Next Article in Journal
Sustained Higher Levels of Plasma hsa-miR-17-5p Expression During Gestational Diabetes Mellitus and Postpartum
Previous Article in Journal
Comparative Mapping of N6-Methyladenine, C5-Methylcytosine, and C5-Hydroxymethylcytosine in a Single Species Reveals Constitutive, Somatic- and Germline-Specific, and Age-Related Genomic Context Distributions and Biological Functions
Previous Article in Special Issue
Role of Ionizing Radiation in Shaping the Complex Multi-Layered Epigenome
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Epigenomes
Volume 9
Issue 3
10.3390/epigenomes9030036
epigenomes-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

m6A RNA Methylation in Psychiatric Disorders: An Emerging Epitranscriptomic Axis

by
Ambrose Loc Ngo
1,
Linda Nguyen
2,
Niki Gharavi Alkhansari
1 and
Huiping Zhang
3,4,*
1
College of Osteopathic Medicine, Kansas City University, Farber-McIntire Campus, 2901 St. Johns Blvd, Joplin, MO 64804, USA
2
College of Pharmacy, Western University, California Campus, 309 E. Second St., Pomona, CA 91766-1854, USA
3
Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, Boston, MA 02118-2526, USA
4
The Biomedical Genetics Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, Boston, MA 02118-2526, USA
*
Author to whom correspondence should be addressed.
Epigenomes 2025, 9(3), 36; https://doi.org/10.3390/epigenomes9030036
Submission received: 30 July 2025 / Revised: 9 September 2025 / Accepted: 17 September 2025 / Published: 19 September 2025
(This article belongs to the Special Issue Features Papers in Epigenomes 2025)
Browse Figure
Versions Notes

Abstract

N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNA (mRNA) and plays a vital role in post-transcriptional gene regulation. In recent years, m6A has emerged as a pivotal epitranscriptomic signal involved in neural development, synaptic remodeling, and the molecular pathophysiology of neuropsychiatric disorders. In this review, we summarize the mechanisms underlying the deposition, removal, and recognition of m6A by dedicated methyltransferases, demethylases, and RNA-binding proteins. We further explore how these dynamic modifications influence neuronal differentiation and memory formation. Recent studies have linked aberrant m6A regulation to psychiatric conditions such as depression, anxiety, schizophrenia, and bipolar disorder. Additionally, we discuss how pharmacological or genetic modulation of m6A pathways may promote adaptive neural plasticity and enhance cognitive and emotional resilience. Despite these promising findings, significant challenges remain in achieving spatial and temporal specificity while minimizing off-target effects in the brain. Therefore, we advocate for more in-depth investigations into m6A function within developmentally defined neural circuits to better understand its enduring role in maintaining neural homeostasis.

1. Introduction

RNA modifications are redefining the landscape of gene regulation. At the forefront of this epitranscriptomic revolution is N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic messenger RNA (mRNA) [1,2]. m6A is estimated to occur in approximately 0.1–0.4% of all adenosines in mammalian mRNAs, typically amounting to ~3–5 m6A sites per transcript, with enrichment near stop codons, in 3′ UTRs, and in long internal exons [3]. The dynamic installation and removal of m6A are orchestrated by a tripartite enzymatic network: methyltransferase dimers, primarily METTL3 (methyltransferase-like 3) and METTL14 (methyltransferase-like 14), serve as “writers”; the demethylases FTO (fat mass and obesity-associated protein) and ALKBH5 (alkB homolog 5) act as “erasers”; and “reader” proteins, notably those containing YTH domains, interpret the methyl mark to direct downstream outcomes [4]. This reversible chemical code modifies RNA without altering its sequence, adding a regulatory layer that is both flexible and tightly controlled [4]. m6A influences virtually every stage of mRNA metabolism, making its biological impact far-reaching. In the central nervous system (CNS), m6A is not merely an accessory mechanism but a key determinant of transcript behavior [5,6]. Genetic and pharmacological studies have shown that disruption of m6A pathways impairs embryonic neurogenesis, interferes with synaptic plasticity underlying learning, and compromises the adaptive remodeling of neural circuits [5,6,7]. These findings suggest that m6A represents a molecular “grammar” by which chemical modifications are translated into adaptive, behaviorally relevant neural responses.
Altered expression or activity of m6A-modifying enzymes has been linked to dysregulated neural gene expression, aberrant synaptic connectivity, and disrupted stress response circuitry [5,8]. These discoveries position m6A as a critical molecular nexus linking genetically encoded programs with dynamic environmental signals in the CNS [9]. Nonetheless, the precise mechanisms through which m6A influences the onset and progression of neuropsychiatric disorders remain incompletely understood. A major challenge lies in elucidating the cell-type-specific and circuit-level consequences of m6A signaling in the brain’s complex cellular environment. Moreover, understanding how environmental perturbations, such as chronic stress or repeated drug exposure, intersect with m6A dynamics may reveal novel insights into neural plasticity and vulnerability to mental illness.
This review seeks to bridge molecular mechanisms with clinically observable outcomes. We summarize recent advances clarifying m6A’s role in neuronal differentiation, synaptic plasticity, memory stabilization, and reward circuitry, and we explore how m6A dysregulation contributes to psychiatric disorders. Finally, we discuss the emerging potential of m6A-modifying enzymes and reader proteins as biomarkers and therapeutic targets in psychiatry and neurology, positioning the m6A epitranscriptome at the nexus of basic research and clinical translation.

