5p interacts with the 3'UTR of YTHDF1 mRNA, inhibiting its expression and reversing the oncogenic role of YTHDF1 in breast cancer [ 72 ].

In conclusion, m6 A regulators (writers, erasers, readers) control miRNA processing, affecting cancer progression by modulating oncogenic or tumor-suppressive miRNAs. Conversely, miRNAs target m6 A machinery, forming feedback loops in cancers like leukemia, bladder cancer, and pancreatic cancer. The m6 A-miRNA regulatory axis represents a promising target for cancer therapy, with significant clinical translation potential.

Mutual regulation of lncRNAs and m6 A modification

Long non-coding RNAs (lncRNAs) constitute a class of transcripts exceeding 200 nucleotides in length but not encoding proteins [ 73 ]. Extensive research has elucidated their pivotal roles in gene expression regulation through interactions with both proteins and nucleic acids within both the nucleus and cytoplasm. These interactions empower lncRNAs to control genomic/epigenomic regulation, profoundly affecting cell differentiation, proliferation and apoptosis. Recent findings reveal that lncRNAs undergo m6 A modification, which is instrumental in regulating their stability, degradation, and functional roles, subsequently affecting numerous physiological processes [ 74 ]. Notably, lncRNAs also target m6 A regulatory factors. The intricate and dynamic interplay between lncRNAs and m6 A modification is especially vital in disease progression.

m6 A modifications mediate various diseases progression by regulating lncRNAs stability and degradation (Fig. 3 ). For example, METTL3 catalyzes the m6 A modification of the TERRA subtelomeric region, thereby regulating its stability and subsequently preserving telomere stability within cancer cells [ 75 ]. In prostate cancer, METTL3 mediates m6 A modification of the lncRNA SNHGH7 and enhances its stability. Consequently, SNHG7 facilitates glycolysis by recruiting SRSF1 to modulate c-Myc expression [ 76 ]. Similarly, METTL3 stabilizes SCIRT in non-small cell lung cancer through m6 A modification, amplifying its role in NSCLC progression. [ 77 ]. In addition to METTL3, other m6 A writers like METTL14 and WTAP also play key roles in regulating lncRNA stability. METTL14 upregulates the stability of lnc-PLCB1 in an m6 A -YTHDF2-dependent manner, which is crucial in inhibiting Helicobacter pylori-induced gastric cancer [ 78 ]. WTAP, an essential cofactor in the m6 A methylation complex, stabilizes DIAPH1-AS1 through an IGF2BP2-dependent pathway, promoting nasopharyngeal cancer growth and metastasis [ 79 ]. ZCCHC4, a recently identified m6 A writer, also plays a role in regulating lncRNA stability. Overexpression of ZCCHC4 accelerates the degradation of lnc-GHRLOS transcripts, thereby modulating their stability and ultimately promoting proliferation and metastasis in colorectal cancer cells [ 80 ].

m6 A erasers, such as ALKBH5, play an equally important role in modulating the stability and degradation of lncRNAs. For example, ALKBH5-mediated reduction of TP53 TG1 m6 A modifications destabilizes the transcript, inhibiting gastric cancer development [ 81 ]. ALKBH5 also regulates the stability of lnc-KCNQ1OT1 in an m6 A—YTHDF2-dependent manner, which in turn influences HOXA9 expression, contributing to LSCC proliferation, invasion, and metastasis [ 82 ]. In addition, ALKBH5 modulates LINC02551 degradation in hepatocellular carcinoma through IGF2BP1 recognition, further promoting hepatocellular carcinoma growth and metastasis [ 83 ]. FTO, another eraser, mediates m6 A-dependent degradation of SNHG14, with consequent downregulation of its expression and suppression of autophagic activity [ 84 ]. Simultaneously, m6 A readers play a pivotal role in cancer progression by finely tuning the stability and degradation of lncRNAs. For instance, YTHDC1 binds to m6 A-modified LINC00294 and positively regulates its stability, accelerating HCC cell proliferation and reduce the apoptosis and glycolysis process [ 85 ]. Meanwhile, YTHDF1 bolsters the stability and expression of LINC00900, enhancing the viability, invasion, and self-renewal capabilities of glioma stem cells [ 86 ]. Likewise, IGF2BP3, the member of the IGF2BPs protein family, acts as an m6 A reader and amplifies the oncogenic effects of KCNMB2-AS1, promoting cervical cancer growth by blocking the degradation and positively regulating the expression of lncRNA-KCNMB2-AS1 [ 87 ].

lncRNAs serve as competitive endogenous RNAs (ceRNAs) that competitively bind miRNAs, effectively regulating the expression of miRNA-targeted genes. The ceRNA regulatory network, first proposed by Pier Paolo Pandolfi's team in 2011, represents a novel paradigm in gene expression regulation [ 88 ]. This model entails competition among ceRNA molecules, including mRNAs, lncRNAs, and circRNAs, for binding to miRNAs via shared microRNA response elements (MREs), ultimately influencing miRNA-mediated gene regulation [ 88 ]. This network is crucial for maintaining normal physiological processes and plays a critical role in disease progression.

