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Epitranscriptomic Regulation of Notch Signaling

Submitted:

07 June 2026

Posted:

09 June 2026

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Abstract
Notch signaling has long been understood to be shaped by post-transcriptional regulation, yet the contribution of RNA chemical modification has only recently begun to be resolved with mechanistic clarity. In this review, an updated account of epitranscriptomic regulation of Notch signaling is provided, with emphasis placed on how RNA networks influence the processing, localization, stability, translation, and editing of transcripts encoding receptors, ligands, modulators, and downstream effectors. The available evidence is evaluated according to mechanistic strength to distinguish direct transcript-level regulation from broader pathway-associated or enrichment-based observations. Across developmental systems, stem cell states, cancer, neurological contexts, and immune or inflammatory settings, Notch activity is considered not only in terms of signaling intensity, but also through its temporal dynamics, persistence, and activation thresholds. Particular attention is given to the predominance of N6-methyladenosine (m6A)-based studies, while evidence for other RNA modifications is examined more cautiously. By integrating a fragmented and methodologically uneven body of literature, this Review proposes a framework for separating validated epitranscriptomic regulation of Notch components from correlative pathway rewiring, in order to define the experimental standards needed to strengthen mechanistic inference and translational relevance.
Keywords: 
epitranscriptomics
;  
Notch signaling
;  
RNA modifications
;  
post-transcriptional regulation
;  
stem cells
;  
cancer
;  
RNA stability
;  
translational control
Subject: 
Biology and Life Sciences  -   Biochemistry and Molecular Biology

1. Introduction

Notch pathway is a developmentally conserved metazoan signaling pathway that mediates signaling between neighboring cells. The Notch receptor is activated by two families of canonical ligands including Delta-like and Serrate/Jagged. The both ligands and receptors are single-pass transmembrane proteins that usually contain large extracellular domains, relative to their intracellular portions [1,2]. Ligand binding triggers sequential proteolytic cleavages that release the Notch intracellular domain (NICD), which subsequently translocates to the nucleus and redirects transcription through a regulatory complex centered on Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJ) and associated co-activators [1,2]. Canonical pathway output is commonly monitored through induction of HES and HEY family genes; however, the biological consequence of Notch activation is not ordered by this transcriptional core alone [1]. Depending on cellular composition, tissue organization, ligand availability, and signaling duration, Notch activity may instead support lineage specification, regenerative responses, tissue boundary maintenance, or malignant persistence [2,3]. Therefore, Notch is now viewed less as a linear signaling cascade than as a contact-dependent communication system whose functional output is determined by spatial and temporal cues [2,3]. The fundamental aspects of ligand–receptor interaction, sequential proteolysis, and NICD-mediated transcriptional output are depicted schematically in Figure 1, which also highlights the primary epitranscriptomic regulatory sites within the system.
The contextual plasticity of Notch signaling has long been attributed to mechanisms operating at the protein level, including receptor trafficking, ligand endocytosis, proteolytic processing, and the availability of nuclear cofactors [1,2]. Post-transcriptional control of Notch signaling had already been established through alternative splicing, RNA-binding proteins, and non-coding RNAs [4,5,6].The regulation of NUMB as a key antagonist of Notch signaling is among the best-characterized examples. Alternative isoform usage has been shown to influence the capacity of NUMB to suppress pathway activity, while translational repression of NUMB transcripts by Musashi-family RNA-binding proteins has been linked to the maintenance of stem-like states in malignancies characterized by persistent Notch activation [4,5]. By altering exon selection, intron retention, and alternative 3’-end formation, RNA modifications can change the abundance and isoform composition of Notch transcripts before protein-level feedback becomes evident[2,7,8]. Current evidence in this area is highly dominated by studies of N6-methyladenosine (m6A), whereas mechanistic data linking other RNA modifications, including m5C and adenosine-to-inosine (A-to-I) editing, to Notch signaling remain comparatively limited and less cohesive [7,8,9,10].
In this review, a transcript-centered evidentiary framework is adopted for evaluating the available evidence. “Direct evidence” is defined as evidence showing that perturbation of an RNA-modification layer changes the fate of a defined Notch-related RNA, alters a Notch signaling readout, and produces a linked phenotypic consequence. By contrast, “associative evidence” refers to studies in which modifier expression, transcriptome-wide profiling, or pathway-enrichment analysis is correlated with Notch activity, but direct target assignment or mechanistic rescue remains unresolved [7,8,9,10]. Distinguishing between these categories facilitate understanding whether Notch signaling is being directly regulated, secondarily buffered, or simply co-varied within broader cell-state transitions.