2. Mechanisms of RNA Methylation

2.1. Overview of m6A Machinery

RNA methylation plays crucial roles in regulating cellular processes such as proliferation, differentiation, and stress responses [10]. It is mediated by a dynamic network of proteins commonly categorized as “writers,” “erasers,” and “readers”. Methyltransferases (“writers”) and demethylases (“erasers”) regulate the reversible methylation of N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA [11]. Transcriptome-wide mapping of m6A has shown that these sites are significantly enriched in certain 5′-DRA*CH-3′ sequences (where A* denotes the methylatable adenosine; D represents A, G, or U; R represents A or G; and H represents A, C, or U) [12,13]. The m6A methyltransferase complex (MTC) comprises three core catalytic subunits [METTL3 (methyltransferase-like 3), METTL14 (methyltransferase-like 14), and WTAP (Wilms tumor 1-associating protein)] alongside four regulatory subunits [VIRMA (also known as KIAA1429 or Vir-like m6A methyltransferase associated), ZC3H13 (zinc finger CCCH-type containing 13), HAKAI (also known as Cbl proto-oncogene like 1 or CBLL1), and RBM15 (RNA binding motif protein 15)] [11]. The core MTC, composed of METTL3, METTL14, and WTAP, catalyzes the methylation of adenosine residues in RNA. Regulatory proteins such as VIRMA, ZC3H13, HAKAI, and RBM15 enhance the specificity and subcellular localization of the complex. METTL3 functions as the primary catalytic component, METTL14 stabilizes METTL3 and enhances RNA binding, and WTAP acts as a scaffold protein critical for nuclear localization of the complex [14]. The regulatory subunits modulate the complex’s specificity and subcellular targeting.
Transcriptomic analyses using PAR-CLIP (photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation) have shown that WTAP and METTL3 cooperatively regulate gene expression and alternative splicing, especially for genes involved in transcription and RNA processing [15]. WTAP forms a stable complex with METTL3 and METTL14 and is essential for localizing the MTC to nuclear speckles, subnuclear domains enriched in pre-mRNA processing factors. WTAP is also required for the catalytic activity of METTL3; its absence significantly reduces METTL3’s RNA-binding capacity, suggesting it is essential for guiding the MTC to its mRNA targets [15].
“Reader” proteins, particularly those in the YTH domain family, recognize m6A-modified RNA and mediate its downstream effects. These include YTHDF1, YTHDF2, YTHDF3 (YTH N6-methyladenosine RNA binding proteins F1-F3), as well as YTHDC1 and YTHDC2 (YTH domain-containing proteins C1 and C2). YTH proteins bind m6A-modified RNA via a conserved YTH domain containing a hydrophobic binding pocket, often referred to as an “aromatic cage” [11]. This cage, formed by conserved aromatic residues, enables selective recognition of methylated RNA through π–π stacking and hydrogen bonding, distinguishing it from unmethylated transcripts [10]. The YTHDF proteins carry out distinct cellular functions due to differences in their low-complexity N-terminal regions: YTHDF1 primarily enhances translation, YTHDF2 promotes mRNA degradation, and YTHDF3 acts as a modulator, cooperating with both YTHDF1 and YTHDF2 to coordinate the translation and decay of target mRNAs [16,17]. YTHDC1 functions mainly in the nucleus, where it regulates mRNA splicing, export, and nuclear retention, whereas YTHDC2 operates in both the nucleus and cytoplasm to regulate mRNA stability and translation. However, its m6A-binding capacity is less well established, and it also possesses RNA helicase activity [18,19]. Additional m6A reader proteins include the insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, IGF2BP3), as well as heterogeneous nuclear ribonucleoproteins (HNRNPs) such as HNRNPA2B1 and HNRNPC. Members of the IGF2BP family bind m6A-modified RNA and promote mRNA stability and translation [20,21], whereas nuclear readers HNRNPA2B1 and HNRNPC recognize m6A-containing sites on nascent transcripts to regulate alternative splicing [22,23]. Together, these m6A reader proteins shape RNA fate and gene expression, thereby influencing diverse biological processes, including development, metabolism, stress responses, and disease.
m6A is a reversible mark, removed by demethylases or “erasers” such as fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5) [24]. FTO, the first identified m6A demethylase, catalyzes oxidative demethylation of m6A, affecting RNA stability and splicing [24]. Overexpression of FTO reduces global m6A levels, while its downregulation leads to increased m6A methylation [25]. Li et al. demonstrated that FTO depletion increases m6A modifications on mRNAs involved in ribosome biogenesis, thereby promoting their YTHDF2-mediated decay [26]. Similarly, ALKBH5 removes m6A marks and modulates nuclear RNA export, mRNA metabolism, and gene expression [27].

2.2. RNA Methylation in mRNA Regulation

Advances in epitranscriptomics have underscored the importance of post-transcriptional modifications in shaping gene expression in the nervous system. Chemical modifications such as m6A, N1-methyladenosine (m1A), and 5-methylcytosine (m5C), dynamically influence mRNA stability, translation, splicing, and intracellular localization. These reversible marks add a critical layer of control to mRNA function, governing key processes like neuronal development, synaptic plasticity, and the stress response.

2.3. m6A: A Central Epitranscriptomic Mark in the Nervous System

Among all known mRNA modifications, m6A is the most prevalent and well-characterized internal mark. It regulates transcript fate at multiple levels, including splicing, stability, transport, and translation, making it essential for neuronal function [28]. Emerging evidence suggests that m6A also plays a role in maintaining neural cell identity and differentiation [29]. m6A methylation affects the stability, splicing, translation, and subcellular localization of mRNA. In neurons, m6A-marked transcripts tend to localize to neurites, implicating this modification in local protein synthesis at synapses—crucial for synaptic plasticity and signaling [30]. FTO, by removing m6A near splice sites, modulates alternative splicing outcomes by influencing spliceosome assembly [25]. m6A also regulates alternative splicing through interactions with splicing factors like SRSF2 and influences translation efficiency by recruiting initiation factors. This regulation is particularly important in neurons, where rapid and spatially restricted protein synthesis is necessary for functional adaptation. In specific contexts, such as when m6A sites are located within coding regions, this modification can trigger translation-dependent mRNA decay, adding a level of fine-tuned control over transcript lifespan [29]. Additionally, m6A RNA methylation, particularly mediated by METTL3, promotes neuroinflammation by enhancing activation of the TRAF6–NF-κB pathway [31,32]. Through increasing the stability and/or translation of TRAF6 mRNA, m6A leads to elevated TRAF6 protein expression. The upregulated TRAF6 then activates NF-κB signaling, which drives the production of pro-inflammatory cytokines and thereby exacerbates neuroinflammatory responses.

2.4. m1A: A Marker of Neuronal Stress Adaptation

N1-methyladenosine (m1A) is another important epitranscriptomic mark, particularly in neuronal responses to stress [33]. In models of oxygen-glucose deprivation and reoxygenation (OGD/R), m1A levels increase markedly in primary neurons, suggesting a protective or adaptive reprogramming response [33]. Beyond mRNA, m1A affects noncoding RNAs by modulating long noncoding RNA (lncRNA)-protein interactions and facilitating circular RNA (circRNA) translation, expanding its regulatory scope beyond protein-coding genes [34].

2.5. m5C: Developmental Regulation in the Brain

5-methylcytosine (m5C) is another RNA modification implicated in neurodevelopment and neural lineage specification [35]. Distinct m5C methylation patterns are observed between neural stem cells and differentiated neurons, suggesting a role for m5C in transcriptomic remodeling during neuronal differentiation and brain maturation [35].
Taken together, epitranscriptomic modifications such as m6A, m1A, and m5C are now recognized as critical regulators of mRNA fate in the nervous system. By dynamically modifying RNA, these marks provide a reversible, fine-tuned mechanism for adapting gene expression in response to developmental cues and environmental challenges. Continued investigation into RNA modifications will enhance our understanding of brain function and may reveal novel therapeutic targets for neurodevelopmental and neurodegenerative disorders.