Recent research has uncovered that m6 A modification profoundly impacts the lncRNA-mediated ceRNA network, particularly in the context of tumorigenesis. For instance, in colon cancer, METTL3-mediated m6 A modification promotes colorectal cancer progression by downregulating LINC02038 in a YTHDF2-dependent manner. Mechanistically, LINC02038 acts as a sponge for miR-552-5p, which leads to regulation of the FAM172 A/PI3 K/AKT pathway and subsequent inhibition of colorectal cancer progression [ 89 ]. Similarly, LINC01599 functions as a sponge for miR-106b-5p, regulating the miR-106b-5p/PTEN axis to suppress colorectal cancer progression, with its m6 A modification sites directly regulated by METTL3 [ 90 ].

In non-small cell lung cancer (NSCLC), FEZF1-AS1 serves as a ceRNA by sponging miR-516b-5p, which regulates ITGA11 expression. This process is positively regulated by m6 A methylation, which enhances FEZF1-AS1 stability [ 91 ]. I In hepatocellular carcinoma, LINC00958 upregulates the expression of hepatocellular carcinoma-derived growth factor (HDGF) through sponging miR-3619-5p, consequently promoting the formation and progression of HCC, with METTL3 playing a key role in increasing LINC00958 stability [ 92 ]. In pancreatic cancer, LINC00857, which is highly enriched with m6 A modifications, acts as a ceRNA for miR-150-5p, upregulating the target gene E2 F3 and regulating the proliferation and apoptosis of pancreatic cancer cells [ 93 ]. In melanoma, the lncRNA SNHG3 functions as a miR-330-5p sponge, promoting tumor invasion and proliferation by upregulating CCHC-type zinc finger nucleic acid binding protein (CNBP) [ 94 ].

Correspondingly, the activities of the m6 A writers, erasers and readers can be finely tuned by lncRNAs to actively participate in diverse cellular processes. For instance, SLC2 A1-DT-induced upregulation of β-catenin stimulates c-Myc expression, subsequently enhancing METTL3 expression through activation of METTL3 transcription. This creates a feedback loop that promotes glycolysis and contributes to the development of hepatocellular carcinoma (HCC) [ 95 ]. Conversely, knockdown of LINC00858 reduces FTO expression, resulting in elevated m6 A modification of MYC. This modification inhibits malignant behavior and triggers apoptosis in esophageal squamous cell carcinoma [ 96 ]. Additionally, the lncRNA lnc-H2 AFV-1 plays a role in head and neck squamous cell carcinoma progression by regulating both the m6 A writers METTL3/14 and the eraser FTO. This regulation alters m6 A modifications on target genes like IFT80, which ultimately facilitates oncogenic processes [ 97 ]. Furthermore, lncRNAs have been shown to influence m6 A readers. As an example, for instance, LINRIS interacts with and protects IGFBP2 from autophagic degradation, resulting in maintained stability of the downstream glycolysis regulator c-Myc mRNA and consequently promoting colorectal cancer progression [ 98 ]. Another instance is MALAT1, which upregulates IGF2BP2 expression, leading to increased MYC expression and promoting proliferation, migration, and invasion of thyroid cancer cells [ 99 ].

In summary, m6 A regulators (writers, erasers, readers) control lncRNA stability and degradation, directly shaping the lncRNA-mediated ceRNA network and its biological functions. Reciprocally, lncRNAs modulate m6 A enzyme activity, forming feedback loops that drive cancer progression through sustained gene dysregulation. Targeting these interactions, we may develop targeted therapies for cancer and related diseases by blocking cancer-promoting pathways or activating tumor-suppressing pathways.

Mutual regulation of circRNAs and m6 A modification

Circular RNAs (circRNAs) represent a distinct category of RNA molecules that are formed through the back-splicing of pre-mRNA, devoid of both the 5’ cap and the 3’ poly (A) tail [ 100 ]. Due to its circular structure, circRNA exhibits greater stability than linear RNA and is resistant to degradation by RNA nucleases [ 101 ]. While the majority of circRNAs are abundantly present in the cytoplasm, a minor fraction can be detected in the nucleus [ 102 ]. These circRNAs exhibit a diverse array of regulatory roles, including functioning as competitive endogenous RNAs that sequester miRNAs, thereby modulating the expression of downstream target genes. They also act as transcription regulators and protein scaffolds to exert their regulatory effects [ 103 ]. Intriguingly, in certain instances, circRNAs may even possess coding potential [ 104 ].