2. RNA Modification Mechanisms Shaping the Notch Transcriptome

Pre-mRNA processing and alternative splicing: RNA modifications can reshape Notch output before translation by altering exon selection, intron retention, and alternative 3′-end formation. In mammalian systems, the nuclear m6A reader YTHDC1 facilitates splice-site selection through coordinated interactions with splicing regulators, promoting recruitment of SRSF3 while limiting access of the exon-skipping factor SRSF10 to overlapping RNA regions [11,12]. Accordingly, germline deletion of YTHDC1 in mouse oocytes leads to widespread abnormalities in alternative splicing and polyadenylation [13]. These abnormalities could be rescued only by reintroduction of wild-type m6A-binding-competent YTHDC1, not by YTHDC1 mutants lacking the m6A-binding domain, which demonstrated that recognition of m6A marks is required for proper exon selection and 3′-end processing [14]. Additionally, YTHDC1 can suppress proximal alternative polyadenylation (APA) site selection through interactions with components of the cleavage machinery, including CPSF6, which favors transcripts with extended 3′ untranslated regions (UTRs) [15,16,17,18]. Through coordinated regulation of pre-mRNA splicing and polyadenylation, YTHDC1 defines the overall transcriptome landscape strictly depending on the presence of m6A marks [14,19,20]. Although Notch signaling changes are frequently observed following perturbation of the m6A machinery, most studies rely on global disruption of epitranscriptomic regulators rather than targeting individual transcripts [21,22,23]. Thus, it is often difficult to distinguish direct regulation of Notch-associated RNAs from indirect effects arising through broader signaling or metabolic networks that converge on Notch activity [24,25,26,27]. However, m6A deposition can destabilize local RNA secondary structures, such as hairpins, exposing previously inaccessible binding motifs for RNA-binding proteins such as HNRNPC and HNRNPG [12,28]. As a result of m6A switch mechanism, m6A can indirectly influence the binding landscape of splicing regulators and alter exon inclusion patterns independently of direct reader engagement in response to various environmental/external cues [29].
Across metazoans and plants, METTL16-family methyltransferases catalyse m6A formation within the conserved ACAGA motif of U6 small nuclear RNA (snRNA) [30,31]. In Arabidopsis, loss of the U6 methyltransferase FIONA1 disrupts recognition of specific 5′ splice-site configurations and causes widespread alterations in exon skipping and intron retention [32]. Structural studies further report that the modified nucleotide within U6 snRNA builds interactions with intronic +4A splice-site motifs during spliceosome assembly [32,33]. When this modification is lost, splice-site usage shifts away from +4A-containing introns toward alternative sequence configurations that can be more efficiently recognized by the unmodified spliceosome [30,34,35]. Collectively, these observations demonstrate that m6A marks on fundamental spliceosomal components can alter competition among splice sites independently of any modification on the pre-mRNA.
Unlike signaling systems that rely on enzymatic amplification cascades, Notch activity scales closely with receptor-ligand interactions occurring at the plasma membrane [36,37]. As a result, relatively modest alterations in the abundance or composition of receptors (Notch1–4) and ligands (Dll1, Dll3, Dll4, Jagged1, Jagged2) can substantially alter signaling intensity [38,39]. Moreover, developmental patterning by Notch is tightly regulated by the stoichiometry and structural diversity of its receptors and ligands, NOTCH1-4, DLL, and JAG family members, which frequently rely on complex alternative splicing programs to generate isoforms with distinct signaling properties [32,40,41,42,43].
In non-small cell lung cancer, RBM5, RBM6, and RBM10 exert opposing effects on NUMB exon 9 inclusion, which can shift the balance between isoforms with different capacities to restrain proliferation and Notch activity [44,45]. RBM10 promotes exon 9 skipping and facilitates production of a NUMB isoform that can enhance ubiquitination and degradation of the NICD, while increased exon 9 inclusion correlates with reduced NUMB function and elevated expression of Notch target genes [4,46]. Loss-of-function mutations in RBM10 further reinforce exon 9 inclusion, which is associated with enhanced Notch signaling and tumor progression [44,47].
Further layers of regulation extend this NUMB-centered splicing paradigm into other developmental and cellular contexts [40,48]. During neuronal differentiation, RBM4 promotes exclusion of NUMB exon 9 while modulating exon 3 usage and generating isoform combinations that guide neurite extension and cell-fate specification [48,49]. Furthermore, in muscle stem cells, RBFOX2-dependent alternative splicing of NUMB exon 6 has been shown to facilitate cell-cycle entry through calibration of Notch activity [40]. Accordingly, exon-specific regulation of NUMB functions as a molecular rheostat for calibrating Notch signaling strength across diverse biological settings [40,48].
Nuclear export and subcellular localization: The nuclear reader YTHDC1 promotes export of methylated RNAs by coordinating with the export factors SRSF3 and NXF1 [14,50]. This regulatory axis has been implicated in the transport of m6A-marked Notch1 and Notch2 mRNAs to the cytoplasm [51]. Within stress-responsive nuclear condensates, particularly during recovery from heat stress, m6A-marked HSATIII long noncoding RNAs recruit the METTL3/METTL14 writer complex and YTHDC1 into nuclear stress bodies (nSBs) [16,52]. This sequestration effectively acts as a molecular sponge, depleting these factors from the surrounding nucleoplasm and, in turn, suppressing global m6A-dependent pre-mRNA splicing and 3′-end processing [52]. Accordingly, m6A regulators can define narrow temporal windows for transcript maturation and export, including transcripts within the Notch pathway [51,52].