2.6. Genetic and Environmental Influences on m6A and Disease Susceptibility

Mutations or dysregulation of the m6A methylation machinery can disrupt the processes of installing, removing, or interpreting the m6A mark [36,37]. Such alterations affect RNA decay and transcriptional output. In parallel, environmental factors, including psychosocial stress, nutrition, and exposure to xenobiotics, can act as stress-like stimuli that reshape the m6A landscape and reprogram cellular transcriptional responses [38,39]. When combined with heritable risk, these context-dependent influences render homeostatic m6A regulatory mechanisms vulnerable to destabilization and adaptive restructuring. The cumulative effects of genetic and environmental perturbations can lead to aberrant changes in neuroectoderm-derived lineages and their glial progeny, laying the groundwork for the emergence of polygenic neurodevelopmental and mood disorders [40,41].

3. m6A Methylation in Brain Development and Function

m6A RNA methylation serves as a fundamental regulatory mechanism during brain development, modulating processes such as neurogenesis, dendritic and axonal development, and synaptic plasticity. As a dynamic and reversible epitranscriptomic mark, m6A influences the trafficking and local translation of mRNAs at synapses, a process essential for proper neuronal function [42]. m6A methylation is crucial for the timing and progression of neurogenesis. In the developing cortex, m6A facilitates the cell cycle progression of neural progenitor cells (NPCs), promoting their timely differentiation. Loss of m6A methyltransferase components such as METTL14 leads to prolonged NPC proliferation and delayed neuronal subtype specification, indicating that m6A promotes the decay of transcripts maintaining the progenitor state [43]. m6A marks are enriched on mRNAs encoding transcription factors and cell cycle regulators, highlighting their role in orchestrating neurodevelopmental gene expression programs [43]. In post-mitotic neurons, m6A regulates dendritic branching and axonal development. In retinal ganglion cells, the m6A reader protein YTHDF2 controls dendritic complexity by modulating the decay of target mRNAs. Knockdown of YTHDF2 increases dendritic branching, highlighting the role of m6A-mediated mRNA decay in shaping dendritic architecture [44]. Similarly, m6A modifications affect the subcellular localization and translation of mRNAs encoding axon guidance molecules and cytoskeletal components. Disruption of m6A pathways impairs axonal growth and pathfinding, underscoring the importance of m6A in establishing neural circuits [45]. m6A also plays a central role in synaptic regulation. Activity-dependent recruitment of the demethylase ALKBH5 to active synapses modulates local m6A levels, thereby regulating the translation of proteins involved in synaptic transmission and plasticity [46]. m6A-modified transcripts are enriched in dendrites and axons, enabling localized protein synthesis in response to neuronal activity, a process essential for synaptic remodeling, long-term potentiation (LTP), and memory formation. Figure 1 depicts RNA methylation dynamics and the roles of m6A regulators in neurodevelopment.

4. m6A Methylation and Learning and Memory

4.1. Mechanisms of m6A in Cognitive Function

Growing evidence supports m6A RNA methylation as a critical regulator of learning and memory. By modulating the stability, localization, and translation of brain mRNAs, m6A enables fine-tuning of synaptic gene expression in response to neuronal stimuli. This regulation affects transcripts encoding key synaptic proteins such as brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and activity-regulated cytoskeleton-associated protein (Arc), all of which are essential for synaptic plasticity [47]. During neuronal activity, m6A levels are dynamically modulated at synaptic sites. Reader proteins such as YTHDF1 and YTHDF3 promote the local translation of m6A-modified mRNAs at activated glutamatergic synapses, facilitating long-term potentiation (LTP) and memory consolidation [46]. Genetic disruption of these reader proteins impairs learning and memory, indicating their essential role in cognitive processing. For instance, conditional knockout of METTL3 in the hippocampus leads to deficits in spatial learning and memory, while YTHDF1 deficiency disrupts memory retrieval [48]. Moreover, FTO, an m6A demethylase, exhibits dose-dependent effects on cognition, i.e., its overexpression enhances, and its depletion impairs, memory performance [49,50].

4.2. Studies on Memory Formation and Retrieval

Experimental studies in animal models further underscore the involvement of m6A in memory processes. In Drosophila, mutations in m6A writer and reader proteins impair short-term memory formation [51]. In mice, reader protein YTHDF1 promotes translation of memory-associated transcripts in the hippocampus, with its loss resulting in learning and memory deficits [48]. Depletion of FTO, an m6A demethylase, impairs object location memory in male mice, indicating that FTO-mediated demethylation plays a role in specific memory tasks [50]. In rats, knockdown of METTL3 in the hippocampus abrogated bisphenol A (BPA)-induced learning and memory deficit [52]. These findings confirm that both the installation and recognition of m6A marks are essential for proper memory formation, retrieval, and storage.

4.3. Therapeutic Implications for Memory Improvement

Targeting m6A pathways presents promising therapeutic avenues for memory-related disorders such as Alzheimer’s disease (AD) and age-associated cognitive decline. In 5 × FAD mouse model of AD, overexpression of METTL16 increases m6A levels, enhances synaptic plasticity, reduces Aβ1–42 accumulation, and improves cognitive performance [53]. Additionally, m6A-regulated genes such as SNRPG and SNRPD2 may serve as biomarkers for progression from mild cognitive impairment to AD [54]. Age-related declines in m6A methylation correlate with reduced synaptic protein synthesis and impaired cognition, suggesting that maintaining m6A homeostasis may be key to preserving brain function in aging populations [55]. Future therapeutic strategies may involve modulating m6A writer, eraser, or reader activity to restore optimal RNA methylation landscapes in the brain. Development of small molecules targeting these regulators could open novel pathways to prevent or treat cognitive dysfunction and neurodegenerative diseases.

5. m6A Methylation and Psychiatric Disorders

m6A RNA methylation plays a significant role in the regulation of mood and stress, with growing evidence linking it to psychiatric phenotypes. In depression models, the m6A demethylase FTO has been shown to influence hippocampal memory and stress adaptation [56]. FTO deficiency enhances fear memory consolidation and alters the expression of stress-responsive genes in the prefrontal cortex, suggesting that m6A dynamics are central to emotional regulation [56]. FTO also modulates neuroplasticity via the brain-derived neurotrophic factor (BDNF) pathway, a key player in mood regulation and synaptic function. In anxiety disorders, similar mechanisms appear to contribute to heightened stress sensitivity, as m6A patterns shift in response to environmental stressors. Moreover, genetic studies have linked schizophrenia risk to polymorphisms in ZC3H13, which is an m6A writer gene. RBM15, another component of the m6A “writer” complex, has been implicated in synapse formation and axonal growth, suggesting that disrupted m6A-mediated synaptic regulation may contribute to cognitive and behavioral impairments in psychiatric disorders [56]. Table 1 summarizes the associations between altered m6A RNA methylation or dysregulation of m6A regulatory genes and psychiatric disorders, with further details from these published studies provided below.

