m6A RNA modification and its emerging roles in diseases: recent advances and therapeutic implications

Abstract

Background

In the recent past, insights in post transcriptional regulation of gene expression have profoundly reshaped our understanding of the molecular mechanisms underlying health and disease. This paradigm shift largely stems from the emerging field of epitranscriptomics, which highlights the pivotal role of chemical RNA modifications. While more than 170 distinct chemical modifications on the RNA are known, the m6A modification is the most abundant internal mRNA modification in higher eukaryotic cells, present not only on protein coding transcripts but also on non-coding RNAs, regulated by “writers”, “erasers”, and “readers” that together modulate alternative splicing, nuclear export, translation efficiency, and mRNA stability.

Main body

This review addresses an important gap by presenting a multilayered regulatory framework that catalogs the full repertoire of m6A machinery and uniquely reveals how non-coding RNAs, transcription factors, histone modifications, and chromatin remodelers governs the spatiotemporal specificity of m6A modification. We explore how dysregulation of m6A modification and its regulatory proteins contribute to the development and progression of various diseases such as cardiovascular disease, neurological disorders, cancer, and type 2 diabetes through context-dependent modulation of gene networks. Furthermore, we present an integrative overview of the therapeutic pipeline, tracing the development of small-molecule inhibitors targeting m6A regulators, thus bridging a crucial link between fundamental mechanisms and new therapies.

Conclusions

Overall, this review integrates current findings and emerging insights to provide a comprehensive understanding of m6A biology. By linking upstream regulatory mechanisms with downstream pathological consequences and therapeutic interventions, we highlight the potential of targeting the epitranscriptome for clinical applications.

Introduction

With changing lifestyles and increasing sedentary habits, the role of the environment in determining cellular function, in addition to the contribution of genetic components, is greatly being researched and studied. Epigenetic modifications mainly include DNA methylation and histone modifications classified as primary epigenetic modifiers which regulate gene expression by altering DNA accessibility and chromatin structure. In recent years, epigenetic-like modifications on RNA, mainly methylations collectively termed epitranscriptomics, have gained the attention of researchers and are studied extensively in various contexts due to the advancements in epitranscriptome-wide mapping and detection methods. Such RNA modifications indirectly regulate gene expression, as implicated by effects on RNA stability and altered translation that determine cell fate and function.

RNA modifications are diverse, occurring across various RNA species, but are most extensively characterised among mRNAs. To date, more than 170 distinct chemical modifications on RNA have been identified. N6-methyladenosine (m6A) is the most abundant internal modification, the methylation occupying ~0.4–0.7% of adenosines; these are typically enriched near stop codons, at the beginning of terminal exons and within long internal exons. 5-methylcytidine (m5C) (~0.02–0.09% of cytidines) is primarily located in the coding sequence (CDS) and 3′ untranslated region (3′ UTR). Pseudouridine (Ψ) is found (~0.2–0.6% of uridines), distributed across the CDS, UTRs, and around start codons. Though less abundant, N1-methyladenosine (m1A) (~0.015–0.05% of adenosines) is concentrated in the 5′ untranslated region (5′ UTR). At the 5′ end of nearly all mature mRNAs, N7-methylguanosine (m7G) serves as the cap structure (0.002–0.05% prevalence), often followed by N6,2′-O-dimethyladenosine (m6Am), which appears in ~30–40% of capped transcripts (0.02–0.05%). Additionally, adenosine-to-inosine (A-to-I) editing (~0.1–0.2% of adenosines) occurs within 3′ UTRs, introns, and occasionally the CDS. N4-acetylcytidine (ac4C), although found at lower levels (~0.2% of cytidines), is localized to the CDS. Together, these modifications are not randomly distributed but strategically positioned to fine-tune mRNA function and post-transcriptional gene regulation [1, 2] (Fig. 1).

Fig. 1.

RNA modifications, structure and distribution. Eukaryotic mRNAs undergo diverse chemical modifications as shown. These modifications exhibit distinct enrichment patterns across key mRNA regions, including the 5’ UTR, CDS, and 3’ UTR. Their dynamic and reversible regulation is orchestrated by modification-specific proteins known as writers, readers, and erasers, highlighting the complexity and precise control of the RNA modification processes. 5′ untranslated region (5′ UTR); coding sequence (CDS); 3′ untranslated region (3′ UTR); 5-methylcytosine (m5C); 7-methylguanosine (m7G); inosine (I); N1-methyladenosine (m1A); N4-acetylcytidine (ac4C); N6,2′-O-dimethyladenosine (m6Am); N6-methyladenosine (m6A); pseudouridine (Ψ). Aly/REF export factor (ALYREF); adenosine deaminase acting on RNA 1 (ADAR1/2); adenosine deaminase acting on tRNA (ADAT2/3); AlkB homolog 1/3/5 (ALKBH1/3/5); DNA methyltransferase 2 (DNMT2); dyskerin pseudouridine synthase 1 (DKC1); fat mass and obesity-associated protein (FTO); methyltransferase like 1/3/14/16 (METTL1/3/14/16); N-acetyltransferase 10 (NAT10); NOP2/Sun RNA methyltransferase 1/2/3/4/5/6/7;(NSUN1/2/3/4/5/6/7); pseudouridine synthase (PUS1/2/3/4/5/6/7/8/9/10); pseudouridine synthase like (PUS7L); RNA pseudouridine Synthase Domain Containing 1/2/3/4 (RPUSD1/2/3/4); RNA binding motif protein 15 (RBM15/15B); RNA guanine-7 methyltransferase (RNMT); sirtuin 7 (SIRT7); tRNA methyltransferase 6/10 (6/10); tRNA methyltransferase 61A/61B (TRMT61A/61B);WD repeat domain 4 (WDR4); Wilms tumor 1–associating protein (WTAP); YTH N6-methyladenosine RNA binding proteins F1/F2/F3 (YTHDF1/F2/F3); YTH domain containing C1/C2 (YTHDC1/C2); zinc finger CCCH-type containing 13 (ZC3H13); zinc Finger CCHC-Type Containing 4 (ZCCHC4)

Among all these modifications, m6A is the most prevalent and comprehensively studied methylation-modification at the N-6 position of the adenosine moiety of mRNAs. MeRIP-seq studies demonstrated that m6A peaks are evolutionarily conserved between the human and mouse transcriptomes, present at tens of thousands of sites and occurring at a frequency of approximately 0.4–0.7% [3] of all adenosines [4]. m6A modifications mainly occur at RRACH signatures (R:Purine [G > A], A, C, H: U/A/C[U > A > C]) and is estimated to occur at an average of about three residues per mRNA [5].

While existing literature concentrates on m6A regulators as distinct entities, this review uniquely integrates a multilayered regulatory perspective by (i) revealing how upstream ncRNAs, transcription factors, and epigenetic machinery orchestrate m6A specificity through dynamic, context-dependent regulation of writer-eraser-reader activities; (ii) mapping context-dependent mechanisms and demonstrating why the same m6A regulator exhibits opposing biological roles across tissues and diseases and (iii) projecting a potential disease-to-therapy pipeline connecting tissue-specific m6A dysregulation to emerging epitranscriptomic inhibitors while systematically addressing translational constraints. This framework addresses a critical gap by explaining why studying dysregulated m6A levels in some conditions is essential for advancing epitranscriptomic medicine from target discovery to clinical efficacy. This review will focus on m6A regulation, their cellular effects and roles in diseases with a clue towards exploring its potential therapeutic implications.

m6A writers, erasers, and readers

The dynamic regulation of m6A is mediated by three distinct classes of proteins: methyltransferases, or “writers”, that catalyze the m6A deposition; demethylases, or “erasers”, that remove the methyl group; and m6A-binding proteins, or “readers”, that recognize and bind to m6A-modified transcripts and subsequently catalyze downstream cellular events. Their coordinated interplay enables the reversible addition, removal, and interpretation of m6A marks by subtly destabilising local RNA duplexes, acting as a “structural switch” that modulates splicing fidelity, translational reprogramming, decay kinetics, and subcellular trafficking over RNA metabolism and gene expression (Fig. 2).

Fig. 2.

Methylation and demethylation of m6A RNA modifications. The writing of m6A marks on RNA is coordinated by the methyltransferase complex (writers) that consists of METTL3, METTL14, WTAP, ZC3H13, and RBM15. Such methylation marks are read by reader proteins YTHDF1-3, YTHDC1, IGF2BPs, HNRNPC, HNRNPA2B1, and eIF3, which recognize and bind to the m6A-modified RNA to mediate its cellular functions. Demethylases, mainly FTO and ALKBH5, act as erasers to erase the methylation marks, thereby completing the cycle of methylation and demethylation. AlkB homolog 5 (ALKBH5); eukaryotic translation initiation factor 3 (eIF3); fat mass and obesity-associated protein (FTO); heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1); heterogeneous nuclear ribonucleoprotein C (HNRNPC/G); insulin-like growth factor 2 mRNA-binding proteins 1/2/3 (IGF2BP1/2/3); methyltransferase like 3/14 (METTL3/14); RNA binding motif protein 15 (RBM15); Wilms tumor 1–associating protein (WTAP); YTH N6-methyladenosine RNA-binding proteins (YTHDF1/2/3); YTH domain containing protein C1/C2 (YTHDC1/C2); zinc finger CCCH-type containing 13 (ZC3H13)

Writers

A multi-component m6A methyltransferase complex (MTC), known as m6A writers, facilitate the enzymatic addition of a methyl group on the N6 position of adenosine bases in RNA primarily at RRACH consensus motifs. This multicomponent complex is primarily composed of key writer proteins, including methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) heterodimer complex and additional adaptor proteins which includes Wilms’ tumor 1–associated protein (WTAP),Vir-like m6A methyltransferase-associated (VIRMA, also known as KIAA1429), HAKAI (E3 ubiquitin ligase CBLL1) [6], zinc finger CCCH type containing 13 (ZC3H13), and RNA-binding motif protein 15 (RBM15) [7, 8]

Within the m6A methyltransferase complex (MTC), METTL3 serves as the sole catalytic subunit of the MTC that binds to S-adenosylmethionine (SAM), which transfers the methyl group, while METTL14 is catalytically inactive but plays a vital structural and regulatory role by stabilizing the heterodimer, enhancing RNA substrate recognition, ensuring methylation fidelity and facilitating METTL3 catalytic activity. Together, METTL3 and METTL14 assemble into a stable 1:1 core complex that markedly enhances the catalytic efficiency of RNA methylation, while Wilms’ tumor 1–associated protein (WTAP) acts as a scaffolding and localization factor that guides the METTL3–METTL14 core complex to nuclear speckles [9].