Transitions between cell states are likewise tightly regulated by the selective nuclear export and translational engagement of m6A-modified RNAs [53,54]. In pulmonary fibrosis models, YTHDC1 promotes nuclear release of the profibrotic lnc668 through assembly of an SRSF3-ALYREF-XPO5 export complex, which illustrates the reinforcement of pathological state changes via epitranscriptomic export programs [54]. In hematopoietic stem and progenitor cells (HSPCs), METTL3 and YTHDF3 support lineage progression in part by enhancing translation of Ccnd1, while METTL3-dependent methylation of Notch1 contributes to early specification of hematopoietic progenitors from endothelial cells [53,55,56]. Collectively, these findings indicate that m6A-controlled nucleocytoplasmic trafficking and translational activation help coordinate the timing of responses to lineage-defining cues.
mRNA stability and decay: The strongest evidence for epitranscriptomic regulation of Notch currently lies at the level of transcript stability. In zebrafish, the endothelial-to-hematopoietic transition (EHT) depends on METTL3-mediated m6A deposition and subsequent YTHDF2-mediated decay of notch1a mRNA [57]. High-resolution mapping approaches, including MeRIP-seq and miCLIP-seq, have shown that notch1a and rhoca mRNAs carry m6A modifications positioned near their stop codons [57,58,59]. Loss of METTL3 reduces m6A abundance, stabilizes notch1a transcripts, prolongs Notch activity in arterial endothelium, and impairs HSPCs emergence [57,60]. Comparable results in ythdf2-deficient embryos support a direct METTL3–m6A–YTHDF2 axis in controlling notch1a transcript turnover, while rescue with wild-type YTHDF2, but not an m6A-binding-defective mutant, further strengthens this interpretation [57,60,61].
A related but context-dependent pattern has been described for NOTCH1 in vascular smooth muscle cells and leukemia [62]. In human aortic smooth muscle cells, METTL3 deposits m6A within the 3’ UTR of NOTCH1 mRNA and promotes an interaction with YTHDF2, which accelerates transcript decay [63]. The reduced abundance of NOTCH1 contributes to a proliferative, dedifferentiated phenotype associated with thoracic aortic dissection [64,65]. In contrast, in T-cell acute lymphoblastic leukemia, m6A-modified NOTCH1 transcripts are recognized by IGF2BP2 rather than YTHDF2, which stabilizes the mRNA and sustains oncogenic Notch signaling [62,66]. Genetic or pharmacological suppression of IGF2BP2 reduces NOTCH1 expression and restrains leukemic growth, which reflects the functional importance of reader identity [62]. By contrast, in epithelial contexts, the YTHDF2 participates as a brake on Notch signaling by promoting degradation of Notch1 mRNA; furthermore, depletion of YTHDF2 or METTL3 stabilizes the transcript, increases NICD abundance, and elevates HES1 and HES5 expression [67].
A similar principle applies to NOTCH3 in nasopharyngeal carcinoma, where IGF2BP3 functions as a stabilising reader that preserves NOTCH3 mRNA and supports invasive behaviors [68]. Although nucleotide-level mapping is less complete than in some developmental systems, RNA immunoprecipitation (RIP), actinomycin D chase, and rescue experiments indicate that this effect depends on m6A [68,69]. By antagonizing CCR4-NOT-mediated deadenylation, IGF2BP3 extends transcript half-life and maintains Notch3 pathway activity [26,68].
Translational control: Translational control represents another direct point at which epitranscriptomic regulation can shape Notch output. In regenerating skeletal muscle, METTL3-dependent m6A deposition increases the translation efficiency of selected regeneration-associated transcripts without matching changes in mRNA abundance, consistent with a rate-setting effect on early pathway activation [70]. Conditional loss of METTL3 in muscle stem cells impairs satellite cell expansion and delays regeneration, while METTL3 overexpression accelerates myoblast proliferation and shortens the regenerative program [70]. Ribosome profiling and reporter assays indicate that this effect reflects preferential enhancement of translation rather than transcript accumulation [51]. Although the majority of the studies have focused on myogenic regulators, the same mechanism is well suited to dosage-sensitive pathways such as Notch, where relatively small changes in protein synthesis could have marked functional consequences [71,72,73].
A closely related mechanism operates in hematopoietic stem cells (HSCs), where METTL3-dependent m6A modifications influence the translational output of key cell-cycle and metabolic regulators and thereby affect fate decisions [74,75]. Accordingly, loss of METTL3 leads to a significant defect in Ccnd1 translation despite little change in mRNA abundance [53,76]. Notably, m6A modification within the 5′ UTR is interpreted by YTHDF3, which recruits translation initiation factors, including PABPC1 and eIF4G2, to promote protein synthesis [26,53,76]. Rescue experiments in which Ccnd1 re-expression restores the phenotype of YTHDF3-deficient cells, and partially corrects the METTL3-deficient state, support a direct translational role for this pathway [53]. These observations show that m6a readers selectively amplify translational output, which governs stem cell competence.
Disease models provide direct evidence that translational control intersects with Notch signaling. In hepatocellular carcinoma (HCC), YTHDF1 binds m6A-modified NOTCH1 mRNA and elevates its translational efficiency and stability, which affect tumor-initiating capacity and self-renewal [77]. Polysome profiling shows enhanced ribosome loading, while actinomycin D chase experiments indicate reduced transcript decay [77,78]. Moreover, re-expression of NOTCH1 in YTHDF1-depleted cells restores sphere formation and resistance to tyrosine kinase inhibitors, demonstrating that NOTCH1 is a proximal functional target of this reader [77]. In this context, m6A-decorated NOTCH1 serves as a direct translational substrate whose increased protein output maintains a Notch-dependent cancer stem cell population [77].