5.1. m6A Methylation and Depression

Compelling evidence suggests that m6A RNA methylation plays a critical role in the pathophysiology of major depressive disorder (MDD). The m6A demethylase FTO is highly expressed in the hippocampus, a brain region consistently implicated in depression. Li et al. demonstrated that reduced hippocampal FTO expression is associated with depression-like behaviors in rodents [66]. Similarly, human postmortem brain studies have shown that reduced FTO expression in the hippocampus [67], as well as reduced FTO expression and increased METTL3 expression in the dorsolateral prefrontal cortex (dlPFC) [68], are associated with MDD. Mechanistically, FTO deficiency disrupts β2-adrenergic receptor (ADRB2) signaling and impairs downstream CaMKII/CREB pathways, which are essential for synaptic plasticity and stress resilience. Moreover, FTO downregulation attenuates responses to common antidepressants, suggesting that m6A dynamics may influence treatment efficacy. Conversely, overexpression of FTO exerts antidepressant-like effects [58]. Further supporting the role of m6A in depression, Fan et al. demonstrated that dysregulation of m6A-related components, specifically the reader protein YTHDF1 and the writer METTL3, modulates neuroimmune signaling [59]. In particular, these alterations impact the TRAF6-NF-κB pathway, a key regulator of microglial activation and neuroinflammation, both of which are increasingly recognized as central to depressive symptomatology. Additionally, m6A modifications influence hippocampal neural stem cell proliferation and differentiation, thereby affecting neurogenesis and structural plasticity, both of which are frequently compromised in MDD. In depression, m6A modifications may also vary in their associations and effects across subtypes, for example, between treatment-resistant and typical depression, with stronger impacts observed on stress-response systems and signaling pathways [57,61]. Together, these findings underscore the multifaceted role of m6A methylation in shaping stress-response pathways, neuroplasticity, and neuroimmune interactions, and highlight its potential as a therapeutic target for depression.

5.2. m6A Methylation and Anxiety Disorders

Although m6A RNA methylation has been more extensively studied in depression, a growing body of evidence indicates its involvement in the molecular mechanisms underlying anxiety disorders. Epitranscriptomic regulation appears to influence gene expression within brain circuits critical for anxiety, particularly through the actions of m6A regulators such as FTO in limbic regions including the hippocampus, anterior cingulate cortex (ACC), and ventral tegmental area (VTA). In animal models, FTO deficiency in the VTA and hippocampus is associated with altered stress reactivity and impaired emotional regulation, implicating m6A methylation in anxiety-like behavior [45]. Notably, the behavioral consequences of FTO manipulation are region-specific. For instance, FTO knockdown in the ACC induces both depressive- and anxiety-like phenotypes, possibly via downregulation of brain-derived neurotrophic factor (BDNF) signaling. In contrast, FTO deletion in the dorsal and ventral hippocampus does not elicit significant anxiety phenotypes, highlighting the context-dependent nature of m6A dynamics in regulating emotional behavior.
Beyond its role in neural circuits, m6A methylation may also modulate anxiety through neuroimmune pathways. Key m6A regulators, such as METTL3 and FTO, have been shown to influence microglial and macrophage polarization via key inflammatory cascades, including the NF-κB and MAPK pathways [61]. Given the well-established role of neuroinflammation in the pathophysiology of anxiety, these findings suggest a mechanistic link between m6A methylation, neuroimmune signaling, and anxiety-like behaviors.
Emerging evidence also supports the role of m6A methylation in modulating neurotransmitter systems involved in anxiety, particularly the monoaminergic pathways. A recent preclinical study by Kanarik et al. demonstrated that pharmacological activation of the METTL3/METTL14 complex using CHMA1004, an m6A RNA methylation activator, produced significant anxiolytic-like effects in rats [60]. Behavioral tests such as the open field and elevated zero-maze revealed increased exploratory behavior and reduced stress-induced defecation, especially in males. Importantly, these anxiolytic effects occurred without signs of psychostimulant activity, as evidenced by unchanged 50-kHz ultrasonic vocalizations and stable dopamine release. Transcriptomic profiling following repeated CHMA1004 administration revealed differential expression of genes involved in dopaminergic neuron viability, neuroinflammatory signaling, and cellular stress responses, particularly in the striatum, frontal cortex, and VTA. These molecular changes were accompanied by region-specific alterations in catecholamine levels, suggesting that m6A methylation may exert its anxiolytic effects, at least in part, through epitranscriptomic regulation of monoamine neurotransmission. Thus, activation of the METTL3/METTL14 complex may represent a promising therapeutic target for novel anxiolytic interventions. In anxiety disorders, m6A modifications may affect signaling pathways and regulatory systems governing stress and neuroendocrine function, thereby influencing both vulnerability and symptom severity [69].
Taken together, these findings underscore the emerging importance of m6A methylation in shaping stress sensitivity and anxiety-like behaviors through coordinated modulation of neuronal circuits, immune signaling, and neurotransmitter systems.

5.3. m6A Methylation and Schizophrenia

Emerging evidence suggests that m6A RNA methylation plays a role in the pathophysiology of schizophrenia, particularly through its regulation of synaptic function and neurodevelopmental gene expression. A recent study by Angelin et al. investigated m6A methylation and other epigenetic markers in peripheral blood mononuclear cells from first-episode schizophrenia patients undergoing treatment with second-generation antipsychotics [62]. While global m6A levels did not differ significantly from healthy controls, treatment non-responders exhibited modestly elevated m6A methylation levels compared to responders [62]. This finding suggests a potential link between m6A dynamics and variability in antipsychotic treatment response. Fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cortical development, dendritic spine maturation, and synaptic plasticity. FMRP is a potential m6A reader protein, modulating neural differentiation through m6A-dependent mRNA nuclear export [63] and stabilizing m6A-marked mRNA targets [64]. Although indirect, dysregulation of FMRP and its interaction with m6A-modified transcripts may contribute to the cognitive and behavioral abnormalities observed in schizophrenia-spectrum disorders. Additionally, mutations associated with autism and schizophrenia can disrupt the m6A “reader” protein YTHDF1, resulting in impaired microtubule function and abnormal neurodevelopment [70]. Collectively, these findings support the hypothesis that m6A RNA methylation contributes to schizophrenia through post-transcriptional dysregulation of neurodevelopmental and synaptic gene networks.