Remarkably, m6 A modifications and circRNAs engage in a mutual regulatory relationship, influencing crucial processes like circRNAs biogenesis, translation, nuclear export, and degradation (Fig. 4 ):

Generation of circRNAs: m6 A methylation has been implicated in the formation of circRNAs across various cancers. For example, in colorectal and pancreatic ductal carcinomas, METTL3 regulates circRNA biogenesis through binding to flanking sequences, thereby contributing to tumor progression [ 105 , 106 ]. In non-small cell lung carcinoma, METTL3 mediates m6 A modification of circIGF2BP3, enabling its reverse splicing and circularization in a YTHDC1-dependent manner, which enhances immune evasion by promoting PD-L1 deubiquitination [ 107 ]. In prostate cancer, WTAP modulates m6 A modification, influencing pre-mRNA splicing and the formation of circDDIT4, driving cancer development [ 108 ]. In hepatocellular carcinoma, the m6 A reader YTHDC1 stimulates circRNAs reverse splicing and biogenesis, promoting hepatocarcinogenesis [ 109 , 110 ]. In chronic lymphocytic leukemia (CLL), RBMX and YTHDC1 regulate CLL progression by binding to the flanking sequences of circTET2, jointly facilitating the splicing and recycling of exon 3 to form circTET2 [ 111 ].

Translation of circRNAs: Although circRNAs are generally considered non-coding, certain cytoplasmic circRNAs possess translation capabilities. Two primary translation mechanisms have been identified: one is driven by internal ribosome entry sites (IRES), and the other is initiated by m6 A modification [ 112 , 113 ]. The latter is dependent on YTHDF3 and eIF4G2 for translation initiation [ 113 ]. In colorectal cancer with liver metastases, circYAP recruits the eIF4G2 translation initiation complex via YTHDF3, efficiently initiating its translation [ 114 ]. Dattilo et al. reported that m6 A modification drives cap-independent translation of circ-ZNF609 through recognition by YTHDF3 and eIF4G2, which subsequently regulates circ-ZNF609 metabolism [ 115 ].

Cytoplasmic Export of circRNAs: circRNAs are predominantly localized in the cytoplasm, highlighting the importance of efficient nuclear export mechanisms. METTL3 has been demonstrated to facilitate the cytoplasmic export of m6 A-modified circTEAD1, resulting in promotion of chordoma tumorigenesis [ 116 ]. In ovarian cancer, YTHDC1 promotes the cytoplasmic translocation of has-circ-0061179 by directly binding to its m6 A modification site, further impacting DNA damage and apoptosis [ 117 ]. Similarly, in hepatocellular carcinoma, YTHDC1 interacts with has-circ-0058493 to promote its cytoplasmic export, accelerating disease progression [ 118 ]. Additionally, HNRNPC mediates the cytoplasmic export of m6 A-modified circMARK2, which stabilizes LIN28B mRNA and contributes to Wilms tumor development [ 119 ].

Degradation of circRNAs: circRNAs are more stable than linear RNAs due to their closed-loop structure, and the mechanisms underlying their degradation are not well understood. Recent research has implicated YTHDF2 in circRNAs degradation. Specifically, YTHDF2 recruits the adaptor protein HRSP12 and the RNase-P/MRP complex (endoribonucleases) to the circRNAs by recognizing the m6 A site, ultimately leading to the degradation of m6 A-modified circRNAs [ 120 – 122 ]. Equally important, YTHDC1 is crucial for maintaining trophoblast activity and placental function by promoting m6 A-mediated circMPP1 degradation [ 123 ]. Conversely, FTO protects circRNAs from degradation by removing m6 A modifications, as exemplified by circFAM192 A, where FTO reduces YTHDF2-dependent recognition and subsequent degradation [ 124 ]. Beyond these effects, m6 A modification can also regulate the ceRNA function of circRNAs. For instance, m6 A modification enhances the binding of circALG1 to miR-342-5p, promoting its ceRNA activity and thereby increasing the migration and invasion of colorectal cancer cells [ 125 ].

Conversely, circRNAs also play a pivotal role in regulating the expression of m6 A regulatory proteins, thereby contributing to disease development. For instance, the downregulation of circRERE expression promotes hepatocellular carcinoma progression by elevating m6 A levels of GBX2, which in turn enhances GBX2 expression through the upregulation of the methyltransferase ZC3H13 [ 126 ]. Similarly, circ-0001187 functions as a sponge for miR-499a-5p, leading to increased expression of the E3 ubiquitin ligase RNF113 A. This enzyme mediates the ubiquitin/proteasome-dependent degradation of METTL3, leading to the suppression of acute myeloid leukemia [ 127 ]. In another example, circRNF13 promotes malignant progression of oral cancer could by enhancing ITGB1 mRNA stability through enhancing IGF2BP1 stability [ 128 ].

circRNAs also have a significant impact on targeting and regulating m6 A erasers. For example, circRAB11 FIP1 directly binds to FTO mRNA and enhances its expression, thereby regulating the m6 A methylation of ATG5 and ATG7 mRNA, which are key regulators of autophagy [ 129 ]. In a different context, circGDI2 reduces m6 A levels by stabilizing FTO protein, which ultimately inhibits proliferation and migration in oral squamous cell carcinoma cells [ 130 ]. Additionally, circ-0005615 upregulates m6 A levels of MAP3 K4 by decreasing ALKBH5, leading to suppressed MAP3 K4 expression and enhanced multiple myeloma progression [ 131 ].