Additional adaptor proteins further refine the specificity and spatial distribution of m6A modification. VIRMA (KIAA1429) confers positional selectivity by interacting with polyadenylation cleavage factors CPSF5 and CPSF6, directing the METTL3–METTL14–WTAP complex toward 3′UTRs and regions near stop codons, which are typically enriched in m6A sites [10]. HAKAI interacts with K homology (KH) domains in METTL3/WTAP via its RING domain, preventing their proteasomal degradation and maintaining m6A methyltransferase activity [6]. ZC3H13 contributes to complex stability by bridging interactions between RBM15 and WTAP while RBM15 and its paralog RBM15B function as sequence-specific adaptors that recognize U-rich motifs within RNA and recruit the writer complex to adjacent adenosines for methylation [7].

Apart from the core m6A writer complex, several distinct methyltransferases independently catalyze substrate-specific m6A modifications. Among these, the monomeric enzyme METTL16 installs m6A marks on U6 snRNA and MAT2A pre-mRNA, thereby regulating splicing and maintaining S-adenosylmethionine (SAM) homeostasis [11, 12]. Likewise, ZCCHC4 specifically methylates 28S rRNA [13], while the METTL5–TRMT112 methyltransferase complex modifies the 18S rRNA [14]. This intricate interplay between the core complex and accessory protein exemplifies the complexity of m6A modification on RNA.

Erasers

One of the defining characteristic features of m6A methylation is its reversibility, enabling post-transcriptional regulation, thereby facilitating regulation of RNA function. This process is mediated by m6A eraser proteins, which function as demethylases and catalyze the removal of m6A through a mechanism that requires ferrous iron and α-ketoglutarate as a cofactor and co-substrate, respectively [15]. As of date, two enzymes have been identified as m6A demethylases, namely fat mass and obesity-associated protein (FTO) and ALKB homologs ALKBH5 [16–18]. FTO, the first discovered demethylase, catalyzes demethylation of m6A in the presence of ferrous ions and α-ketoglutarate by oxidizing N6-methyladenosine (m6A) to N6-hydroxymethyladenosine (hm6A), which is further converted into N6-formyladenosine (F6A) and adenosine [15]. Studies show that FTO exhibits greater affinity for demethylating N6,2’-O-dimethyladenosine (m6Am) compared to m6A [19], and the demethylation of m6A and cap m6Am from polyadenylated RNA varies depending on their location in the nucleus or cytoplasm [20]. On the other hand, ALKBH5 specifically demethylates m6A and does not target m6Am; it regulates RNA synthesis and mRNA export from the nucleus [21].

Readers

m6A reader protein recognize and bind to m6A-modified RNA, regulating various RNA downstream processes. These include members of the YTH domain-containing family - (YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2) and the heterogeneous nuclear ribonucleoprotein (HNRNP) family - (HNRNPA2B1, HNRNPC, and HNRNPG). Additional m6A-binding proteins include insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, and IGF2BP3), eukaryotic initiation factor (eIF3), fragile X mental retardation protein (FMRP) [22], proline-rich coiled-coil protein (PRRC2A) [8, 23]. Among these, the primary nuclear m6A reader protein, YTHDC1 exhibits multifaceted roles [24]. By binding m6A-modified RNAs and recruiting context-specific partners, YTHDC1 modulates mRNA splicing [25], mRNA nuclear export and also suppresses proximal alternative polyadenylation by disrupting CPSF4–FIP1L1 interactions at m6A-adjacent polyadenylation sites [26, 27]. In addition, YTHDC1 specifically binds m6A-modified XIST lncRNA enabling its transcriptional silencing function during X-chromosome inactivation [28]. Other nuclear HNRNP family members contribute to m6A-dependent RNA processing through distinct mechanisms. HNRNPA2B1 facilitates pri-miRNA processing in cooperation with DGCR8 and regulates alternative splicing [29] while HNRNPC and HNRNPG exploit m6A-induced RNA structural remodeling to modulate RNA splicing and subcellular localization [23, 30].

In the cytoplasm, YTHDC2, representing the sole m6A reader with ATP-dependent RNA helicase activity, binds m6A-modified RNAs and utilizes its helicase domain to unwind mRNA secondary structures thereby regulating translation or promoting degradation processes by recruiting decay factors [31]. Other cytoplasmic readers display specialized and coordinated functions. YTHDF1 enhances translation initiation [32], whereas YTHDF2 facilitates degradation of m6A-modified mRNA [33]. In contrast, YTHDF3 acts synergistically with YTHDF1 to stimulate translation and concurrently modulates YTHDF2-mediated RNA decay [34]. Additionally, eIF3 directly binds to m6A residues within the 5‘UTR to unwind the secondary structure of the mRNA and recruiting the 43S pre-initiation complex for cap-independent translation during cellular stress [35]. IGF2BP1, IGF2BP2 and IGF2BP3 further contribute to cytoplasmic mRNA regulation by enhancing mRNA stability and translation [36]. In addition, PRRC2A recognizes GG(m6A)CU motifs in the cytoplasm through its GRE domain, where it promotes stability of m6A-modified transcripts by competing with YTHDF2 for binding sites [37]. Collectively, these m6A reader proteins, through their distinct yet coordinated molecular functions, form a finely tuned regulatory network that ensures precise control over RNA metabolism.

Effects of m6A on cellular transcripts

m6A exerts extensive control over the fate of mRNA transcripts, dynamically regulating RNA processing and gene expression at multiple levels. By modulating alternative splicing, nuclear export, translation, miRNA biogenesis, chromatin remodelling and mRNA stability through diverse writer, eraser, and reader proteins (Fig. 3), m6A fine-tunes cellular responses to environmental and developmental cues, supporting physiological functions and disease outcomes [38, 39].

Fig. 3.

The multifaceted role of m6A RNA modifications in regulating levels and functions of m6A-modified cellular transcripts. In the nucleus, depending on the position of methylation, (a) m6A affects alternative splicing in the presence of readers, namely YTHDC1, HNRNPC/G, and HNRNPA2B1; (b) mediates RNA degradation by YTHDF1 and YTHDC1; (c) promotes RNA stabilization through YTHDC1, IGF2BP1/2/3, and FMRP; and (d) facilitates mRNA export by YTHDC1 and FMRP protein. In the cytoplasm, m6A regulates translation (e) via YTHDF1/3, YTHDC2, and eIF3; controls mRNA degradation (f) through YTHDF2/3; and enhances mRNA stability (g) via YTHDF3, PRRC2A, IGF2BP1/2/3, and FMRP proteins. Such coordinated action of diverse reader proteins underscores the pivotal role of m6A in post-transcriptional gene expression regulation. YTH N6-methyladenosine RNA binding proteins 1/2/3 (YTHDF1/2/3); YTH domain-containing proteins C1/C2 (YTHDC1/C2); heterogeneous nuclear ribonucleoprotein C (HNRNPC/G); heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1); insulin-like growth factor 2 mRNA-binding protein 1/2/3 (IGF2BP1/2/3); fragile X mental retardation protein (FMRP); eukaryotic translation initiation factor 3 (eIF3); proline-rich coiled-coil protein 2A (PRRC2A)

Alternative splicing

Alternative splicing, a crucial post-transcriptional process, contributes to protein diversity by generating protein isoforms through mechanisms such as exon inclusion/skipping and intron retention within the RNA [39]. It involves processing of pre-mRNA into mature mRNA within the nucleus [40]. The m6A methyltransferase complex-METTL3, METTL14, WTAP and the demethylase ALKBH5, predominantly localize in domains enriched with splicing factors, known as nuclear speckles, suggesting their role in pre-mRNA processing. Although the demethylase, FTO mainly resides in the nucleoplasm yet it exhibits limited but overlapping localization with nuclear speckles [41]. m6A is deposited on exonic regions of nascent pre-mRNA, with intronic methylation occurring at lower levels [42]. On average, pre-mRNA transcripts contain about four m6A residues, which reduces to approximately two in a mature mRNA after splicing, reflecting its role in coordinating mRNA maturation [43]. Depletion of METTL3 in mouse embryonic stem cells leads to intron retention and exon skipping [44]. During spermatogenesis, METTL3 regulates the alternative splicing of transcripts SOHLH1 and DAZL through altered m6A deposition [45]. In addition, depletion of FTO in mouse pre-adipocytes leads to elevated m6A levels, enhancing binding of splicing factor SRSF2 to its target RNAs, promoting exon inclusion during splicing [46].

mRNA export

Following nuclear processing, mature mRNA is exported from the nucleus to the cytoplasm, regulating gene expression. Multiple studies highlight the critical role of m6A modifications in mRNA nuclear export, mediated by m6A readers [47]. ALKBH5 knockdown in macrophages alters nuclear-cytoplasmic distribution of antiviral transcripts, implicating the role of m6A in nuclear retention [48]. In contrast, increased methylation in ALKBH5-deficient mice enhances nuclear export in the cerebellum tissues exposed to hypobaric hypoxia [49]. METTL3 knockdown slowed down the circadian rhythm by reducing the export of mRNA clock factor transcripts ARNTL and PER2 [50]. In blood cancer, nuclear lncRNA MALAT1 interacts with METTL3–METTL14, hijacks fusion proteins and chimeric mRNAs in nuclear speckles, and their export from the nucleus [51]. YTHDC1 is known to bind to m6A-modified transcripts and facilitates their export to the cytoplasm. Its knockdown leads to nuclear accumulation and reduced cytoplasmic levels of these transcripts, a process mediated through YTHDC1’s interaction with SRSF3 [26]. During neural differentiation, Fragile X mental retardation protein (FMRP) binds m6A-marked mRNAs and drives their nuclear export via the XPO1-dependent export pathway [22].