5.4. m6A Methylation and Bipolar Disorder

Emerging evidence implicates m6A RNA methylation in the pathophysiology of mood disorders, including bipolar disorder. Transcriptomic profiling of the striatum has revealed differential expression of genes involved in dopaminergic neurotransmission, neuroplasticity, and stress response—processes frequently dysregulated in bipolar disorder. Notably, upregulated genes included Vwa5b2, previously associated with lithium responsiveness in bipolar patients [65], and Nxph3, a synaptic gene downregulated after loss of m6A in chronic stress models [69]. These findings suggest that enhancing m6A methylation via METTL3/METTL14 activation may modulate gene networks underlying affective instability and stress sensitivity. In bipolar disorder, m6A dysregulation may also affect genes associated with circadian rhythm and synaptic plasticity, potentially contributing to mood shifts and altered neural signaling [61,71]. Collectively, these results provide compelling preclinical evidence that m6A methylation contributes to mood regulation and treatment response in bipolar disorder, highlighting its potential as a target for novel epitranscriptomic therapies.

6. Future Directions and Limitations

Despite significant advances, numerous challenges remain in the study and clinical application of m6A methylation. Current epitranscriptomic methods lack sufficient resolution and sensitivity, likely missing many modification sites. In the brain, the complexity of m6A regulation is further compounded by its heterogeneous cellular architecture, which obscures cell-type-specific patterns and highlights the need for single-cell and spatially resolved analyses. Developing pharmacological agents that selectively target m6A methyltransferases, demethylases, or binding proteins without affecting other pathways remains particularly challenging. Because these regulators are broadly expressed and participate in multiple biological processes, global modulation risks adverse side effects. Moreover, existing technologies cannot yet engineer m6A marks in a transcript-specific, spatially localized, and cell-type-specific manner. Delivering m6A-targeted therapies to the brain poses another major hurdle, as both gene-based and small-molecule approaches require sophisticated delivery systems capable of crossing the blood–brain barrier without causing toxicity or triggering immune responses. Given the dynamic and reversible nature of m6A, longitudinal studies are needed to determine how transient versus chronic alterations affect brain function across development, aging, stress, and disease states. In addition, many current studies rely on rodent models or cultured cells, which may not fully capture the complexity of human psychiatric disorders. Integrating data from postmortem human brain tissues, patient-derived induced pluripotent stem cells (iPSC), and multi-omics strategies will be critical to establish the clinical relevance of m6A dysregulation. Importantly, m6A should be studied within the broader epigenetic landscape, in concert with DNA methylation, histone modifications, and noncoding RNAs, to fully understand its role in mental health and disease.
Another major limitation is the poorly defined relationship between DNA CpG methylation and RNA m6A modification. Whether CpG density influences m6A deposition or if they represent independent processes remains unresolved. Similarly, the mechanisms governing the deposition and removal of m6A in neurons are not well understood. While m6A is thought to be added co-transcriptionally and removed dynamically in both the nucleus and cytoplasm, the functional rationale for this regulation is still unclear. Interactions between m6A and other RNA processes, such as A-to-I editing, translational decoding, or ribosome kinetics, warrant further investigation. Likewise, the rules guiding site selection within DRACH motifs in neurons remain to be elucidated. Another open question concerns the impact of m6A on microRNA cleavage and target recognition. These unresolved issues point to fundamental gaps linking m6A to brain function and psychiatric disease. Addressing them will require functional studies integrated with epitranscriptomic and genomic analyses, ultimately clarifying how m6A contributes to vulnerability and resilience in mental illness.

7. Conclusions

This review highlights the expanding role of m6A RNA methylation in brain development, cognition, and neuropsychiatric disorders. By fine-tuning mRNA fate, m6A methylations shape neurogenesis, synaptic plasticity, and stress responses. Dysregulation of m6A pathways has been implicated in a range of conditions, including depression, anxiety, schizophrenia, bipolar disorder, and addiction. Clinically, m6A research opens new avenues for developing blood-based biomarkers and targeted therapeutics aimed at correcting specific molecular deficits. Modulating m6A turnover through selective inhibition or activation of methyltransferases, demethylases, or reader proteins holds promise for precision medicine, particularly in treatment-resistant cases. Looking ahead, major challenges remain, including achieving selective targeting, ensuring tissue- and cell-type-specific delivery, and establishing long-term safety. Comprehensive mapping of m6A methylation patterns across brain regions and developmental stages in humans will be vital for translating laboratory discoveries into effective clinical interventions. As technologies for probing and manipulating the epitranscriptome advance, m6A is poised to become a powerful lever for deepening our understanding of mental health and improving therapeutic outcomes.

Author Contributions

Conceptualization, H.Z. and A.L.N.; writing—original draft preparation, A.L.N., L.N., N.G.A. and H.Z.; writing—review and editing, A.L.N. and H.Z.; supervision, H.Z.; funding acquisition, H.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Institute on Alcohol Abuse and Alcoholism [grant number R01AA029758].

Informed Consent Statement

Not applicable.