RNA editing impacts: Despite the lack of direct evidence, A-to-I RNA editing mediated by the ADAR enzymes family is capable of altering coding potential, RNA structure, splice choice, and miRNA targeting, and therefore remains mechanistically relevant to Notch biology in principle [7,79]. Large-scale sequencing studies across normal tissues and cancers have mapped millions of such editing events and consistently found that transcripts belonging to the Notch signaling network are highly enriched among edited targets [80,81,82,83]. These global patterns often correlate with stemness-related or oncogenic transcriptional programs [84]. However, site-resolved, rescue-validated evidence that a specific editing event in a canonical Notch receptor, ligand, or effector alters signalling output is still lacking [82,84,85]. Unlike m6A, which is deposited at relatively tractable sequence contexts, A-to-I editing depends on structured double-stranded RNA regions; therefore, functionally validating individual sites within large transcripts such as NOTCH1 is likely to be difficult [82,86]. Of note, editing may influence Notch indirectly by reshaping intersecting pathways, including immune and cytokine signaling modules that modulate Notch signaling indirectly [87,88].
It has been indicated that ADAR-mediated edits have the potential to rewire the epitranscriptome by creating or eliminating microRNA-binding motifs in the 3′ UTR, recoding amino acids within key functional domains, or reshaping local RNA structure to influence splicing and the recruitment of RNA-binding reader proteins [89,90]. Future investigations should combine high-resolution editome profiling with targeted analysis of core Notch components, including NOTCH, DLL, JAG, HES, and HEY transcripts [91,92,93]. Functional validation will also be needed through editing-mimic and editing-dead reporters, along with ADAR knockdown and rescue experiments, to determine direct mechanistic causality [89,94,95].
Mechanistic checklist for direct targeting: A Notch transcript should be classified as a direct epitranscriptomic target only when four elements are satisfied: site-resolved mapping of the modification on the RNA, evidence that perturbation of a writer, eraser, or reader alters transcript fate, demonstration of a corresponding change in Notch signaling output, and transcript-specific rescue or epistasis experiments confirming causality [7,57,77]. In the absence of this sequence of evidence, pathway-level association should remain provisional. In zebrafish hematopoietic development, METTL3 and YTHDF2 regulation of notch1a mRNA stability, has been supported by transcript-level mapping, functional perturbation, and rescue using m6A-insensitive reporter constructs [22,60]. Similarly, in HCC, integrated profiling approaches demonstrated that YTHDF1 directly enhances translation of m6A-modified NOTCH1, while restoration of NOTCH1 expression rescues the stem-like and drug-resistant phenotypes observed after YTHDF1 depletion [77]. In nasopharyngeal carcinoma, the stabilizing interaction between IGF2BP3 and NOTCH3 mRNA was further validated using GGAC-mutant reporters that disrupt m6A-reader recognition motifs [68]. Transcripts associated with Notch that presently satisfy or roughly approximate this four-step evidential requirement across developmental, cancer, epithelial, and immunological settings are presented in Table 1.
By contrast, mounting evidence offers only partial mechanistic coverage. In thoracic aortic smooth muscle cells, METTL3-dependent methylation and YTHDF2-mediated degradation of NOTCH1 have been mapped, yet full rescue experiments employing m6A-insensitive NOTCH1 constructs have not been reported [96,97]. In cerebral arteriovenous malformations, reduced METTL3 expression correlates with altered expression of Notch-associated ubiquitin ligases, including DTX1 and DTX3L, yet the directly modified transcripts remain unresolved at nucleotide level [98,99].
Table 1. Overview of the most compelling transcript-resolved instances when a specific RNA alteration or reader directly influences a Notch-pathway transcript. Columns represent biological environment, changed transcript, writer/reader or enzyme, RNA destiny, downstream Notch output, functional consequence, and proof robustness. Examples include zebrafish EHT, HCC, NPC, T-ALL, epithelial cells, and γδ T-cell development.
Table 1. Overview of the most compelling transcript-resolved instances when a specific RNA alteration or reader directly influences a Notch-pathway transcript. Columns represent biological environment, changed transcript, writer/reader or enzyme, RNA destiny, downstream Notch output, functional consequence, and proof robustness. Examples include zebrafish EHT, HCC, NPC, T-ALL, epithelial cells, and γδ T-cell development.
Biological context Modified transcript Writer /Reader
/Eraser		 RNA fate RNA modification NOTCH output Ref
Zebrafish EHT Notch1a METTL3 (WRITER)
YTHDF2 (READER)		 m6A-dependent Block EHT/HSPC emergence Reduced [57]
HCC Notch1 YTHDF1 (READER) m6A-translation Promote cancer stemness/tumor growth/therapy resistant Increased [77,78,112]
T-ALL Notch1 IGF2BP3 (READER) m6A-stability/maintenance Proliferation/leukemia survivor Increased [63]
NPC Notch3 IGF2BP3 (READER) m6A-dependent metastatic potential/promote stemness invasion Increased [68,69]
Epithelial cells Notch1 METTL3/14 (WRITER)
YTHDF2 (READER)		 m6A-associated Control epithelial stem-cell homeosteosis /limit Hes1/5 Reduced [67,108,109,111]
Yδ T Cells Jagged1/Notch2 ALKBH (ERASER) m6A-mediated Expands precursors / alters host defense Reduced [162,163]