Translational regulation

Once exported to the cytoplasm, reader proteins recognize m6A marks on mRNAs and modulate translation initiation, elongation, or termination depending on the m6A location, abundance, and the specific m6A-binding protein involved. For example, in mouse embryonic stem cells (mESCs) and embryoid bodies (EBs), translation efficiency was significantly increased on METTL3 knockdown, suggesting correlation of translation efficiency with m6A abundance on mRNA transcripts. [44]. Conversely, METTL3 interacts with eIF3 and cap-associated proteins to form a mRNA loop, and it binds close to the 3′ UTR stop codon and enhances translation via ribosome recycling [52]. Knockdown of YTHDF1 reduces translation efficiency of its target transcripts in an m6A-dependent manner, an effect intensified by concurrent METTL3 knockdown confirming YTHDF1’s role in promoting translation via m6A recognition [53]. m6A in the coding region can cause steric constraints, destabilising the codon-anticodon complex, leading to tRNA drop-off, and reducing the efficiency of translation elongation [54]. In the 5′ UTR, m6A interacts with eIF3 to facilitate recruitment of the 43S pre-initiation complex, promoting cap-independent translation initiation [35].

mRNA stability

m6A influences mRNA stability by directing transcripts either towards degradation or protection from decay, depending on the reader proteins involved. YTHDF2 promotes degradation by directly interacting with the CCR4–NOT transcription complex subunit (CNOT1) and recruiting the CCR4–NOT deadenylase complex, which removes the poly(A) tail, destabilising the mRNA and facilitating its decay within processing bodies (P-bodies) [33]. METTL3/14 knockdown increases the stability of target mRNAs for genes encoding developmental regulators by reducing m6A marks. Additionally, the mRNA stabilizer, HuR regulates transcript fate in an m6A-dependent manner—m6A near HuR binding sites reduces its affinity for mRNAs and facilitates their rapid decay [55]. While YTHDF2 typically promotes decay, IGF2BPs stabilize m6A transcripts by shielding them from degradation, demonstrating that m6A can enhance or suppress mRNA stability, depending on the reader and context involved [56].

Transcriptional regulation

Depending on the context, m6A along with reader proteins can also regulate transcription and balance the interplay between transcriptional activation and repression, according to the cellular requirements. For example, in mouse cells, m6A-modified lncRNA HEAT binds heat shock factor 1 (HSF1) to repress heat shock genes during stress by repressing their transcription. While m6A is dispensable for initial HSF1 recruitment to target promoters, it is essential for assembling a YTHDC1-centered transcriptional silencer complex, which recruits repressive factors like SETDB1 for H3K9me3 chromatin marks and RNA decay machinery [57].

Another study in human cells exemplifies m6A-mediated transcriptional repression through lncRNA scaffolding, in which METTL3–METTL14 deposits dense m6A marks on XIST lncRNA, which recruits the adaptor proteins RBM15 and RBM15B, which further bridges with the nuclear m6A reader YTHDC1. YTHDC1 binding retains XIST on chromatin, enabling heterochromatin factors like PRC2 recruitment to repress the entire X chromosome. Loss of METTL3 reduces XIST m6A, impairing RBM15/YTHDC1 binding, and leading to derepression of X-linked genes suggesting a role of m6A in transcriptional repression [28]. Recent studies have also shown that m6A methylation on enhancer RNAs (eRNAs), particularly long eRNAs, modulates their own transcription and that of downstream target genes. These m6A marks recruit YTHDC1, whose C-terminal intrinsically disordered region (IDR2) and arginine residues drive phase separation into nuclear liquid-like condensates that co-localize with BRD4 (bromodomain-containing protein 4) coactivators, enhancing strong enhancer activity and target gene induction [58].

miRNA biogenesis

m6A, primarily known for regulating mRNA fates, also modulates microRNA (miRNA) biogenesis. miRNA synthesis begins by the formation of pri-miRNAs, transcribed by RNA polymerase II, which are then processed into pre-miRNAs by the nuclear microprocessor complex (Drosha/DGCR8), then finally into mature miRNAs by cytoplasmic endoribonuclease Dicer [59]. Evidences indicate that these steps are influenced by m6A modifications, thereby modulating miRNA biosynthesis. Studies have found that METTL3 methylates pri-miRNAs that are then recognised and processed by DGCR8. When METTL3 was depleted, binding of DGCR8 to pri-miRNAs was impaired, thus reducing levels of mature miRNAs while accumulating pri-miRNAs. In vitro processing reactions confirmed m6A sufficiency in promoting miRNA biosynthesis, thus establishing m6A as an important regulator of miRNA biosynthesis initiation [60]. In Arabidopsis thaliana, homolog of METTL3, mRNA adenosine methylase (MTA), adds m6A on pri-miRNAs and also interacts with RNA Polymerase II and TOUGH(TGH), a plant protein, further influencing miRNA biosynthesis. MTA-deficient mutant (mta) has decreased levels of microRNAs (miRNAs) but accumulates primary miRNA transcripts (pri-miRNAs), suggesting a role of m6A in miRNA biosynthesis [61]. Additionally, studies have also found that NF-κB activator protein (NKAP), interacts with DGCR8 and then recognizes and binds to the m6A site on pri-miR-25, thus further promoting its processing [62]. Also, HNRNPC directly binds m6A-modified sites on pri-miR-21 to enhance miR-21 expression [63]. Notably, HNRNPA2B1 promotes processing of select pri-miRNAs by recruiting DGCR8, yet inhibits cleavage of others, with the repressive mechanism remaining unclear [29].

Chromatin remodelling

Chromatin remodeling dynamically switches DNA between an open, transcription permissive state and a compact, repressive configuration, for DNA binding proteins. Recent studies have uncovered crosstalk between remodeling complexes and the m6A RNA modification. For example, BAF155, a core ATP-dependent chromatin remodeler, is post-transcriptionally silenced by the m6A writer-reader axis: RBM15 binds BAF155 transcripts, recruits METTL3, and deposits m6A marks that trigger YTHDC1-mediated decay, shortening BAF155 mRNA half-life. Consequently, loss of METTL3 or YTHDC1 stabilizes BAF155, enhancing chromatin opening and promoting pluripotency associated gene expression, whereas their up-regulation tightens chromatin and favours differentiation [7]. In mouse embryonic stem cells, genome-wide analyses reveal an inverse correlation between METTL3/YTHDC1 abundance and chromatin accessibility: high METTL3/YTHDC1 levels coincide with reduced ATAC-seq signals, indicating a more closed chromatin landscape. Mechanistically, METTL3 installs m6A on chromosome-associated regulatory RNAs (carRNAs); YTHDC1 recognizes these marks and directs rapid degradation of the carRNAs, thereby limiting their ability to scaffold open chromatin modifying complexes [64].

These suggest that m6A modifications act as epitranscriptomic switches, exerting diverse modulatory effects on RNA processing that can either promote or inhibit a range of physiological processes.

Regulation of m6A

The activities of m6A writers, erasers, and readers are tightly controlled by multiple upstream layers including ncRNAs, transcription factors and epigenetic modifications (Fig. 4). These regulatory networks ensure highly dynamic and context-specific modulation of m6A methylation.

Fig. 4.