Furthermore, circRNAs can influence m6 A readers by acting as miRNA sponges. For instance, circMAP2 K4 functions as a sponge for has-miR-1395p, promoting the expression of YTHDF1 and thereby stimulating the proliferation of hepatocellular carcinoma cells [ 132 ].. Similarly, circBACH2 (has-circ-0001625) sponges has-miR-944 to promote breast cancer cell proliferation by stimulating HNRNPC expression via the MAPK signaling pathway [ 133 ]. Moreover, circRNAs also target the IGF2BP family to regulate m6 A modification levels. CircNDUFB2 reduces the stability of IGF2BPs through a ubiquitin/proteasome-dependent pathway, effectively inhibiting non-small cell lung cancer growth and metastasis [ 134 ]. Lastly, circPTPRA interacts with the KH3 and KH4 structural domains of IGF2BP1, blocking its recognition of downstream m6 A-modified mRNAs and inhibiting bladder cancer progression [ 135 ].

Overall, the m6 A writers, erasers, and readers regulate circRNA biogenesis through well-characterized pathways, including generation, translation, cytoplasmic export, and degradation. Conversely, circRNAs regulate m6 A regulators via two mechanistically distinct pathways: (1) direct binding to m6 A-modified sites on downstream target genes to alter their modification patterns. (2) indirect miRNA sponging that subsequently affects m6 A enzyme activity or substrate availability. In cancer, this intricate interplay between circRNAs and m6 A modification prompts further investigation into their inter-regulatory mechanisms, offering new perspectives for therapeutic strategies.

Mutual regulation of other ncRNAs and m6 A modification

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a novel class of small regulatory RNAs (24–31 nt) that are evolutionarily conserved across multiple species [ 136 ]. Functionally, piRNAs primarily bind to the PIWI subfamily of Argonaute proteins, mediating gene silencing, transposon suppression, and germline genome stability maintenance [ 137 ]. Mechanistically, the PIWI/piRNA complex can facilitate epigenetic regulation through recruiting modulatory enzymes such as m6 A methyltransferase [ 138 ]. Recent studies have shown that piRNAs play a role in regulating m6 A methylation levels and are involved in cancer progression. piRNA-31106 promotes the malignant behavior of breast cancer cells by increasing the level of METTL3-mediated m6 A methylation [ 139 ]. Similarly, in triple-negative breast cancer, piR-31115 increases the m6 A level of cancer cells via METTL3 of YAP, which promotes cancer cell proliferation and migration [ 140 ]. piRNA-17458 targets the 3'-UTR of WTAP and increases its stability, thereby contributing to cervical cancer cell proliferation [ 141 ], while piRNA-14633 upregulates METTL14 expression by stabilizing its mRNA, activating the METTL14/CYP1B1 axis to enhance cervical cancer invasion [ 142 ]. Contrastingly, piR-26441 increases YTHDC1 protein levels by decreasing YTHDC1 ubiquitination, which in turn inhibits tumor growth and mitochondrial metabolism via the YTHDC1/TSFM axis [ 143 ]. Notably, exosome-derived piR-17560 from senescent neutrophils enhances FTO-mediated m6 A demethylation in breast cancer. The upregulation of FTO subsequently increases the stability of ZEBI transcripts, conferring chemoresistance to tumor cells [ 144 ]. Structurally distinct from piRNAs, small nuclear RNAs (snRNAs) (~ 150 nt) are essential components of the spliceosome that catalyze pre-mRNA splicing [ 132 ]. Studies have shown that m6 A modifications exist on snRNAs and are widely implicated in cancer progression. For instance, NORD9 binds and stabilizes METTL3 while simultaneously recognizing m6 A sites on NFYA mRNA in an IGFBP2-dependent manner, upregulating the expression of NFYA proteins and driving ovarian cancer progression [ 145 ].

In summary, the mutual regulation between ncRNAs and m6 A modification is crucial in disease progression. m6 A modifications influence ncRNAs biogenesis, cytoplasmic export, translation, stability, and degradation, while ncRNAs regulate the expression of m6 A writers, erasers, and readers, thereby modulating the m6 A status of downstream target genes and contributing to disease development (Table 1 ).

Clinical application of ncRNA-m6 A interplay in cancer therapeutic resistance

Therapeutic resistance remains a major hurdle in cancer treatment, driven by intricate mechanisms. Recent research underscores the pivotal role of the interplay between ncRNAs and m6 A in the emergence of therapeutic resistance. Dysregulation of both ncRNAs and m6 A has been implicated in this process, as they modulate the expression of crucial therapeutic resistance genes via various signaling pathways [ 147 – 149 ] (Table 2 ).