3. Notch Control in Development and Tissue Stem Cell Programs

Studies on zebrafish embryos have demonstrated that METTL3-dependent m6A deposition promotes YTHDF2-mediated decay of notch1a mRNA, which leads to preventing persistent arterial-endothelial Notch activity and permitting HSPCs emergence [57]. MeRIP-seq and miCLIP-seq revealed m6A enrichment near the stop codons and within the 3′ UTR of notch1a and rhoca transcripts [57,100]. When METTL3 is lost, these mRNAs escape YTHDF2-dependent turnover, which leads to sustained Notch signaling that blocks EHT and prevents HSPC formation [57,100]. Notably, genetic ablation of ythdf2 produces a similar phenotype, while YTHDF2 overexpression restores HSPC formation [60]. A comparable principle observed in the mouse aorta-gonad-mesonephros (AGM) niche reflected that endothelial deletion of METTL3 impairs definitive hematopoiesis, reduces long-term repopulating HSPCs, and is accompanied by increased expression of Notch genes, including notch1 and hes1 [101,102,103]. Although these findings reveal an accumulation of m6A-dependent control of Notch, the underlying mammalian transcripts have yet to be resolved with the same nucleotide-level precision achieved in zebrafish [104].
A similar principle extends to adult muscle regeneration, where METTL3-dependent m6A in satellite cells promotes proliferative expansion and efficient repair after injury by enhancing translation of selected Notch-pathway transcripts through YTHDF1 [70]. After acute muscle damage, METTL3 expression and global m6A abundance elevate during the early proliferative phase and decline as myogenic differentiation progresses [23,70,105]. MeRIP-seq and polysome profiling indicate that transcripts encoding Notch2, Jag1, RBPJ, and MAML1 are among the methylated targets whose translational efficiency increases without major changes in steady-state mRNA abundance [70,105]. As a result, YTHDF1 can reinforce ribosome loading on these transcripts, while YTHDF2 participates in terminating the proliferative programme by promoting decay of selected anti-myogenic mRNAs such as TM4SF1 [106]. Collectively, these data support that m6A-dependent pathways can operate as a temporal gain module by amplifying signaling to initiate a robust regenerative response, as well as engaging selective mRNA clearance to enable terminal differentiation.
Direct epitranscriptomic targeting of Notch transcripts remains less well defined in epithelial stem compartments [107]. In the intestinal epithelium, loss of METTL3 or METTL14 disrupts stem cell homeostasis and alters both Wnt and Notch pathway activity, however, current evidence mainly supports indirect regulation through upstream negative regulators such as Grb10 and Ifrd1 rather than direct modification of Notch receptors or ligands [108,109,110]. Similarly, in the skin, m6A is clearly required for epidermal and follicular development, yet the most firmly established direct targets are chromatin regulators and lineage factors rather than major Notch components [111]. These settings are therefore best regarded as biologically plausible but still transcript-unassigned with respect to direct epitranscriptomic control of Notch [109,111].