Data Availability Statement

This is a review article; no new data were created or analyzed, and therefore data sharing is not applicable.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of this study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Yao, Q.; Chen, Y.; Zhang, X.; Wang, L.; Li, J.; Lv, J.; Chen, J.; Chen, D. Decoding m6A RNA methylation in kidney disorders: From molecular insights to therapeutic strategies. J. Transl. Med. 2025, 23, 771. [Google Scholar] [CrossRef] [PubMed]
  2. Imam, H.; Kim, G.W.; Siddiqui, A. Epitranscriptomic(N6-methyladenosine) Modification of Viral RNA and Virus-Host Interactions. Front. Cell Infect. Microbiol. 2020, 10, 584283. [Google Scholar] [CrossRef]
  3. Li, Y.; Chen, J.; Sun, Z. N6-methyladenosine (m6A) modification: Emerging regulators in plant-virus interactions. Virology 2025, 603, 110373. [Google Scholar] [CrossRef]
  4. Zhang, G.; Cheng, C.; Wang, X.; Wang, S. N6-Methyladenosine methylation modification in breast cancer: Current insights. J. Transl. Med. 2024, 22, 971. [Google Scholar] [CrossRef]
  5. Loedige, I.; Baranovskii, A.; Mendonsa, S.; Dantsuji, S.; Popitsch, N.; Breimann, L.; Zerna, N.; Cherepanov, V.; Milek, M.; Ameres, S.; et al. mRNA stability and m6A are major determinants of subcellular mRNA localization in neurons. Mol. Cell 2023, 83, 2709–2725.e10. [Google Scholar] [CrossRef]
  6. Yu, J.; She, Y.; Ji, S.J. m6A Modification in Mammalian Nervous System Development, Functions, Disorders, and Injuries. Front. Cell Dev. Biol. 2021, 9, 679662. [Google Scholar] [CrossRef] [PubMed]
  7. Crabtree, G.W.; Gogos, J.A. Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia. Front. Synaptic Neurosci. 2014, 6, 28. [Google Scholar] [CrossRef]
  8. Maqbool, M.; Khan, Y.; Arab, M.M.; Alshammari, S.O.; Hussain, M.S.; Almufarriji, F.M. m6A methylation: A new frontier in epilepsy research and therapeutics. EXCLI J. 2025, 24, 578–611. [Google Scholar] [CrossRef]
  9. Qu, W.; Li, Q.; Wang, M.; Zhao, X.; Wu, J.; Liu, D.; Hong, S.; Yang, Y.; Shu, Q.; Li, X. m6A Modification Involves in Enriched Environment-Induced Neurogenesis and Cognition Enhancement. Front. Cell Dev. Biol. 2022, 10, 903179. [Google Scholar] [CrossRef]
  10. Patil, D.P.; Pickering, B.F.; Jaffrey, S.R. Reading m6A in the Transcriptome: m6A-Binding Proteins. Trends Cell Biol. 2018, 28, 113–127. [Google Scholar] [CrossRef] [PubMed]
  11. Gao, Z.; Zha, X.; Li, M.; Xia, X.; Wang, S. Insights into the m6A demethylases FTO and ALKBH5: Structural, biological function, and inhibitor development. Cell Biosci. 2024, 14, 108. [Google Scholar] [CrossRef]
  12. Bayoumi, M.; Munir, M. Evolutionary conservation of the DRACH signatures of potential N6-methyladenosine (m6A) sites among influenza A viruses. Sci. Rep. 2021, 11, 4548. [Google Scholar] [CrossRef]
  13. Linder, B.; Grozhik, A.V.; Olarerin-George, A.O.; Meydan, C.; Mason, C.E.; Jaffrey, S.R. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat. Methods 2015, 12, 767–772. [Google Scholar] [CrossRef]
  14. Ma, Z.; Li, Q.; Liu, P.; Dong, W.; Zuo, Y. METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP. Cell Biol. Int. 2020, 44, 2524–2531. [Google Scholar] [CrossRef]
  15. Ping, X.L.; Sun, B.F.; Wang, L.; Xiao, W.; Yang, X.; Wang, W.J.; Adhikari, S.; Shi, Y.; Lv, Y.; Chen, Y.S.; et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014, 24, 177–189. [Google Scholar] [CrossRef]
  16. Zou, Z.; He, C. The YTHDF proteins display distinct cellular functions on m6A-modified RNA. Trends Biochem. Sci. 2024, 49, 611–621. [Google Scholar] [CrossRef] [PubMed]
  17. Chen, L.; Gao, Y.; Xu, S.; Yuan, J.; Wang, M.; Li, T.; Gong, J. N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms. Front. Immunol. 2023, 14, 1162607. [Google Scholar] [CrossRef] [PubMed]
  18. Larivera, S.; Meister, G. Domain confusion 2: m6A-independent role of YTHDC2. Mol. Cell 2022, 82, 1608–1609. [Google Scholar] [CrossRef]
  19. Bailey, A.S.; Batista, P.J.; Gold, R.S.; Chen, Y.G.; de Rooij, D.G.; Chang, H.Y.; Fuller, M.T. The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline. eLife 2017, 6, e26116. [Google Scholar] [CrossRef] [PubMed]
  20. Bell, J.L.; Wachter, K.; Muhleck, B.; Pazaitis, N.; Kohn, M.; Lederer, M.; Huttelmaier, S. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): Post-transcriptional drivers of cancer progression? Cell. Mol. Life Sci. 2013, 70, 2657–2675. [Google Scholar] [CrossRef]
  21. Huang, H.; Weng, H.; Sun, W.; Qin, X.; Shi, H.; Wu, H.; Zhao, B.S.; Mesquita, A.; Liu, C.; Yuan, C.L.; et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat. Cell Biol. 2018, 20, 285–295. [Google Scholar] [CrossRef] [PubMed]
  22. Alarcon, C.R.; Goodarzi, H.; Lee, H.; Liu, X.; Tavazoie, S.; Tavazoie, S.F. HNRNPA2B1 Is a Mediator of m6A-Dependent Nuclear RNA Processing Events. Cell 2015, 162, 1299–1308. [Google Scholar] [CrossRef] [PubMed]
  23. Chen, J.J.; Lu, T.Z.; Wang, T.; Yan, W.H.; Zhong, F.Y.; Qu, X.H.; Gong, X.C.; Li, J.G.; Tou, F.F.; Jiang, L.P.; et al. The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway. Cell Death Dis. 2024, 15, 390. [Google Scholar] [CrossRef]
  24. Du, B.; Wang, P.; Wei, L.; Qin, K.; Pei, Z.; Zheng, J.; Wang, J. Unraveling the independent role of METTL3 in m6A modification and tumor progression in esophageal squamous cell carcinoma. Sci. Rep. 2024, 14, 15398. [Google Scholar] [CrossRef] [PubMed]