MAPK signaling pathway

Mitogen-activated protein kinases (MAPKs) are a highly conserved family of serine/threonine protein kinases associated with key cellular processes, including cell proliferation, differentiation, and apoptosis, as well as tumorigenesis and development [ 150 ]. There are four major subfamilies of the MAPK signaling pathway: extracellular signal-regulated kinase (ERK, MAPK), C-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38, MAPK) and extracellular signal-regulated kinase 5 (ERK5) [ 151 ]. In recent years, studies have confirmed that abnormal activation of specific proteins within the MAPK signaling pathway contributes to resistance in cancer therapy [ 152 ]. A prominent example is BRAF mutant melanoma, where constitutive MAPK pathway activation drives tumor progression. Clinical trials demonstrate that combined inhibition of MEK (trametinib) and BRAF (dabrafenib) significantly improves outcomes in BRAF V600-mutated stage III melanoma, with hazard ratios of 0.52 for relapse/death and 0.56 for distant metastasis/death. Trametinib (MEK inhibitor) in combination with darafenib (BRAF inhibitor) result in durable recurrence-free survival (hazard ratio for relapse or death, 0.52) and distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56) with BRAF V600-mutated stage III melanoma [ 153 ]. This study evidence solidifies clinical importance of MAPK-targeted therapy. Indeed, mounting evidence indicates that ncRNAs harboring m6 A modifications can directly interact with components of the MAPK signaling pathway, orchestrating a pivotal role in tumor resistance through this crosstalk mechanism.

In gastric cancer, METTL14-mediated m6 A modification of circUGGT2 promotes cisplatin resistance by sponging miR-186-3p and subsequently upregulating mitogen-activated protein kinase kinase kinase 9 (MAP3 K9) [ 154 ]. In lung adenocarcinoma, circASK1 encodes ASK1-272a.a. to enhance the sensitivity of LUAD cells to gefitinib by activating the ASK1/JNK/p38.

pathway and triggering apoptosis. Conversely, in gefitinib-resistant cells, elevated YTHDF2-mediated degradation of m6 A-modified circASK1 leads to reduced expression, thereby contributing to drug resistance [ 155 ]. In hepatocellular carcinoma, lnc RNA DUXAP8, stabilized by m6 A methylation, promotes HCC chemoresistance by competitively binding miR-584-5p to target MAPK1, thus activating the MAPK/ERK pathway [ 156 ]. In colorectal cancer, the expression of lncRNA ADIRF-AS1 and AL139035.1 is modulated by m6 A modification levels, which in turn regulate the expression of genes associated with the MAPK signaling pathway, including target genes FOS and Dual Specificity Phosphatase (DUSP). This regulatory mechanism plays a role in 5-FU resistance and the progression of CRC [ 157 ] (Table 2 ).

PI3 K/Akt/mTOR signal pathway

The PI3 K/AKT/mTOR (PAM) signaling is an important pathway in eukaryotic cells of cell survival, proliferation, and apoptosis, comprising three effector molecules, PI3 kinase (PI3 K), protein kinase B (Akt), and mammalian target of rapamycin-like protein (mTOR) [ 158 ]. Dysregulation of this pathway has been extensively linked to human cancers, where it drives tumor migration, invasion, and resistance. The aberrant activity of PAM signaling is modulated through multiple molecular mechanisms, including genetic alterations and post-transcriptional regulation of its components. These discoveries are further supported by clinical evidence: Phase I trials of mTORC1/2 dual inhibitors (e.g., LXI-15029) demonstrated both manageable toxicity and preliminary efficacy in stabilizing advanced solid tumors [ 9 ]. Notably, recent research has revealed that ncRNAs and m6 A modifications play critical roles in activating this pathway in drug-resistant cancer cells [ 159 ].

In cisplatin-resistant ovarian cancer cells, METTL3 enhances the stability of RHPN1-AS1 in a m6 A-dependent manner, leading to increased activation of the PI3 K/AKT pathway, which contributes to cisplatin resistance [ 160 ]. In another example, METTL3-catalyzed m6 A modification stabilizes and promotes the expression of circPLPP4 through recognition by IGF2BP1. circPLPP4 then functions as a miR-136 sponge to upregulate PIK3R1 expression, thereby enhancing cisplatin resistance in ovarian cancer cells [ 161 ]. In gastric cancer, METTL3 promotes the processing of pri-miR-17–92 into oncogenic miRNA clusters, which target PTEN and TMEM127, activating the Akt/mTOR signaling pathway, thus promoting gastric cancer sensitivity to everolimus [ 162 ]. Furthermore, in non-alcoholic fatty liver-associated hepatocellular carcinoma, ALKBH5-modified LINC01468 facilitates CUL4 A binding to SHIP2, promoting its ubiquitination and degradation. This, in turn, activates the PI3 K/Akt/mTOR signaling pathway, driving chemoresistance in non-alcoholic fatty liver-hepatocellular carcinoma [ 163 ]. Moreover, in pancreatic cancer, ALKBH5-modified DDIT4-as1 physically associates with UPF1 to enhance its phosphorylation, subsequently leading to DDIT4 destabilization and activation of the mTOR pathway, ultimately resulting in decreased chemosensitivity [ 164 ]. In leukemia, LINC00470 decreases the stability and downregulates the expression of PTEN by interacting with METTL3, thus activating Akt and contributing to chemoresistance in chronic myeloid leukemia cells [ 165 ] (Table 3 ).