4. Epitranscriptomic Notch Rewiring in Cancer and Cancer Stem Cells

Stemness and self-renewal: HCC provides an example of reader-dependent NOTCH1 translation, which supports stemness and sustained tumor-initiating properties. Importantly, rescue by NOTCH1 re-expression placed Notch as a proximal effector rather than a secondary correlate [77]. Related observations in colorectal cancer revealed that elevated YTHDF1 expression is similarly associated with enhanced tumor sphere formation and self-renewal capacity [77,112,113]. Additionally, pan-cancer transcriptomic surveys indicate that elevated expression of YTH family readers, particularly YTHDF1 and YTHDF2, is frequently associated with adverse prognosis and remodeled immune microenvironments across a wide range of tumor types [114,115,116,117]. However, the majority of these larger datasets remain correlative and do not establish defined transcript-level regulation of Notch components across all tumor contexts.
Therapy resistance: The YTHDF1-NOTCH1 axis in HCC can directly contribute to therapeutic resistance; depletion of YTHDF1, and enhanced sensitivity to Lenvatinib and Sorafenib, while enforced expression of NOTCH1 causes resistance [77].In other malignancies, the relationship between epitranscriptomic regulation and therapy resistance appears less straight. For instance, in acute myeloid leukemia and related hematologic cancers, m6A-associated resistance programs are more often linked to stress-response, metabolic, or DNA-repair networks that potentially influence Notch activity indirectly instead of targeting Notch transcripts [118,119,120,121,122].
Invasion and metastasis: Direct epitranscriptomic regulation of Notch can also contribute to metastatic progression. In nasopharyngeal carcinoma, IGF2BP3 binds m6A-modified NOTCH3 transcripts, which suppresses their deadenylation and prolongs transcript stability, in order to extend Notch3 signaling and promote metastatic behavior [68]. Loss of IGF2BP3 reduces stem-like properties and impairs metastatic outgrowth, which supports a direct functional connection between reader-dependent NOTCH3 stabilization and tumor dissemination [68]. Collectively, these observations highlight that under homeostatic conditions, YTHDF2 generally acts as an intrinsic brake by accelerating NOTCH1 mRNA decay [67], while pathological upregulation of readers such as IGF2BP3 can override this repressive layer, thereby sustaining oncogenic Notch activity and enabling persistent metastatic behavior [26,68].
Notch as a primary driver versus a downstream pathway: Studies on lung adenocarcinoma have indicated that IGF2BP3 can stabilize m6A-modified MCM5 mRNA, which protects NICD1 protein during partial epithelial- mesenchymal transition (EMT) and metastatic plasticity [123,124]. Elevated MCM5 protein interferes with SIRT1-mediated deacetylation of NICD1, indirectly stabilizing Notch signaling and promoting metastatic plasticity [123]. Similar upstream rewiring mechanisms may also operate through m6A-dependent regulation of ubiquitin ligases or other modulators that control NICD turnover. Epitranscriptomic circuits can influence Notch output by acting on transcripts encoding E3 ubiquitin ligases such as WWP2, which oversee proteasomal degradation and nuclear turnover of NICD [67,125,126]. In these systems, Notch signaling is clearly reshaped by epitranscriptomic regulation; however, the immediate modified transcripts lie outside the canonical pathway [125,127,128]. Identifying direct transcript targeting from indirect upstream rewiring has important therapeutic implications [129,130].
When Notch receptors or ligands constitute the primary m6A-regulated transcripts, as in HCC or nasopharyngeal carcinoma, targeting relevant readers or writers may achieve relatively focused suppression of Notch-dependent phenotypes [68,131]. By contrast, when Notch behaves as a downstream passenger of an m6A-modified regulator, manipulating the m6A machinery is likely to produce pleiotropic and less predictable effects [132,133,134,135]. In this regard, direct pharmacologic blockade of Notch signaling, including γ-secretase inhibitors or receptor-targeting antibodies, may offer a more selective approach [136,137]. Accordingly, classifying cancer studies into models of direct transcript targeting versus indirect upstream rewiring is crucial for identifying settings in which Notch serves as a primary epitranscriptomic driver rather than a secondary passenger within wider m6A-governed networks [68,136].

5. Notch Regulation in the Nervous System and Brain Disease

Glioma and glioblastoma: In glioma and glioblastoma (GBM), Notch signaling is well established as a determinant of stemness, tumor maintenance, and therapy resistance [138]. Epitranscriptomic regulators are also functionally active in glioma stem-like cells, but the mapped targets identified so far have predominantly been non-Notch RNAs, including FOXM1, LINC00900, MYC, VEGFA, SOX2, and related stemness-associated transcripts [139,140,141,142,143,144]. Accordingly, the current literature supports epitranscriptomic rewiring in a Notch-relevant disease state, but transcript-resolved evidence of direct Notch targeting in most glioma models remains limited [138,145]. One recent study suggests that METTL3 may directly influence NOTCH3, DLL3, and HES1 transcripts to promote glioma initiation [145,146,147].
Other nervous-system and brain-disease contexts: Cerebral arteriovenous malformation is one of the neurological examples in which epitranscriptomic regulation converges on a defined Notch-modulating node [99,148]. In this condition, loss of METTL3 destabilizes DTX3L transcripts, which can disrupt the DTX1-DTX3L ubiquitin-ligase complex that normally restrains Notch activity [99]. The resulting persistence of Notch signaling alters endothelial angiogenic behavior and can be partially reversed by pharmacological Notch inhibition [99]. Although the modified RNA is not a canonical receptor or ligand transcript, the effect still represents a route by which RNA methylation influences Notch-dependent vascular pathology [99]. However, neurodevelopmental studies have not yet mapped m6A sites on NOTCH1/2, DLL ligands, or HES/HEY transcripts with the same transcript-level precision achieved in hematopoietic or muscle systems, and reader-dependent rescue of specific Notch transcripts remains unproven [149,150,151].As a result, epitranscriptomic mechanisms that impact Notch during neural development are, for now, best described as associative or pathway-level interactions rather than fully transcript-resolved relationships [152].
Neurodevelopment and neurodegeneration: In Alzheimer’s disease models, reduced FTO expression has been associated with increased m6A on Notch1 mRNA along with elevated Notch1 and HES1 signaling [153,154,155,156]. This apparently paradoxical behavior suggests that m6A-mediated stabilization or improved translation of Notch1 transcripts may contribute to disease-associated gliosis and neuronal dysfunction [157,158,159]. This pattern is compatible with altered transcript stability or translation, but the available data do not include site-resolved mapping, reader identification, or transcript-specific rescue experiments [151,153,160,161].