Regulatory factors modulating the m6A machinery and influencing m6A patterns. The cellular factors that regulate the epitranscriptomic machinery include epigenetic modifications such as DNA methylation and histone modifications, ncRNAs and transcription factors that alone or together orchestrate the expression and activity of m6A writers, erasers, and readers. Through these multilayered controls, m6A modifications dynamically regulate mRNA metabolism, mainly splicing, export, translation, stability, and degradation, thereby ultimately impacting a wide range of downstream cellular functions and physiological processes. AlkB homolog 5 (ALKBH5); fat mass and obesity-associated protein (FTO); methyltransferase like 3/14 (METTL3/14); non-coding RNA (ncRNA); Wilms tumor 1–associating protein (WTAP)

ncRNAs and m6A crosstalk

ncRNAs play an active role in regulating m6A modifications by interacting with the regulatory enzymes and modulating the stability and half-life of m6A proteins [65]. LINRIS lncRNA knockdown leads to repressed expression of IGF2BP2 in colorectal cancer (CRC), while LNC942 upregulates METTL14 in breast cancer, thus affecting the stability of downstream mRNAs [66, 67]. The lncRNA, GATA3-AS, recruits VIRMA to methylate GATA3 pre-mRNA, leading to decreased GATA3 expression in liver cancer and promoting metastasis [68]. In bladder cancer, the circRNA, circ0008399, binds WTAP thereby influencing the expression of target RNA via m6A modification and reducing cisplatin sensitivity [69]. In triple negative breast cancer (TNBC) cells, circMETTL3 sponges miR-34c-3p, which upregulates the expression of METTL3, thereby inhibiting proliferation, invasion, and metastasis of the tumor cells [70]. In addition, miRNAs also regulate m6A by targeting the m6A machinery and, in turn, altering m6A levels. For instance, in hepatocellular carcinoma (HCC), microRNA-145 targets the 3’UTR of YTHDF2 and inhibits its expression [71], and miR-186 targets METTL3, thereby activating Wnt/β-catenin signaling in hepatoblastoma [72].

Transcription factors

Several transcription factors directly regulate m6A by recruiting the m6A machinery to specific gene loci. In Embryonic stem cells (ESCs), zinc-finger protein 217 (ZFP217) activates key pluripotency and self-renewal genes and binds METTL3, sequestering it to prevent the deposition of m6A on ZFP217 target transcripts, thereby affecting its expression [73]. In AML (acute myeloid leukemia), SPI1 suppresses the expression of METTL14, suggesting a role for transcription factor-mediated repression [74]. SMAD2/3 recruits the METTL3–METTL14-WTAP complex to the NANOG transcript, thereby increasing m6A methylation and reducing its stability as a mechanism to promote differentiation [75]. Additionally, METTL3 interacts with CEBPZ (CCAAT/enhancer binding protein zeta) to methylate transcripts that drive leukemogenesis, aiding translation and maintaining the leukemic phenotype [76].

Epigenetic factors

Epigenetic factors, involving changes in DNA methylation, histone modifications, and chromatin remodeling, can regulate m6A modification. In pancreatic cancer, cigarette smoke condensate (CSC) weakens the binding of DNMT1 and DNMT3a to the METTL3 gene promoter, resulting in increased levels of METTL3, contributing to tumor progression [62]. In esophageal squamous cell carcinoma, CSC induces hypomethylation of CpG islands in the ALKBH5 promoter region, leading to increased ALKBH5 expression [77]. Chromatin remodeling and m6A modification also involve reciprocal regulation, modulating chromatin state and gene expression. RBM15 reduces the stability of BAF155 mRNA, a chromatin remodeling factor, via METTL3 [7]. In mouse ESCs, METTL3 and YTHDC1 negatively regulate chromatin accessibility by methylating and degrading chromosome-associated regulatory RNAs (carRNAs), thereby affecting chromatin state and transcription [64]. Significant crosstalk between m6A and histone modifications also exists that affects transcript biosynthesis and processing. H3K36me3, a marker of transcriptional elongation, plays a key role in guiding m6A deposition on RNA. Loss of H3K36me3 (via SETD2 knockdown or KDM4A overexpression) reduces global m6A levels. Mechanistically, METTL14 binds H3K36me3 at transcribed chromatin regions, enabling localized m6A occupancy. Additionally, histone demethylase KDM5C represses METTL14 transcription by removing H3K4me3 at its promoter, highlighting the role of chromatin modifications in modulating m6A machinery levels [78]. In CRC, METTL14 is downregulated and negatively correlates with KDM5C. Knockdown of KDM5C increases the H3K4me3 enrichment at the METTL14 promoter, increasing METTL14 expression and demonstrating that KDM5C regulates m6A methyltransferase expression through histone modification at its promoter [79].

These multilayered regulatory mechanisms—spanning ncRNA interactions, transcription factor targeting, and epigenetic modification crosstalk—ensure precise spatial and temporal control of m6A installation and removal, enabling context-dependent and dynamic gene expression regulation.

m6A and disease

Emerging studies have revealed that abnormal patterns of m6A methylation and altered signatures of the epitranscriptomic machinery are closely linked in the development of numerous diseases, including cardiovascular diseases, neurological disorders, cancer, and metabolic diseases (Fig. 5). In this section, we discuss how m6A RNA modifications contribute to the onset and progression of diverse diseases.

Fig. 5.

Aberrant expression of m6A regulators of the epitranscriptomic machinery in diverse diseases. Altered expression signatures of m6A modification enzymes—mainly writers, readers, and erasers—in various diseases, including cardiovascular conditions such as atherosclerosis; neurological disorders like Alzheimer’s disease; multiple cancers, including breast cancer, colorectal cancer, acute myeloid leukaemia, and pancreatic cancer; and metabolic diseases such as type 2 diabetes are shown. Deregulated levels of m6A writers, readers, and erasers contribute to the disease pathogenesis by disrupting normal RNA methylation and impairing transcript levels of target mRNAs. AlkB homolog 5 (ALKBH5); fat mass and obesity-associated protein (FTO); insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2); methyltransferase like 3/14 (METTL3/14); Wilms tumor 1-associating protein (WTAP); YTH N6-methyladenosine RNA binding proteins 1/2/3 (YTHDF1/2/3); YTH domain containing 2 (YTHDC2); zinc finger CCCH-type containing 13 (ZC3H13)

Cardiovascular diseases

Cardiovascular diseases (CVDs) include a variety of diseases, primarily affecting the heart and blood vessels, causing morbidity and death globally. Recent studies have revealed that m6A modifications modulate essential cellular processes, including differentiation, proliferation, inflammation, autophagy, and apoptosis in cardiovascular cells, significantly contributing to the onset and progression of CVDs, including conditions such as cardiac hypertrophy, heart failure, ischemic heart disease, aortic aneurysm, vascular calcification, and pulmonary hypertension [80, 81]. Knockdown of METTL14 decreases FOXO1 expression, subsequently suppressing the expression of TNF-α-triggered inflammatory adhesion molecules like ICAM-1 and VCAM-1, thereby reducing endothelial inflammation and atherosclerosis progression [82]. WTAP slows atherosclerosis progression by elevating p16 expression by increasing m6A marks, which inhibits vascular smooth muscle cells (VSMC) proliferation and migration and limit plaque development [83]. Conversely, METTL3 exacerbated the inflammatory response by promoting PGC-1α degradation and enhancing adhesion of monocytes to endothelial cells [84]. FTO influences the phenotype of VSMCs by reducing m6A on KLF5 mRNA, promoting migration and phenotypic switching, and driving atherosclerosis progression and related conditions like aortic dissecting aneurysms [85]. Additionally, aortic dissection progression occurs by m6A-dependent inhibition of pri-miR-143-3p, mediated by ALKBH5, which promotes VSMC apoptosis, contributing to the weakening of the aortic wall [86]. In pulmonary hypertension, suppression of METTL3 and METTL14 mitigates disease progression by inhibiting the proliferation and migration of pulmonary arterial smooth muscle cells [87]. m6A also drives disease progression via the circRNA-miRNA-mRNA regulatory network [88]. In coronary heart disease, METTL3 modifies hypoxia-related mRNA at the 5’-UTR regions, facilitating their translation and causing hypoxia-induced injury [89]. FTO knockout mice show increased heart rate variability and altered ventricular repolarisation, resulting in cardiac remodeling which promotes arrhythmias [90].

Neurological diseases

Neural stem cell formation and regeneration are prominently regulated by the mRNAs involved in neurodevelopment and tissue repair [91]. Recent findings highlight a pivotal role of m6A modification in orchestrating the temporal regulation of mammalian cortical neurogenesis, fostering both neurogenesis and neuronal development. m6A methylation is abundantly present in the brain and is crucial for neural cell fate determination, neuronal maturation, and synaptic function. Conditional deletion of METTL14 or METTL3 in embryonic mouse brains delays the neuronal progenitor cell cycle, prolongs cortical neurogenesis into postnatal stages, and maintains populations of radial glia, demonstrating that m6A is indispensable for timely neural differentiation and CNS development [92]. m6A dysregulation and its associated proteins can disrupt neurological function, affecting brain volume and cognitive functions like learning and memory processes, thus promoting the development of neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, multiple sclerosis, and brain tumors [93]. In AD, aberrant m6A methylation together with reduced METTL3 in certain regions of the brain influences the expression of neurodegeneration-related genes. Elevated METTL3 modifies Lingo2 mRNA via YTHDF2 degradation, promoting amyloid precursor proteins and beta-site amyloid precursor protein cleaving enzyme 1 (BACE) interaction, increasing production of amyloid-beta (Aβ) and promoting plaque formation [94]. Hippocampal METTL3 and MFN2 expression is reduced in a mice model of Alzheimer’s disease (AD) [95]. METTL3 elevates m6A modification levels on MFN2 and this increases its transcript levels that alleviates mitochondrial dysfunction, amyloid-β accumulation, and cognitive deficits; on the other hand, decreased levels of MFN2 abrogates these protective effects, thereby authenticating the METTL3–MFN2 m6A regulatory axis in AD pathology [95]. METTL14 alleviates Aβ1–42-induced neuronal toxicity in AD through m6A methylation of CBLN4 mRNA, thereby enhancing its stability and elevating CBLN4 expression levels, and consequently inhibiting apoptosis, inflammation, oxidative stress, and endoplasmic reticulum stress in neuronal cells [96]. FTO regulates adult neurogenesis and cognition by upregulating Tuberous Sclerosis Complex 1 (TSC1) mRNA and increasing tau phosphorylation by activating the mTOR pathway [97]. In Parkinson’s disease (PD), decreased m6A levels in the stratum driven by ALKBH5 upregulation result in increased NMDA receptor 1 expression and dopaminergic neuron degeneration [98]. FTO expression is elevated in PD mouse models and its in vitro silencing mitigates ferroptosis-associated phenotypes in neuronal cells. Mechanistically, FTO directly targets NRF2, destabilizing NRF2 mRNA through m6A demethylation [99]. In contrast, METTL14 suppresses TRAF6 expression via m6A methylation, leading to inactivation of the cGAS-STING pathway and thereby alleviating mitochondrial dysfunction and ferroptosis in dopaminergic (DA) neurons during PD [100]. Consistently, in PD mouse models, NRF1 alleviates motor dysfunction and dopaminergic neuron degeneration by transcriptionally activating METTL3, leading to enhanced m6A methylation of GLRX mRNA [101]. m6A modifications are linked to neuropsychiatric disorders like autism and schizophrenia [102]. In ischemic stroke, reduced FTO levels elevate m6A modifications on inflammatory and apoptotic transcripts and worsen stroke prognosis [103, 104]. All these suggest implications of aberrant m6A methylation in impaired neuronal physiology.