  25. Jia, G.; Fu, Y.; Zhao, X.; Dai, Q.; Zheng, G.; Yang, Y.; Yi, C.; Lindahl, T.; Pan, T.; Yang, Y.G.; et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011, 7, 885–887. [Google Scholar] [CrossRef]
  26. Li, W.; Zhao, Y.; Wu, D.; Chen, Z.; Qing, Y.; Yang, F.; Ji, F.; Zhang, L.; Sau, L.; Chen, J.; et al. FTO degrader impairs ribosome biogenesis and protein translation in acute myeloid leukemia. Sci. Adv. 2025, 11, eadv7648. [Google Scholar] [CrossRef]
  27. Zheng, G.; Dahl, J.A.; Niu, Y.; Fedorcsak, P.; Huang, C.M.; Li, C.J.; Vagbo, C.B.; Shi, Y.; Wang, W.L.; Song, S.H.; et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 2013, 49, 18–29. [Google Scholar] [CrossRef]
  28. Roundtree, I.A.; Evans, M.E.; Pan, T.; He, C. Dynamic RNA Modifications in Gene Expression Regulation. Cell 2017, 169, 1187–1200. [Google Scholar] [CrossRef]
  29. Zhou, Y.; Corovic, M.; Hoch-Kraft, P.; Meiser, N.; Mesitov, M.; Kortel, N.; Back, H.; Naarmann-de Vries, I.S.; Katti, K.; Obrdlik, A.; et al. m6A sites in the coding region trigger translation-dependent mRNA decay. Mol. Cell 2024, 84, 4576–4593.e12. [Google Scholar] [CrossRef]
  30. Flamand, M.N.; Meyer, K.D. m6A and YTHDF proteins contribute to the localization of select neuronal mRNAs. Nucleic Acids Res. 2022, 50, 4464–4483. [Google Scholar] [CrossRef]
  31. Qi, L.; Wang, Y.; Hu, H.; Li, P.; Hu, H.; Li, Y.; Wang, K.; Zhao, Y.; Feng, M.; Lyu, H.; et al. m6A methyltransferase METTL3 participated in sympathetic neural remodeling post-MI via the TRAF6/NF-kappaB pathway and ROS production. J. Mol. Cell. Cardiol. 2022, 170, 87–99. [Google Scholar] [CrossRef]
  32. Wen, L.; Sun, W.; Xia, D.; Wang, Y.; Li, J.; Yang, S. The m6A methyltransferase METTL3 promotes LPS-induced microglia inflammation through TRAF6/NF-kappaB pathway. Neuroreport 2022, 33, 243–251. [Google Scholar] [CrossRef]
  33. Qi, Z.; Zhang, C.; Jian, H.; Hou, M.; Lou, Y.; Kang, Y.; Wang, W.; Lv, Y.; Shang, S.; Wang, C.; et al. N1-Methyladenosine modification of mRNA regulates neuronal gene expression and oxygen glucose deprivation/reoxygenation induction. Cell Death Discov. 2023, 9, 159. [Google Scholar] [CrossRef]
  34. Zhang, C.; Yi, X.; Hou, M.; Li, Q.; Li, X.; Lu, L.; Qi, E.; Wu, M.; Qi, L.; Jian, H.; et al. The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons. eLife 2023, 12, e85324. [Google Scholar] [CrossRef]
  35. Johnson, Z.; Xu, X.; Lin, Y.; Xie, H. Dynamics of RNA m5C modification during brain development. Genomics 2023, 115, 110604. [Google Scholar] [CrossRef] [PubMed]
  36. Jiang, X.; Liu, B.; Nie, Z.; Duan, L.; Xiong, Q.; Jin, Z.; Yang, C.; Chen, Y. The role of m6A modification in the biological functions and diseases. Signal Transduct. Target. Ther. 2021, 6, 74. [Google Scholar] [CrossRef] [PubMed]
  37. Zhou, Z.; Lv, J.; Yu, H.; Han, J.; Yang, X.; Feng, D.; Wu, Q.; Yuan, B.; Lu, Q.; Yang, H. Mechanism of RNA modification N6-methyladenosine in human cancer. Mol. Cancer 2020, 19, 104. [Google Scholar] [CrossRef] [PubMed]
  38. Wu, J.; Frazier, K.; Zhang, J.; Gan, Z.; Wang, T.; Zhong, X. Emerging role of m6A RNA methylation in nutritional physiology and metabolism. Obes. Rev. 2020, 21, e12942. [Google Scholar] [CrossRef]
  39. Dos Santos Guilherme, M.; Tsoutsouli, T.; Todorov, H.; Teifel, S.; Nguyen, V.T.T.; Gerber, S.; Endres, K. N6-Methyladenosine Modification in Chronic Stress Response Due to Social Hierarchy Positioning of Mice. Front. Cell Dev. Biol. 2021, 9, 705986. [Google Scholar] [CrossRef]
  40. Schmitt, A.; Malchow, B.; Hasan, A.; Falkai, P. The impact of environmental factors in severe psychiatric disorders. Front. Neurosci. 2014, 8, 19. [Google Scholar] [CrossRef]
  41. Kriegstein, A.; Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 2009, 32, 149–184. [Google Scholar] [CrossRef]
  42. Tegowski, M.; Meyer, K.D. Studying m6A in the brain: A perspective on current methods, challenges, and future directions. Front. Mol. Neurosci. 2024, 17, 1393973. [Google Scholar] [CrossRef]
  43. Yoon, K.J.; Ringeling, F.R.; Vissers, C.; Jacob, F.; Pokrass, M.; Jimenez-Cyrus, D.; Su, Y.; Kim, N.S.; Zhu, Y.; Zheng, L.; et al. Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell 2017, 171, 877–889.e17. [Google Scholar] [CrossRef]
  44. Niu, F.; Han, P.; Zhang, J.; She, Y.; Yang, L.; Yu, J.; Zhuang, M.; Tang, K.; Shi, Y.; Yang, B.; et al. The m6A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells. elife 2022, 11, e75827. [Google Scholar] [CrossRef]
  45. Jiang, L.; Li, X.; Wang, S.; Yuan, Z.; Cheng, J. The role and regulatory mechanism of m6A methylation in the nervous system. Front. Genet. 2022, 13, 962774. [Google Scholar] [CrossRef]
  46. Martinez De La Cruz, B.; Markus, R.; Malla, S.; Haig, M.I.; Gell, C.; Sang, F.; Bellows, E.; Sherif, M.A.; McLean, D.; Lourdusamy, A.; et al. Modifying the m6A brain methylome by ALKBH5-mediated demethylation: A new contender for synaptic tagging. Mol. Psychiatry 2021, 26, 7141–7153. [Google Scholar] [CrossRef] [PubMed]
  47. Chokkalla, A.K.; Mehta, S.L.; Vemuganti, R. Epitranscriptomic regulation by m6A RNA methylation in brain development and diseases. J. Cereb. Blood Flow Metab. 2020, 40, 2331–2349. [Google Scholar] [CrossRef] [PubMed]