Wnt/β-catenin signal pathway

The Wnt/β-catenin signaling pathway is a highly intricate and tightly regulated network comprising various proteins and transcription factors that play crucial roles in biological processes such as embryonic development, tissue homeostasis, and tumorigenesis [ 166 – 168 ]. The activation of this pathway is a multifaceted process involving the binding of Wnt proteins to Frizzled and LRP receptors, which form a complex that prevents the degradation of β-catenin. The stabilized β-catenin subsequently translocates to the nucleus, where it assembles into a transcriptional activation complex with TCF/LEF to drive the expression of target genes. Aberrant activation of this pathway has been implicated in tumor progression, metastasis, and therapeutic resistance, as exemplified in non-small cell lung cancer (NSCLC) [ 169 , 170 ]. A landmark study by Guan et al. established a direct genotype–phenotype correlation, demonstrating that the FOXM1 rs3742076_G single-nucleotide polymorphism (SNP) promotes β-catenin nuclear accumulation and constitutive Wnt activation. This molecular mechanism underlies the development of gefitinib resistance in EGFR-mutant non-small cell lung cancer (NSCLC) [ 171 ].

Recent research has underscored the significance of ncRNAs and m6 A modifications in regulating the Wnt/β-catenin signaling pathway, especially in the context of cancer therapeutic resistance. Specifically, in gliomas, METTL3-catalyzed m6 A modification stabilizes and boosts the expression of LINC00839 through a YTHDF2-dependent mechanism. This, in turn, activates the Wnt/β-catenin signaling pathway by facilitating c-src-mediated phosphorylation of β-catenin, thereby promoting radiation resistance [ 172 ]. Li et al. showed that circTTLL13 increases the expression of oxidized LDL receptor 1 (OLR1) by recruiting METTL3 and YTHDF2. Subsequently, OLR1 activates the Wnt/β-catenin pathway, leading to enhanced temozolomide resistance in glioma [ 173 ]. In lung adenocarcinoma, circFBXW7 translates into circFBXW7-185 AA and reverses resistance to tyrosine kinase inhibitors (TKIs) by ubiquitinating and inhibiting β-catenin expression to activate the Wnt/β-catenin pathway and this action is dependent on m6 A linkage [ 174 ]. In hepatocellular carcinoma, m6 A-modified circRNA-SORE competitively binds to miR-103a-2-5p and miR-660-3p by acting as a ceRNA to activate the Wnt/β-catenin pathway, further promoting resistance to sorafenib [ 175 ]. In pancreatic ductal carcinoma, FTO-mediated m6 A modification of LINC01134 enhances its stability and upregulates its expression, activating Wnt signaling through the miR-140-3P/WNT5 A pathway and contributing to chemoresistance [ 176 ]. In pancreatic cancer, decreased expression of ALKBH5 enhances the level of lncRNA SH3BP5-AS1, which acts as a sponge for miR-139-5p, leading to the activation of the Wnt signaling pathway and increasing gemcitabine sensitivity in pancreatic cancer cells [ 177 ]. Moreover, in both gastric and colorectal cancers, the interplay between lncRNAs and hnRNPA2B1 contributes to heightened chemoresistance through activation of the Wnt signaling pathway. Specifically, in gastric cancer, the interaction between hnRNPA2B1 and NEAT1 amplifies chemoresistance [ 178 ]. Similarly, in colorectal cancer, the association of MIR100HG with hnRNPA2B1 stabilizes TCF7L2 mRNA, thereby sustaining cetuximab resistance [ 179 ] (Table 4 ).

Other signal pathways

The interaction between m6 A modification and ncRNAs in cancer therapeutic resistance is also regulated by other signaling pathways. A notable example is the HIPPO signaling pathway, which is pivotal in regulating organ development and tissue homeostasis. Its core components encompass mammalian STE20-like kinase 1/2 (MST1/2), Salvador homolog 1 (SAV1), large tumor suppressor kinase 1/2 (LATS1/2), and the downstream transcription complex YAP/TAZ-TEADs [ 180 ]. For instance, METTL3-catalyzed m6 A modification leads to the upregulation of lncRNA SNHG17 by enhancing its stability, which subsequently promotes gefitinib resistance in lung adenocarcinoma by suppressing LATS2 expression and thus activating the HIPPO pathway [ 181 ]. Similarly, the NF-κB signaling pathway, a critical regulator of immune responses and inflammation, also contributes to cancer resistance [ 182 , 183 ]. In non-small cell lung cancer, miR-486-5p is upregulated by isoproterenol in an m6 A-dependent manner, enhancing cisplatin sensitivity by inactivating the RAP1-NF-κB pathway [ 184 ]. Another significant signaling pathway is the Notch pathway, which is highly conserved across evolution and plays a crucial role in determining cell fate, influencing organ development, tissue homeostasis, and regulating tumorigenesis, invasion, and drug resistance [ 185 , 186 ]. In lung adenocarcinoma, YTHDF2 inhibits the expression of lncRNA TUSC7, which functions as a sponge for miR-146a, orchestrating its expression and inhibiting the Notch signaling pathway to enhance sensitivity to targeted therapies [ 187 ].