Cancer

Recent advances in epitrancriptomics have highlighted the role of m6A modifications in cancer, with its dysregulation driving tumor initiation and progression. Altered m6A methylation promotes uncontrolled proliferation, impaired differentiation, tumorigenesis, invasion, and metastasis. m6A regulators can function either as promoter or inhibitor for cancer progression by regulating oncogenes and tumor suppressor genes [105]. METTL3/14 promote cancer by stabilising lipogenesis-associated lncRNAs (LINC00958 and lncDBET) and enhancing lipid metabolism [106, 107]. In addition to modulating coding transcripts, m6A maintains oncogenic feedback loops via ncRNAs such as DANCR and FAM225A, which promote metastasis in pancreatic, ovarian, and head and neck cancers [108]. Conversely, ncRNAs can modulate m6A pathway components, forming intricate autoregulatory feedback loops that control cancer cell behaviour. Furthermore, m6A modifications intersect with major oncogenic signaling cascades – AKT, NF-κB, MAPK, and ERK pathways – demonstrating their multifaceted role in supporting tumorigenesis and its progression. m6A regulators also impact immune regulation within the tumor microenvironment (TME). METTL3 controls T cell differentiation and homeostasis by regulating suppressor of cytokine signaling (SOCS) transcripts, impacting IL-7–STAT5 signaling [109]. It also intersects with mTOR signaling to modulate tumor metabolism. In gastric cancer and retinoblastoma, METTL3 enhances proliferation, invasion, and EMT by activating downstream targets of the PI3K–Akt–mTOR and Wnt pathways under conditions of altered m6A [110]. Cancer-type-specific targets of m6A are well documented. In colorectal cancer (CRC), METTL3 drives invasion and metastasis of tumor by activating MAPK signaling by methylation of pri-miR-1246 and thereby decreasing SPRED2 expression [111]. FTO functions as an oncogene by targeting MYC [112], while ALKBH5 functions as a repressor by targeting RP11 [113]. FTO also modulates aerobic glycolysis in colon cancer by regulating PKM2 expression. While its overexpression enhances glycolytic activity in colon cancer cells, its depletion attenuates glycolysis, highlighting a direct functional association between FTO and PKM2 [114]. In parallel, METTL3-mediated m6A modification upregulates RanGAP1 expression by facilitating YTHDF1-mediated mRNA translation, leading to CRABP2 suppression and subsequent activation of the MAPK pathway, which collectively drives colorectal cancer progression [115].

Additionally, IGF2BP2 promotes glycolysis and tumor growth by modulating MYC- related genes expression [66]. In breast cancer, METTL3 interacts with HBXIP, repressing tumor suppressor let-7 and enhancing cell proliferation [116]. Studies suggest that certain writers such as METTL3, METTL14, and ZC3H13 can act as tumor suppressors [117]. For instance, in triple-negative breast cancer, METTL3 reduces COL3A1 expression via m6A modification, which inhibits its metastasis potential [118]. Conversely, in pancreatic cancer, METTL14 promotes proliferation and migration by destabilising PERP mRNA, a key factor in p53-mediated apoptosis, while METTL3 stabilizes ID2 mRNA through interaction with YTHDF2, thereby activating the PI3K-AKT pathway and increasing stemness factors, NANOG and SOX2 and tumor growth [119, 120]. Similarly, METTL3-driven m6A modification of circCEACAM5 facilitates pancreatic cancer progression by increasing DKC1 expression and conversely, silencing of METTL3 reverses circCEACAM5-dependent malignant traits [121]. In contrast, ALKBH5 modulates WIF-1, PER1 and the lncRNA KCNK15–AS1, inhibiting tumor progression [122]. YTHDF2 plays a dual role; it binds to m6A sites on YAP, destabilising it and inhibiting migration and invasion, but paradoxically promotes proliferation through activation of the AKT/GSK3β/cyclin D1 pathway [123]. In acute myeloid leukemia (AML), METTL14 overexpression due to the abnormal downregulation of its upstream negative regulator SPI1 promotes development and maintenance and enhances the self-renewal of leukemia-initiating cells (LSC/LICs) by stabilising and enhancing the translation of MYC and MYB mRNA [74]. FTO decreases m6A methylation on ASB2 and RARA mRNAs, thereby inhibiting ATRA-induced differentiation of AML cells, promoting leukemic transformation and leukemogenesis [124]. Elevated expression of METTL3 has been consistently reported in CRC as well as in gastric, lung, breast, and liver malignancies, particularly in metastatic tumors compared to para-cancerous tissues, and is strongly correlated with poor clinical prognosis [122]. It predominantly exhibits oncogenic roles in haematological malignancies and solid tumors but has a tumor suppressor role in endometrial cancer [125]. METTL3 levels are elevated in lung adenocarcinoma, and both its knockdown and overexpression studies reveal METTL3 significantly promotes proliferation, survival, and invasiveness in lung cancer cells [126]. ALKBH5, too, exhibits variable effects—functioning as either oncogenic or anti-oncogenic, depending on the cancer type—and is particularly linked to cancer stemness across several malignancies such as breast cancer, AML, glioblastoma, and gynaecological cancers [127–129].

Type 2 diabetes (T2D)

Type 2 diabetes (T2D) is a complex, polygenic hereditary condition shaped by the interplay of both genetic predisposition and environmental influences, with growing evidences linking environmental factors to epitranscriptomic regulatory mechanisms. Recent evidences suggest that epitranscriptomic modifications such as m6A modulate key signaling and metabolic pathways—including insulin/IGF1-AKT-PDX1, MAPK/ERK, EGFR, cell cycle, and metabolic regulation [75, 130]. The primary affected organs -pancreas, liver, adipose tissue, and skeletal muscle—all exhibit unique m6A-related dysfunctions that together contribute to the diabetic phenotype.

Pancreas

The acquisition and maintenance of β-cell function, including insulin secretion, maturation, and proliferation, are essential for maintaining glucose homeostasis, and their disruption is associated with the progression of T2D [131]. Aberrant m6A methylation patterns in pancreatic islets drive β-cell dysfunction in T2D [132]. m6A sequencing of pancreatic islets from T2D individuals and HFD mice revealed a global reduction in m6A methylation, primarily affecting genes that regulate the cell cycle and the insulin/IGF1-AKT-PDX1 signaling pathway [133, 134]. Knockout of METTL3/14 in β-cells leads to reduced m6A methylation [135], lower proinsulin and insulin levels, increased β-cell apoptosis, impaired cell differentiation, and reduced β-cell mass, leading to glucose intolerance and diminished insulin secretion [136]. METTL3/14 are crucial for maintaining neonatal β-cell identity, maturation, and mass expansion; their loss destabilises MAFA mRNA, causing impaired Glucose-Stimulated Insulin Secretion (GSIS), hyperglycemia, and hypoinsulinemia [137]. WTAP deficiency impairs METTL3 protein levels and β-cell function, while METTL3 overexpression partially rescues these effects. Mettl3-βKO and Wtap-βKO mice revealed downregulation of critical β-cell transcription factors and insulin secretion genes [138]. RNA sequencing in pancreatic β-cells of T2D patients shows downregulation of METTL14, FTO, ALKBH5, YTHDF1, HNRNPC, and YTHDF3 and elevated expression of IGF2BP2-3 [133, 139]. Knockdown of FTO in β-cells reduces GSIS, downregulates insulin mRNA, and upregulates genes crucial for maintaining β-cell identity [140]. IGF2BP2 binds the m6A-modified site on PDX1 mRNA, enhancing its stability and translation, thereby promoting insulin secretion [139], while YTHDC1 modulates glucose metabolism by regulating mRNA splicing and export [141].