6. Immune Cell Differentiation and Inflammatory Microenvironments

A strong example of direct evidence for epitranscriptomic control of Notch in immune-lineage specification comes from thymic γδ T-cell development. Accordingly, ALKBH5 restrains m6A accumulation on Jagged1 and Notch2 transcripts, which can preserve their stability and supporting downstream Notch signalling [162,163]. Loss of ALKBH5 increases m6A on these RNAs, accelerates their decay, weakens Notch output, and expands γδ T-cell precursors [163]. Notably, the modified RNAs are pathway components, which links RNA modification, transcript fate, and immune differentiation within a single mechanistic chain [163].
Notch-pathway genes often appear in enriched gene-set signatures after perturbation of m6A regulators; nevertheless, most immune-related association outside the ALKBH5–Jagged1/Notch2 and IGF2BP2–NOTCH1 axes are best classified as indirect [164,165,166,167]. In T-cell acute lymphoblastic leukemia (T-ALL), IGF2BP2 directly stabilizes NOTCH1 mRNA in an m6A-dependent manner, which provides a stronger example of transcript-level Notch regulation in an immune-derived malignancy [62,163,167,168,169]. By contrast, another set of studies identify alternative primary substrates such as MYC or IRF8 [164,165,166,170].
A similar caution applies to inflammatory microenvironments. Notch signaling can organize stromal, vascular, and immune crosstalk in tumors and inflamed tissues, while m6A has been implicated broadly in immune microenvironment homeostasis and immune disease [171,172]. However, cell-resolved causal chains linking RNA modification events to a defined Notch-pathway RNA across interacting stromal, vascular, and immune compartments remain limited [171,172]. In vascular inflammation, for example, m6A regulators often act through non-Notch substrates such as TNFAIP3, EGFR, PI3K, or RIP3, while Notch emerges as a downstream participant in the remodeling response [173,174,175]. Furthermore, modification of these RNAs activates downstream cascades, including NF-κB [173,174]. In abdominal aortic aneurysms and atherosclerosis, m6A machinery controls vascular smooth muscle cell phenotypic switching and inflammatory necroptosis predominantly via non-Notch transcripts such as PI3K and RIP3 [167,173,174]. These observations support biological relevance, but not yet direct assignment of Notch transcripts as the primary modified targets.

7. Mapping Causality and Therapeutic Translation

Across the systems reviewed here, the most convincing epitranscriptomic–Notch connections are those that satisfy four criteria: site-resolved mapping on a specific Notch-pathway RNA, modifier- or reader-dependent alteration of transcript fate, a matched change in Notch signaling output, and transcript-specific rescue or epistasis. Studies meeting this standard show that m6A can either attenuate or reinforce Notch signaling depending on the reader protein engaged in a given context [60,62,67,68,77]. In developmental conditions, METTL3-dependent methylation of notch1a recruits YTHDF2 to promote transcript decay during zebrafish endothelial-to-hematopoietic transition [26,60]. Similarly, in human epithelial cells YTHDF2-mediated degradation of NOTCH1 limits downstream effectors such as HES1 and HES5 [67]. In malignancies, however, the same chemical mark can support the opposite outcome. [62,68,77]. YTHDF1 stabilizes and enhances translation of m6A-modified NOTCH1 in HCC, reinforcing stem-like traits and therapy resistance [77]. In nasopharyngeal carcinoma, IGF2BP3 preserves NOTCH3 mRNA by protecting it from deadenylation, thereby sustaining metastatic behavior [68]. A similar stabilizing effect is seen in T-ALL, where IGF2BP2 maintains NOTCH1 expression; pharmacologic inhibition of IGF2BP2 with the small molecule JX5 successfully attenuates leukemogenesis [62,176,177]. In addition, removal of m6A marks by erasers can function as a key developmental checkpoint, as ALKBH5 deficiency accelerates decay of Jagged1 and Notch2 transcripts and relaxes lineage restraints during γδ T-cell development [163,178,179,180]. Taken together, these findings support a model in which epitranscriptomic machinery dynamically controls Notch signaling through reader-specific promotion of transcript decay or stabilization [60,62,68,77].
This reader-dependent hierarchy, along with the differentiation between direct Notch RNA targets and indirect upstream rewiring, can be structured into a translational landscape that emphasizes contexts in which epitranscriptomic interventions or traditional Notch-directed agents are most likely to be efficacious (Figure 2).
The direct epitranscriptomic modification of Notch transcripts opens a promising avenue for targeted therapeutic intervention [60,62,68,77]. When a Notch transcript is the direct epitranscriptomic substrate, reader-focused intervention may offer a proximal approach to modulate pathway activity compared to broad targeting of the m6A machinery [60,68,77]. The IGF2BP2 inhibitor JX5 provides a concrete example, as in T-ALL, it reduces NOTCH1 expression and suppresses leukemogenesis in vivo [62]. Given the substantial limitations and toxicities associated with classical Notch-directed therapies such as γ-secretase inhibitors, small-molecule modulators of the m6A machinery, exemplified by JX5, may represent safer alternative strategies [62]. Accordingly, incorporating these RNA-modifying interventions into preclinical pipelines could enable rational combination regimens designed to counteract Notch-driven malignancies [62,77].