Beyond these aforementioned pathways, ncRNAs and m6 A also contribute to cancer therapeutic resistance by modulating cellular pyroptosis. For example, LINC00969 interacts with METTL3 to suppress NLRP3 expression in an m6 A-dependent manner, thereby inhibiting the activation of the NLRP3/caspase-1/gsdmd-associated classical pyroptosis signaling pathway and enhancing TKI resistance in lung cancer [ 188 ]. In breast cancer, lncRNAs such as A1BG-AS1 and KCNQ1OT1, promote Adriamycin resistance by interacting with m6 A regulatory proteins to upregulate the expression of ATP binding cassette subfamily B member 1 (ABCB1, also named MDR1), a key player in drug efflux [ 189 , 190 ]. Additionally, the activation of the caspase pathway has been linked to radioresistance. In hypopharyngeal squamous cell carcinoma, METTL3 stabilizes circCUX in an m6 A-dependent manner, leading to the activation of the caspase-1 pathway and conferring radioresistance [ 191 ]. It has also been demonstrated that m6 A-modified LINC00115 promotes chemoresistance in triple-negative breast cancer by acting as a scaffold for the SETDB1/PLK3/HIF1α positive feedback loop [ 192 ]. In addition, m6 A-modified ncRNAs also contribute to tumor therapeutic resistance by targeting c-Myc, inducing regulatory T cells, and modulating the adipocyte-rich microenvironment [ 193 – 195 ] (Table 5 ).

Collectively, the interplay between m6 A modification and ncRNAs holds a pivotal role in tumor therapeutic resistance, mediated via diverse signaling pathways including MAPK, PI3 K/Akt/mTOR, Wnt/β-catenin, HIPPO, NF-κB, and Notch, as well as processes such as pyroptosis and caspase activation. These insights imply that the interaction between ncRNAs and m6 A offers novel strategies for surmounting therapeutic resistance in cancer therapy (Table 6 ).

Although clinical trials targeting m6 A and ncRNA regulatory mechanisms are still in their early stages, emerging preclinical studies have identified several potential therapeutic strategies with translational promise. For instance, in"driver-negative"lung adenocarcinoma (LUAD), Yang et al. performed RNA sequencing on 46 tumor-paraneoplastic tissue pairs and discovered 154 m6 A-associated lncRNAs (m6 A-lncRNAs). By constructing a prognostic risk model based on 9 key lncRNAs, they demonstrated its ability to stratify high- and low-risk patients (C-index = 0.824) and established the risk score as an independent predictor of overall survival [ 196 ]. This work not only provides potential prognostic biomarkers but also highlights m6 A-lncRNAs as therapeutic targets for cancer. Similarly, STM2457, an inhibitor of METTL3, a key driver of the m6 A modification, is under preclinical investigation and has shown promising anti-tumor activity in a variety of cancers, including acute myeloid leukemia (AML), prostate cancer, and neuroblastoma [ 197 – 199 ]. These examples illustrate the feasibility of modulating m6 A-related pathways for cancer therapy. Despite these advances, clinical studies examining the anti-tumor effects of m6 A and ncRNAs are still limited, and further research is essential to fully elucidate the roles of m6 A, ncRNAs, and their mutual regulation in tumorigenesis and progression. Such studies could lead to the identification of new therapeutic targets. In conclusion, the accumulating evidence underscores the emerging potential of targeting m6 A and ncRNAs pathways to overcome therapeutic resistance and enhance clinical outcomes in cancer treatment.

Conclusion, limitations and perspectives

In this comprehensive review, we have delved into the intricate and multifaceted interactions between m6 A modifications and ncRNAs, shedding light on their pivotal role in the development of tumor therapeutic resistance. Initially, we elaborated on the mechanisms through which m6 A modifications regulate ncRNAs, encompassing their production, maturation, translation, export, stabilization, and degradation. These regulatory processes underscore the profound influence of m6 A on ncRNA function and, consequently, on cellular physiology and disease states. Subsequently, we illuminated the reciprocal relationship, where ncRNAs act as key regulators of m6 A writers, readers, and erasers. This bidirectional interplay not only highlights the complexity of the m6 A-ncRNA network but also underscores its critical involvement in disease progression, particularly in the context of cancer.

Further, we explored the intricate ways in which the interaction between m6 A modifications and ncRNAs contributes to tumor therapeutic resistance. This resistance is mediated through various signaling pathways, including the well-established MAPK, PI3 K/Akt/mTOR, and Wnt/β-catenin pathways. These pathways are known to play crucial roles in cell growth, survival, and differentiation, and their dysregulation is a hallmark of many cancer types.