Liver

The liver regulates glucose and lipid metabolism to maintain systemic energy balance. Hepatic insulin resistance (IR), characterised by post-receptor defects in the insulin signaling pathway, is an early hallmark of T2D and is linked to the dysregulation of m6A methylation-mediated mRNA fate [142]. Accumulating evidence suggests that m6A is a negative regulator in hepatic IR. In both T2D patients and HFD mice, global m6A and METTL3 levels are upregulated, positively correlating with Homeostatic Model Assessment (HOMA-IR) and negatively with HOMA-β. Knockout of hepatocyte-specific METTL3 in HFD mice significantly enhanced insulin sensitivity by reducing METTL3-mediated stabilisation of fatty acid synthase (FASN) mRNA [143], whereas overexpression of METTL3/14 in NAFLD models enhances the stability of ACLY and SCD1 transcripts, promoting lipid synthesis and accumulation [144]. In inorganic arsenic (iAs)-induced T2D, METTL14 mediates m6A methylation of NLRP3 mRNA, increases its stability, and increases recognition by IGF2BP2, driving inflammasome activation and hepatic insulin resistance [145]. FTO regulates hepatic gluconeogenesis via FOXO1-mediated regulation of gluconeogenic genes, G6PC and PCK1 [146] and additionally influences leptin and glucose metabolism through m6A-independent activation of the LepRb–STAT3 signaling pathway [147]. YTHDC2 is downregulated in the livers of obese mice and NAFLD patients. It binds to the mRNAs of major lipogenic genes SREBP1c, FASN, SCD1, and ACC1, consequently reducing their mRNA stability and expression [148]. In contrast, YTHDF2 and eIF3G are upregulated in T2D mouse livers [144].

Adipose tissue

Adipose tissue orchestrates glucose and lipid metabolism by secreting adipokines. In insulin resistant adipose tissue (Adipo-IR), this regulation is impaired, impairing the suppression of lipolysis and leading to elevated circulating free fatty acids. These fatty acids accumulate in the liver and muscle, further compromising insulin sensitivity [149]. m6A modification is essential for proper adipose tissue development, regulating both stem cell differentiation into preadipocytes and adipocyte maturation. Its disruption impairs adipogenesis and exacerbates insulin resistance in T2D [150]. METTL3, in coordination with YTHDF2, regulates adipogenic differentiation by increasing JAK1 mRNA stability and activating the JAK1/STAT5/C/EBPβ signaling pathway [151]. In contrast, METTL3 is equally critical for brown adipocyte maturation, maintaining expression of thermogenic genes PRDM16, PPARG, and UCP1 [152]. WTAP promotes brown adipocyte differentiation by promoting METTL3/14 stability to mediate m6A modifications, thereby improving insulin sensitivity [153]. FTO regulates thermogenesis and white fat browning by reducing m6A levels on HIF1A mRNA, enhancing YTHDC2-mediated translation, activating thermogenic gene transcription (PPARGC1A, PRDM16, PPARG), driving UCP1 expression, and promoting beige adipocyte formation [154]. However, excess FTO leads to C/EBPβ overexpression, promoting adipocyte proliferation and lipid overload, which worsens insulin resistance [155]. Complicating this, FTO directly upregulates CCNA2 and CDK2 levels, stabilising their mRNAs to accelerate adipogenesis, while YTHDF2 promotes their mRNA decay, thereby inhibiting lipogenesis [156].

Skeletal muscle

Skeletal muscle accounts for approximately 80% of postprandial glucose disposal and is crucial in maintaining whole-body glucose homeostasis. As the primary site of insulin-stimulated glucose uptake, insulin resistance in skeletal muscle is a major driver of T2D development. METTL3 upregulation and elevated m6A levels promote skeletal muscle hypertrophy by methylating ACVR2A mRNA, promoting its YTHDF2-mediated degradation to limit growth [157]. METTL3 specifically regulates the proliferation-to-differentiation transition in muscle stem cells (MuSCs) and myoblasts and its expression is decreased after initiation of differentiation [158], while both METTL3 and METTL14 promote skeletal muscle cell proliferation and differentiation [159]. WTAP⁺/₋ mice show increased tyrosine phosphorylation of IRS-1, enhancing insulin sensitivity [160]. In T2D patients, FTO mRNA is significantly upregulated and contributes to insulin resistance by regulating p70/85-S6 kinase activity and PKB phosphorylation [161]. Through m6A demethylation, FTO suppresses the PPARβ/δ and AMPK pathways, both of which are important for mitochondrial function, fatty acid oxidation, and glucose uptake [162]. During myoblast differentiation, FTO expression increases, and its deletion reduces PGC-1α mRNA expression through inhibition of the mTOR–PGC-1α pathway, resulting in reduced mitochondrial energy output and increased myogenin levels [163].

These collective evidences establish that m6A modification is a crucial epitranscriptomic regulator across various diseases, including cardiovascular, neurological, and metabolic diseases such as type 2 diabetes and cancers. Table 1 presents an overview of m6A-modified RNAs, sites of methylation and correlation to varied diseases, associated regulatory proteins, functional outcomes and their potential treatment. Dysregulation of m6A or its modifying proteins fundamentally alters gene expression networks, driving improper cellular behaviors such as impaired differentiation, abnormal metabolism, dysregulated immune responses, and resistance to cell death that underlie these diverse pathologies.

Table 1.

Overview of m6A-modified RNAs, their methylation sites across diseases, associated regulatory proteins, functional outcomes, and their potential treatment

m6A modified RNA species	Location of m6A	Proteins involved	Outcome	Disease	Potential Treatment	Reference
miR-25-3p	Pri-miR25 splicing site	METTL3 NKAP	Increased miRNA biogenesis	Pancreatic cancer	-	[62]
miR-21	-	hnRNPC	-	Glioblastoma	Silencing hnRNPC	[63]
MYC mRNA	3` terminal exon	METTL14	Increased mRNA stability translation	AML	Depletion of METTL14 expression	[74]
MYB mRNA	-	METTL14	Increased mRNA stability and translation	AML	Depletion of METTL14 expression	[74]
FOXO1 mRNA	3`UTR	METTL14, YTHDF1	Translation promotion	Atherosclerosis	METTL14 Knock out	[82]
RP11 lncRNA	-	METTL3, hnRNPA2B1	-	CRC	Inhibiting RP11	[113]
COL3A1 mRNA	-	METTL3	-	TNBC	Targeting METTL3 or COL3A1	[118]
PERP mRNA	3’UTR	METTL14, YTHDF2	Decreased mRNA stability	Pancreatic Cancer	Inhibition of METTL14	[119]
ID2 mRNA	CDS	METTL3, YTHDF2	Increased mRNA stability	Pancreatic Cancer	-	[120]
YAP mRNA	-	YTHDF2	-	Pancreatic Cancer	Targeting YTHDF2	[123]
RARA mRNA	3` and 5`UTR	FTO, METTL3, METTL14	Decreased mRNA stability	AML	Inhibition of FTO	[124]
ASB2 mRNA	3`UTR	FTO, METTL3, METTL14	Decreased mRNA stability	AML	Inhibition of FTO	[124]
NANOG mRNA	3`UTR	ALKBH5	Increased mRNA stability	Breast cancer	Antagonists of ALKBH5	[127]
MAFA mRNA	Exon Region	METTL3, METTL14	Decreased mRNA stability	T2D (Pancreas)	Targeting METTL3, METTL14	[137]
PDX1 mRNA	Near stop codon	IMP2	Translation promotion	T2D (Pancreas)	M6A modulators	[139]
FASN mRNA	-	METTL3	Increased mRNA decay	T2D (Liver)	Inhibition of METTL3	[143]
ACLY mRNA	CDS	METTL3, METTL14, YTHDC2	Increased mRNA stability	HCC	Targeting YTHDC2	[144]
SCD1 mRNA	3`UTR	METTL3, METTL14, YTHDC2	Increased mRNA stability	HCC	Targeting YTHDC2	[144, 148]
HIF1A mRNA	CDS	FTO, YTHDC2	Translation promotion	Obesity (White adipocyte browning)	Inhibitor of FTO	[154]
CDK2 mRNA	-	FTO, YTHDF2	Increased mRNA decay	Obesity (adipogenesis)	Branched chain amino acids prevent obesity and adipogenesis	[164]

- : Not known or not available

Therapeutics of m6A

Distinct cell- and tissue-specific epitranscriptomic profiles are characteristics of varied physiological and pathological states. This enables precise targeting of key effector proteins using epitranscriptomic drugs to slow or reverse disease progression and holds promise for future clinical application. Current efforts to develop epitranscriptomic drugs are primarily focused on inhibitors targeting m6A writers and erasers. STM2457 and STM2120 are small-molecule inhibitors designed to target the catalytic activity of the METTL3–METTL14 heterodimer. Between these, STM2457 is a highly potent and selective inhibitor for METTL3, while STM2120 is structurally related but less active. In patient-derived xenograft mouse models, the METTL3 inhibitor, STM2457 impairs AML expansion by increasing the overall survival with a favourable tolerability profile and no long-term toxicity [165]. STM2457 has also been shown to reduce tumor growth in NAFLD-HCC [166] and CRC [167]. Inhibition of the METTL3 catalytic domain by STM2457 induces specific, lineage-dependent effects on normal haematopoiesis. In normal mice treated with STM2457, global m6A reduction triggers a bias towards the myeloid lineage and away from erythroid differentiation, resulting in reduced haemoglobin and red blood cell (RBC) counts with elevated platelet levels. Concomitant gene expression analysis reveals upregulation of interferon-response genes (Ifitm1, Cybb, Oasl2) across haematopoietic populations. Importantly, haematopoietic stem and progenitor cells (HSPCs) are selectively spared from these effects, demonstrating that lineage specification rather than stem cell function is affected. Critically, these haematopoietic alterations are transient and fully reversible upon drug cessation, with no long-term toxicity [168]. Beyond haematopoietic tissues, STM2457 demonstrates potent anti-tumor efficacy in NAFLD-HCC and CRC models while improving hepatic function and metabolic parameters in fatty liver disease models. In HepG2 hepatic cells, STM2457 protects cells from lipid-induced mitochondrial dysfunction, suggesting selectivity for malignant transformation while maintaining or improving hepatic homeostasis [169].