8. Conclusion and Future Directions

Current evidence supports that epitranscriptomic regulation functions as a precision layer superimposed on the intrinsically dosage- and duration-sensitive Notch pathway. Studies indicated that m6A can either destabilize transcripts in development or stabilize and enhance them in cancer and immune-lineage settings, according to the reader engaged [57,60,102,181]. In a wide array of additional Notch-dependent systems ranging from intestinal and epidermal epithelia to glioma, neurodevelopment and neurodegeneration, and inflammatory microenvironments, epitranscriptomic regulation clearly influences cellular state, yet the directly modified RNAs that mechanistically connect these programs to Notch signaling remain incompletely assigned [57,60,62,68,70,77,99,163]. Notably, the main challenge is to distinguish direct transcript-level regulation from broader regulatory systems.
Looking forward, a key objective will be comprehensive mapping of the Notch epitranscriptome across tissues and disease states. Single-nucleotide-resolution modification profiling in combination with quantitative measurements of decay, export, and translation will be essential for determining which NOTCH, DLL/JAG, and HES/HEY transcripts are directly regulated under biological conditions. Applying the same four-point mechanistic checklist across endothelial, epithelial, neural, vascular, and immune compartments should also clarify whether a conserved core of epitranscriptomic Notch regulation exists or whether most interactions are fundamentally context-specific. Equally important will be defining the true contribution of non-m6A marks, including m5C and A-to-I editing.
From a translational standpoint, the most promising scenarios are those dominated by a single writer-reader-transcript triad at a pivotal decision node. Examples such as YTHDF1-m6A-NOTCH1 in HCC stemness and kinase-inhibitor resistance, IGF2BP3-m6A-NOTCH3 in nasopharyngeal carcinoma metastasis, or IGF2BP2-m6A-NOTCH1 in T-ALL, illustrate the value of directly targeting reader proteins in selective modulation of Notch output at the RNA level [62,68,77]. However, epitranscriptomic intervention will likely function best in combination with established Notch-directed approaches, including γ-secretase inhibitors, receptor-directed antibodies, or conventional anticancer therapies. As increasingly sophisticated transcript-resolved and single-cell approaches are applied to this field, a more unified framework should emerge for integrating RNA-modifying enzymes and reader proteins into strategies aimed at precise control of Notch signaling in development, regeneration, immunity, and disease.

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Preprints 217413 g001
Figure 1. A schematic representation of classic Notch signaling between neighboring ligand-expressing and receptor-expressing cells, illustrating ligand binding, sequential S2 and S3 cleavage, NICD release, nuclear translocation, and RBPJ-mediated activation of HES/HEY transcription. The lower panel delineates RNA-level regulatory mechanisms influencing Notch-related transcripts, encompassing m6A-associated splicing and polyadenylation, nuclear export, transcript stability or degradation, translational regulation, and potential RNA editing and conceptual module for A-to-I RNA editing.
Figure 1. A schematic representation of classic Notch signaling between neighboring ligand-expressing and receptor-expressing cells, illustrating ligand binding, sequential S2 and S3 cleavage, NICD release, nuclear translocation, and RBPJ-mediated activation of HES/HEY transcription. The lower panel delineates RNA-level regulatory mechanisms influencing Notch-related transcripts, encompassing m6A-associated splicing and polyadenylation, nuclear export, transcript stability or degradation, translational regulation, and potential RNA editing and conceptual module for A-to-I RNA editing.
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Figure 2. Conceptual framework that connects therapeutic potential to both direct and indirect epitranscriptomic modulation of Notch signaling. Zebrafish endothelial-to-haematopoietic transition, hepatocellular carcinoma, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma, and epithelial systems are among the typical disease settings that are displayed with direct Notch RNA targets. Potential therapies such as writer or reader inhibitors, m6A site-specific editing, γ-secretase inhibitors, anti-NOTCH antibodies, and combination methods are displayed with indirect Notch rewiring through noncanonical targets. While dashed arrows show sensitizer or combination logic, solid arrows show situations where the epitranscriptomic axis is probably a key therapeutic handle.
Figure 2. Conceptual framework that connects therapeutic potential to both direct and indirect epitranscriptomic modulation of Notch signaling. Zebrafish endothelial-to-haematopoietic transition, hepatocellular carcinoma, T-cell acute lymphoblastic leukemia, nasopharyngeal carcinoma, and epithelial systems are among the typical disease settings that are displayed with direct Notch RNA targets. Potential therapies such as writer or reader inhibitors, m6A site-specific editing, γ-secretase inhibitors, anti-NOTCH antibodies, and combination methods are displayed with indirect Notch rewiring through noncanonical targets. While dashed arrows show sensitizer or combination logic, solid arrows show situations where the epitranscriptomic axis is probably a key therapeutic handle.
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