However, translating these findings into clinical practice faces three major challenges. One major concern is the off-target effects of targeting m6 A regulators. For instance, the FTO inhibitor FB23 was found to cross-inhibits human dihydroorotate dehydrogenase (hDHODH), due to structural similarity between their catalytic pockets. This dual inhibition leads to dihydroorotate (DHO) accumulation and conferred FTO-independent anti-leukemic effects [ 200 ]. In addition, in neuroblastoma models, the METTL3 inhibitor STM2457 may indirectly disrupt global translation by decreasing m6 A levels on neuronal transcripts, while exerting antitumor effects, indicating a trade-off between efficacy and specificity [ 199 ]. Additionally, the lack of tumor specificity is another limitation. m6 A modifications are widely present in both tumor and non-tumor cells, which means that systemic toxicity may occur when dealing with aberrant expression of m6 A regulators in tumor cells. Finally, the efficient delivery of RNA-based therapies to solid tumors represents a significant hurdle. Delivery for RNA-based therapies faces numerous challenges and obstacles, including rapid degradation by RNases and nucleases, endosomal escape inefficiency, non-specific immunogenicity, off-target effects, non-specific organ accumulation, and the presence of biological barriers such as the blood–brain barrier [ 201 , 202 ]. Notably, nanoparticle-based delivery systems (e.g., lipid or polymer nanoparticles) have shown promise in preclinical studies by improving stability and targeting [ 203 ].

To address these limitations, emerging technologies such as CRISPR-based RNA editing and RNA-targeted small molecules offer transformative potential for clinical translation. Based on the above challenges and limitations, future research should focus on the following directions. The inability to specifically install m6 A sites in individual transcripts has hampered efforts to elucidate the causal relationship between the presence of a specific m6 A and phenotypic outcomes. Wilson et al. investigated the development of a CRISPR-Cas13-based targeted RNA methylation (TRM) system that mediates m6 A installation in endogenous RNA transcripts with high specificity, achieves site-specific m6 A modification, and exhibits low off-target activity [ 204 ]. In addition to CRISPR-based tools, RNA-targeted small molecule technology is a powerful tool for regulating RNA function. RNA-targeted small molecules regulate non-coding RNA-mediated transcription and translation through multiple mechanisms. A growing library of RNA-targeted small molecules suggests that RNA is indeed amenable to pharmacological treatment, and several compounds are already in clinical trials or have been approved [ 205 ]. Synergizing these approaches—where CRISPR achieves precision editing and small molecules enable reversible modulation—could overcome current specificity and delivery barriers.

In conclusion, the interplay between m6 A modifications and ncRNAs emerges as a promising therapeutic target for overcoming tumor therapeutic resistance in clinical settings. As both m6 A and ncRNAs represent cutting-edge and rapidly evolving research fields within the life sciences, further exploration of their interactions is poised to yield novel therapeutic strategies and guide the development of future drugs.

Moving forward, the following key directions for transformation are worth exploring in depth. First, the development of precise epitope transcriptomics tools, particularly CRISPR-based m6 A site-specific editing systems in combination with RNA-targeted small molecules, can effectively overcome specificity limitations to a limited extent. Second, innovative drug delivery platforms must be advanced to bridge the gap between mechanistic understanding and clinical application. Nanoparticles as drug delivery vehicles hold great promise. As both m6 A and ncRNA research continue to advance rapidly. By identifying key regulatory nodes and elucidating the signaling pathways involved, we can develop targeted therapies that modulate the m6 A-ncRNA network. Such therapies have the potential to revolutionize personalized cancer treatment, offering new hope for patients facing the challenges of therapeutic resistance. In this endeavor, collaborative efforts across disciplines and the integration of advanced technologies will be crucial to unraveling the complexities of the m6 A-ncRNA interplay and harnessing its therapeutic potential.

Abbreviations

5-Fluorouracil

AlkB homolog 5

Acute myeloid leukemia

Competitive endogenous RNA

Circular RNA

Chronic myeloid leukemia

Colorectal cancer

Clustered regularly interspaced short palindromic repeats

Epithelial-mesenchymal transition

Esophageal squamous cell carcinoma

Fat mass and obesity-associated protein

Gastrointestinal stromal tumor

Hepatocellular carcinoma

Hippo signaling pathway

Insulin-like growth factor 2 mRNA-binding proteins

Long non-coding RNA

N6-methyladenosine

Mitogen-activated protein kinase

Methyltransferase-like 3

Methyltransferase-like 14

MicroRNA

Non-coding RNA

Nuclear factor kappa-light-chain-enhancer of activated B cells

Non-small cell lung cancer

Prostate cancer

Phosphoinositide 3-kinase/Protein kinase B/Mechanistic target of rapamycin

PIWI-interacting RNA

Small nuclear RNA

Tyrosine kinase inhibitor

Tumor microenvironment

Wnt/β-catenin signaling pathway

YTH domain-containing family proteins

Author contributions

Conceptualization, D.F., Y.S. and H.Z.; formal analysis, D.F., Y.S., Y.C., Y.J., N.L. and H.Z.; writing—original draft preparation, D.F.; writing—review and editing, H.Z.; supervision, H.Z.; project administration, D.F. and H.Z.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82060503), the Project of the Guizhou Provincial Department of Science and Technology (Grant No. QKH-JC-ZK-2022-622 and No. QKH-JC-2019-1334), the College Students' Innovation and Entrepreneurship Training Program Project of Zunyi Medical University (Grant No. S202310661167).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.