STM2120 is a structurally related METTL3 inhibitor identified during the development of STM2457 but exhibits significantly reduced potency. Unlike STM2457, STM2120 shows no inhibitory effect on normal haematopoietic cell proliferation or differentiation in vitro and does not impair AML cell growth. This lack of activity in both normal and leukaemic cells—despite sharing the same SAM-competitive binding mechanism—demonstrates that catalytic potency is essential for therapeutic efficacy. STM2120 serves as a reference control compound, validating that the biological effects observed with STM2457 are mechanism-dependent and potency-driven [165].

Other METTL3 inhibitors, such as UZH1a, UZH2 [170], and STM3006 [171], have been developed to increase specificity and cellular potency. UZH1a and UZH2 and structurally refined METTL3 inhibitors and are expected to induce similar on-target hematopoietic lineage effects as STM2457 due to their shared catalytic inhibition mechanism of METTL3. However, their detailed characterization in normal cells remain limited in current literature. UZH1a reduces m6A levels and inhibits proliferation and self-renewal in glioblastoma stem cells [172] while inducing apoptosis and cell cycle arrest in AML cells [173]. Building on UZH1a, UZH2 shows anti-cancer potential across multiple cancers, including AML, prostate cancer, and glioblastoma stem cells [174].

STC-15 (STM3480), the first METTL3 inhibitor to enter clinical trials (Phase 1, NCT05584111), is an orally bioavailable treatment for subjects with advanced malignancies [171]. Given its almost identical mechanism to STM2457, STC-15 offers a critical opportunity to evaluate whether the lineage-biased hematopoietic effects observed in preclinical METTL3 inhibition studies translate to clinically manageable effects in human patients. Preliminary Phase 1 safety data indicate a favorable tolerability profile with no dose-limiting toxicities at tested doses [175].

Parallel to METTL3 inhibitors, numerous epitranscriptomic drugs have been designed for inhibition of m6A erasers. FTO inhibitors include rhein, MO-I-500, MA/MA2, fluorescein, R-2HG, FB23/FB23-2, entacapone, CS1/CS2, Dac51, FTO-4, FTO-43, 18,097, and C6 [176]. FB23-2 is widely studied as a prototype FTO inhibitor, demonstrating potent anti-leukemic efficacy in AML xenograft mouse models through FTO-dependent m6A demethylation on apoptotic and differentiation pathways. FB23-2 increases global m6A levels with selective upregulation of p53 and apoptosis pathways in AML cells while minimally altering proliferation of normal bone marrow cells isolated from healthy donors in vitro, thereby achieving remarkable selectivity for leukemic cells [177]. Dac51 represents a more potent FTO inhibitor than FB23-2 (5-fold increased potency) and demonstrates remarkable selectivity for leukemic cells while showing minimal toxicity to normal bone marrow cells in preclinical studies. In T-cell acute lymphoblastic leukemia (T-ALL) models, Dac51 induced profound lethal effects on various T-ALL cell lines while sparing normal bone marrow cells. The compound achieves superior potency as compared to FB23-2, suggesting enhanced selectivity. Mechanistically, Dac51 targets the FTO-ELK3 metabolic axis in leukemic cells, suppressing glycolytic gene expression and inhibiting glycolysis. Notably, minimal body weight differences were detected between Dac51-treated and untreated animal groups, indicating tolerable systemic toxicity, if any [178].

ALKBH5 inhibitors comprise IOX1, MV1035, ALK04, Ena15, 20 m, and DDO-2728 [176]. These compounds reveal distinct tissue-selective effects based on differential ALKBH5-dependent substrate selectivity across cellular and tissue contexts. IOX1, an ALKBH5 inhibitor, shows tissue-selective protective effects in renal ischemia-reperfusion injury (IRI) models. Notably, IOX1 treatment alleviates renal IRI by modulating epitranscriptomic regulation through m6A accumulation on Ccl28 mRNA, enhancing its stability and influencing the Treg/inflammatory cell axis [179]. In normal renal tubular epithelial cells (HK-2 cells), ALKBH5 inhibition by IOX1 did not induce cytotoxicity but rather enhanced cell protection against cisplatin-induced ferroptosis. This renoprotective effect contrasts with toxicity profiles in other cellular contexts, suggesting that IOX1‘s effects in normal cell are tissue-specific and potentially beneficial in renal injury. The mechanism involves ferroptosis suppression through enhanced expression of antioxidant pathways, including glutathione (GSH) and glutathione peroxidase-4 (GPX4) [180]. IOX1 shows selectivity for epitranscriptomic targets without broad systemic toxicity in renal injury models. These findings position IOX1 as a renoprotective agent that can be selectively deployed for intervention of acute kidney injury. MV1035, an ALKBH5 inhibitor, reduces glioblastoma cell migration and invasiveness by increasing m6A RNA methylation. However, comprehensive characterization of MV1035‘s effects on normal cells remains limited in current literature. In glioblastoma stem cells (GSC), MV1035 alone does not significantly reduce cell viability but synergizesd with the chemotherapeutic drug, temozolomide (TMZ), suggesting mechanism-dependent selectivity for transformed cells. The compound achieves dual targeting of both ALKBH5 and ALKBH2, which may contribute to overcoming TMZ resistance through epitranscriptomic modulation [181]. The selective ALKBH5 inhibitor DDO-2728 demonstrates epitranscriptomic context-dependency through tissue-specific substrate selectivity. In acute myeloid leukemia, DDO-2728 suppresses tumor growth by targeting TACC3-dependent proliferation [182]. In normal tissues, DDO-2728 engages in distinct regulatory networks that promote protective phenotypes rather than toxicity. In myopia models, intravitreal injection of DDO-2728 attenuated myopia progression, suppressed inflammatory mediators, and modulated early extracellular matrix (ECM) dysregulation through suppression of ERK1/2 hyperphosphorylation. Importantly, genetic ablation of ALKBH5 recapitulated the protective phenotype, confirming on-target engagement. In normal retinal tissues, DDO-2728 elicited protective effects without overt toxicity, positioning it as a potential therapy for myopia control [183]. In cisplatin-induced acute kidney injury (AKI) models, DDO-2728 provided significant renal protection by suppressing ferroptosis-related pathways and improving renal function [180]. DDO-2728 suppressed tumor growth in a MV4-11 xenograft model while displaying satisfactory safety profiles, thereby advancing ALKBH5-targeted cancer therapy. However, DDO-2728 demonstrated relatively weak toxicity in normal HEK293 cells and HUVECs [182].

The epitranscriptomic drugs described above show the context-dependent selectivity wherein the same epitranscriptomic inhibitor produces dramatically different functional outcomes depending on tissue type, cellular state, and disease context. This context-dependency arises from tissue-specific expression patterns of m6A writers, erasers, reader proteins, and downstream effectors, enabling selective engagement of therapeutic targets while sparing or protecting normal tissue function. Although in-depth and extensive research is the need to wholly elucidate the clinical applications of epitranscriptomic drugs, the few molecules that have been researched upon have shown promise towards the potential of epitranscriptomic drugs for therapeutic intervention. Table 2 summarises small-molecule inhibitors of m6A writers and erasers, detailing their mechanisms, preclinical findings, and clinical stage.

Table 2.

Comprehensive list of small-molecule inhibitors of m6A writers and erasers, detailing their mechanisms, preclinical findings, and clinical stage

Drug name	Target protein	Binding mode and mechanism	Key biological findings	Preclinical Cell Models	Development stage/Clinical Trial ID	References
STM2457	METTL3	SAM-binding pocket antagonist; inhibits METTL3–METTL14 heterodimer	Impairs AML expansion; transient, reversible hematopoietic lineage bias (myeloid increased via interferon response; erythroid decreased with anemia; thrombocytosis); HSCs spared; favorable tolerability; fully reversible upon cessation	AML (PDX models); HepG2 hepatocytes	Preclinical; leads to STC-15 (NCTO5584111)	[165–169]
STM2120	METTL3	SAM-binding site antagonist; SAM-competitive (less potent variant)	Less active than STM2457; reference compound; no effect on normal hematopoietic proliferation/differentiation in vitro; does not impair AML cells	Human AML cell lines; Normal bone marrow cells	Preclinical	[165]
UZH1a	METTL3	SAM-competitive; structure-based design with increased selectivity	Decreased m6A levels; decreased GSC proliferation; increased apoptosis and cell cycle arrest in AML cells	Glioblastoma stem cells (GSCs); AML cell lines; Mouse xenograft models	Preclinical	[170, 172, 173]
UZH2	METTL3	SAM-competitive; enhanced binding vs UZH1a	Anti-cancer potential against AML, prostate cancer, GBM; decreased proliferation; increased cell death	AML cell lines; Prostate cancer cell lines; Glioblastoma stem cells; Mouse xenograft models	Preclinical	[170, 174]
STC-15 (STM3480)	METTL3	METTL3 catalytic domain antagonist; optimized for oral bioavailability	First METTL3 inhibitor in clinical trials (Phase 1, NCT05584111). Favorable tolerability profile; no dose-limiting toxicities at tested doses. Identical mechanism to STM2457; clinical monitoring of hematopoietic effects ongoing on	Phase 1 Clinical: Advanced solid tumors Preclinical: AML models	Phase 1 Clinical/NCTO5584111	[171, 175]
STM3006	METTL3	METTL3 catalytic domain-selective antagonist	Enhanced specificity; designed for reduced off-target effects; improved selectivity over STM2457	AML cell lines; In vitro and in vivo models (optimization ongoing)	Preclinical	[171]
FB23 (compound 16a)	FTO	L-shaped MA-pocket binding; Ser229 H-bond; Arg96 contact; 140-fold improvement over MA inhibitor	Decreased AML proliferation; increased m6A abundance; direct target engagement; potent structural precursor	AML models (in vivo studies)	Preclinical (in vivo)	[177]
FB23-2 (compound 16b)	FTO	L-shaped MA-pocket binding; improved penetration; intramolecular H-bond vs FB23	Increased m6A abundance; decreased AML proliferation; selective p53/apoptosis upregulation; minimal effects on normal bone marrow cells	AML cell lines (HL60, MV4-11); Normal bone marrow (from healthy donors); Mouse xenografts	Preclinical (in vivo)	[177]
Dac51	FTO	Selective FTO antagonist; blocks m6A demethylation on immune genes	5-fold potency vs FB23-2; T-ALL-specific: suppresses glycolytic gene expression; profound lethal effects on T-ALL cell lines; minimal toxicity to normal bone marrow; minimal body weight changes; tolerable systemic toxicity	T-ALL cell lines (KOPTK1, CUTLL1, etc.); Normal bone marrow cells (from healthy donors); Mouse xenograft models (T-ALL)	Preclinical (in vivo validated)	[178]
IOX1	ALKBH5 (limited FTO selectivity)	2-oxoglutarate analog; chelates Fe2 +/Mn2 + in AlkB domain; selective ALKBH5 inhibition with FTO cross-reactivity at higher concentrations	Alleviates renal IRI; modulates epitranscriptomic regulation through m6A accumulation; enhanced cell protection against ferroptosis in normal renal cells; preserved antioxidant pathways (GSH, GPX4)	Renal tubular epithelial cells (HK-2); C57BL/6J mice (renal IRI model); Normal kidney tissue showed selectivity	Preclinical	[179, 180]
MV1035	ALKBH5	Optimized for ALKBH5 restricted cavity; dual-target ALKBH5 + ALKBH2	Decreased GBM migration/invasiveness; increased m6A methylation; overcomes temozolomide (TMZ) resistance; synergizes with TMZ in patient-derived GSCs; partial monotherapy effect; synergistic combo activity	Glioblastoma stem cells (patient-derived lines); U87 GBM cells; HK-2 renal cells	Preclinical (in vitro validated; in vivo ongoing)	[181]
DDO-2728	ALKBH5	Selective ALKBH5 inhibitor; pyrazolo[1,5-a] pyrimidine scaffold	Paradigmatic example of context-dependency: • AML: Suppresses tumor growth via TACC3-dependent proliferation • Myopia: Attenuates progression; suppresses inflammatory mediators; modulates ECM dysregulation through ERK1/2 suppression • AKI: Suppresses ferroptosis; improves renal function • All contexts: Protective in normal tissues without overt toxicity	AML: MV4-11 xenografts Myopia: FDM mouse retinal models AKI: Cisplatin-induced AKI mice + HK-2 cells Normal tissues tested: Renal, retinal	Preclinical (multiple indications)	[180, 182, 183]

Conclusions

There has been an exponential growth in the field of epitranscriptomics in the recent years. Evidence suggests a significant role of m6A modification in post-transcriptional gene regulation and cellular metabolism. The dynamic interplay between the m6A regulators – writers, readers and erasers – is maintained for proper functioning of cellular processes, mainly splicing, stability, translation, and degradation. The function of m6A in health and disease is context-specific, determined by the coordinated action of m6A-associated proteins. Although extensive studies have revealed various aspects of m6A regulators, critical gaps remain in our understanding. The mechanisms responsible for the selective recruitment of these regulators to their targets, as well as the spatiotemporal regulation of m6A modifications, are yet to be explored. While reader proteins dictate the specific outcomes of m6A modifications, the molecular events that occur following m6A recognition remain to be fully characterized to better understand how m6A regulates cellular metabolism.Current m6A mapping methods offer various limitations related to precision, quantification, specificity and complexity. Towards more rapid, accurate and quantitative detection of m6A, sequencing and imaging techniques with high specificity and less complexity need to be developed to better understand the dynamic mechanisms of modified RNAs. Also, the development of advanced technologies for manipulating m6A marks will be essential for translating these insights into novel diagnostic tools and targeted therapies across a spectrum of human diseases. The discovery of novel m6A-interacting proteins will expand our understanding of other layers of gene regulation—such as DNA methylation, histone modifications, and other RNA marks—and will provide a broader and more interconnected perspective of the regulation of gene expression. Ultimately, comprehensive integration of m6A profiling with multi-omics datasets—including dietary, microbiota-derived, circadian, and environmental factors—will be critical towards achieving a deeper understanding of m6A-mediated regulatory mechanisms.

Abbreviations

3′ UTR

3′ untranslated region

5′ UTR

5′ untranslated region

ac4C

N4-acetylcytidine

AD

Alzheimer’s disease

ADAR1/2

Adenosine deaminase acting on RNA 1/2

ADAT2/3

Adenosine deaminase acting on tRNA 2/3

AKI

Acute kidney injury

ALKBH 1/3/5

AlkB homolog 1/3/5

ALYREF

Aly/REF export factor (ALYREF)

AML

Acute myeloid leukemia

CDS

Coding sequence

cGAS-STING

Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes

circCEACAM5

Circular RNA Carcinoembryonic Antigen Cell Adhesion Molecule 5

circRNA

Circular RNA

CNS

Central nervous system

CRABP2

Cellular Retinoic Acid Binding Protein 2

CRC

Colorectal cancer

CVD

Cardiovascular disease

DA

Dopaminergic neurons

DKC1

Dyskerin pseudouridine synthase 1

DNMT2

DNA methyltransferase 2

EMT

Epithelial-mesenchymal transition

ESC

Embryonic stem cell

FDM

Form-deprivation myopia

FTO

Fat mass and obesity-associated protein

GBM

Glioblastoma

GLRX

Glutaredoxin

GSC

Glioblastoma stem cell

HCC

Hepatocellular carcinoma

HNRNP

Heterogeneous nuclear ribonucleoprotein

HNRNPA2B1

Heterogeneous nuclear ribonucleoprotein A2B1

HNRNPC

Heterogeneous nuclear ribonucleoprotein C

HNRNPG

Heterogeneous nuclear ribonucleoprotein G

IGF2BP1

Insulin-like growth factor 2 mRNA-binding protein 1

IGF2BP2

Insulin-like growth factor 2 mRNA-binding protein 2

IGF2BP3

Insulin-like growth factor 2 mRNA-binding protein 3

I

Inosine

IR

Insulin resistance

IRI

Ischemia-reperfusion injury

KIAA1429

Vir-like m6A methyltransferase-associated

lncRNA

Long non-coding RNA

m1A

N1-methyladenosine

m5C

5-methylcytosine

m6A

N6-methyladenosine

m6Am

N6,2′-O-dimethyladenosine

m7G

7-methylguanosine

MeRIP-seq

Methylated RNA immunoprecipitation sequencing

METTL14

Methyltransferase-like 14

METTL16

Methyltransferase-like 16

METTL3

Methyltransferase-like 3

METTL5

Methyltransferase-like 5

miRNA

MicroRNA

mRNA

Messenger RNA

NAFLD

Non-alcoholic fatty liver disease

NAT 10

N-acetyltransferase 10

ncRNA

Non-coding RNA

NRF2

Nuclear factor erythroid 2-related factor 2

NSUN1/2/3/4/5/6/7

NOP2/Sun RNA methyltransferase 1/2/3/4/5/6/7

PD

Parkinson’s disease

PDX

Patient-derived xenograft

PKM2

Pyruvate Kinase M2

PUS 1//2/3/4/5/6/7/8/9/10

Pseudouridine synthase 1/2/3/4/5/6/7/8/9/10

PUS7L

Pseudouridine synthase like

RANGAP1

Ran GTPase Activating Protein 1

RBM15/15B

RNA-binding motif protein 15/15B

RNMT

RNA guanine-7 methyltransferase

RPUSD1/2/3/4

RNA Pseudouridine Synthase Domain Containing 1/2/3/4

rRNA

Ribosomal RNA

SAM

S-adenosylmethionine

SIRT7

Sirtuin 7 (SIRT7)

snRNA

Small nuclear RNA

T2D

Type 2 diabetes

T-ALL

T-cell acute lymphoblastic leukemia

TRAF6

TNF Receptor-Associated Factor 6

TRMT61A/61B

tRNA Methyltransferase 61A/61B

VIRMA

Vir-like m6A methyltransferase-associated (also known as KIAA1429)

WDR4

WD repeat domain 4

WTAP

WT1-associated protein

YTHDC1/2

YTH domain-containing 1/2

YTHDF1/2/3

YTH N6-methyladenosine RNA binding protein 1/2/3

ZC3H13

Zinc finger CCCH type containing 13

ZCCHC4

Zinc finger CCHC-type containing 4

ZFP217

Zinc-finger protein 217

Ψ

Pseudouridine

Authors contributions

M.D conceptualised and supervised the contents of the article; R.K, V.S and P.P collected the contents and wrote the first draft; all authors edited and approved the manuscript.

Funding

This work was supported by the SERB POWER Fellowship Awarded to M.D (SPF/2022/000135).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.