  48. Li, M.; Zhong, X.; Zhao, Z.; Zeng, Z.; Yuan, Q.; Xiao, X.; Zu, X.; Liu, J. The expression of m6A enzymes in the hippocampus of diabetic cognitive impairment mice and the possible improvement of YTHDF1. Brain Res. 2022, 1777, 147766. [Google Scholar] [CrossRef] [PubMed]
  49. Leonetti, A.M.; Chu, M.Y.; Ramnaraign, F.O.; Holm, S.; Walters, B.J. An Emerging Role of m6A in Memory: A Case for Translational Priming. Int. J. Mol. Sci. 2020, 21, 7447. [Google Scholar] [CrossRef]
  50. Leonetti, A.M.; Galluzzo, I.R.; McLean, T.A.D.; Stefanelli, G.; Ramnaraign, F.; Holm, S.; Winston, S.M.; Reeves, I.L.; Brimble, M.A.; Walters, B.J. The role of the m6A/m demethylase FTO in memory is both task and sex-dependent in mice. Neurobiol. Learn. Mem. 2024, 210, 107903. [Google Scholar] [CrossRef]
  51. Kan, L.; Ott, S.; Joseph, B.; Park, E.S.; Dai, W.; Kleiner, R.E.; Claridge-Chang, A.; Lai, E.C. A neural m6A/Ythdf pathway is required for learning and memory in Drosophila. Nat. Commun. 2021, 12, 1458. [Google Scholar] [CrossRef]
  52. Li, D.; Huang, C.; Liu, Z.; Ai, S.; Wang, H.L. Decreased expression of Chrna4 by METTL3-mediated m6A modification participates in BPA-induced spatial memory deficit. Environ. Res. 2023, 236, 116717. [Google Scholar] [CrossRef]
  53. Chen, H.; Guo, F.; Zhao, Y.; Liu, W.; Chen, B.; Wang, C.; Huang, L.; Jiang, S.; Ma, X.; Ren, H.; et al. Effects of m6A methylation of MAT2A mRNA regulated by METTL16 on learning and memory, hippocampal synaptic plasticity and Aβ1–42 in 5 × FAD mice. Front. Aging Neurosci. 2025, 17, 1572976. [Google Scholar] [CrossRef]
  54. Du, B.; Zhang, Y.; Liang, M.; Du, Z.; Li, H.; Fan, C.; Zhang, H.; Jiang, Y.; Bi, X. N6-methyladenosine (m6A) modification and its clinical relevance in cognitive dysfunctions. Aging 2021, 13, 20716–20737. [Google Scholar] [CrossRef]
  55. Castro-Hernandez, R.; Berulava, T.; Metelova, M.; Epple, R.; Pena Centeno, T.; Richter, J.; Kaurani, L.; Pradhan, R.; Sakib, M.S.; Burkhardt, S.; et al. Conserved reduction of m6A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts. Proc. Natl. Acad. Sci. USA 2023, 120, e2204933120. [Google Scholar] [CrossRef]
  56. Li, J.; Yang, X.; Qi, Z.; Sang, Y.; Liu, Y.; Xu, B.; Liu, W.; Xu, Z.; Deng, Y. The role of mRNA m6A methylation in the nervous system. Cell Biosci. 2019, 9, 66. [Google Scholar] [CrossRef]
  57. Mitsuhashi, H.; Lin, R.; Chawla, A.; Mechawar, N.; Nagy, C.; Turecki, G. Altered m6A RNA methylation profiles in depression implicate the dysregulation of discrete cellular functions in males and females. iScience 2024, 27, 111316. [Google Scholar] [CrossRef] [PubMed]
  58. Liu, S.; Xiu, J.; Zhu, C.; Meng, K.; Li, C.; Han, R.; Du, T.; Li, L.; Xu, L.; Liu, R.; et al. Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice. Nat. Commun. 2021, 12, 6937. [Google Scholar] [CrossRef] [PubMed]
  59. Fan, Y.; Lv, X.; Chen, Z.; Peng, Y.; Zhang, M. m6A methylation: Critical roles in aging and neurological diseases. Front. Mol. Neurosci. 2023, 16, 1102147. [Google Scholar] [CrossRef]
  60. Kanarik, M.; Liiver, K.; Norden, M.; Teino, I.; Org, T.; Laugus, K.; Shimmo, R.; Karelson, M.; Saarma, M.; Harro, J. RNA m6A methyltransferase activator affects anxiety-related behaviours, monoamines and striatal gene expression in the rat. Acta Neuropsychiatr. 2024, 37, e52. [Google Scholar] [CrossRef] [PubMed]
  61. Mitsuhashi, H.; Nagy, C. Potential Roles of m6A and FTO in Synaptic Connectivity and Major Depressive Disorder. Int. J. Mol. Sci. 2023, 24, 6220. [Google Scholar] [CrossRef]
  62. Angelin, M.; Gopinath, P.; Raghavan, V.; Thara, R.; Ahmad, F.; Munirajan, A.K.; Sudesh, R. Global DNA and RNA Methylation Signature in Response to Antipsychotic Treatment in First-Episode Schizophrenia Patients. Neuropsychiatr. Dis. Treat. 2024, 20, 1435–1444. [Google Scholar] [CrossRef]
  63. Hsu, P.J.; Shi, H.; Zhu, A.C.; Lu, Z.; Miller, N.; Edens, B.M.; Ma, Y.C.; He, C. The RNA-binding protein FMRP facilitates the nuclear export of N6-methyladenosine-containing mRNAs. J. Biol. Chem. 2019, 294, 19889–19895. [Google Scholar] [CrossRef]
  64. Zhang, F.; Kang, Y.; Wang, M.; Li, Y.; Xu, T.; Yang, W.; Song, H.; Wu, H.; Shu, Q.; Jin, P. Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets. Hum. Mol. Genet. 2018, 27, 3936–3950. [Google Scholar] [CrossRef] [PubMed]
  65. Marie-Claire, C.; Lejeune, F.X.; Mundwiller, E.; Ulveling, D.; Moszer, I.; Bellivier, F.; Etain, B. A DNA methylation signature discriminates between excellent and non-response to lithium in patients with bipolar disorder type 1. Sci. Rep. 2020, 10, 12239. [Google Scholar] [CrossRef] [PubMed]
  66. Li, M.; Yang, Y.; Chen, T.; Luo, Y.; Zhang, Y.; Liu, H.; Maes, M. FTO (fat-mass and obesity-associated protein) deficiency aggravates age-dependent depression-like behaviors and cognitive impairment. Behav. Brain Funct. 2025, 21, 18. [Google Scholar] [CrossRef] [PubMed]
  67. Meng, K.; Liu, Z.; Yu, Y.; Zhang, E.; Yu, X.; Meng, P.; Xiu, J. The RNA Demethyltransferase FTO Regulates Ferroptosis in Major Depressive Disorder. Int. J. Mol. Sci. 2025, 26, 1075. [Google Scholar] [CrossRef]
  68. Roy, B.; Dwivedi, Y. M6A RNA epitranscriptome dynamics linked to major depressive disorder and suicide risk. Neuropsychopharmacology 2025, 50, 1524–1535. [Google Scholar] [CrossRef]
  69. Engel, M.; Eggert, C.; Kaplick, P.M.; Eder, M.; Roh, S.; Tietze, L.; Namendorf, C.; Arloth, J.; Weber, P.; Rex-Haffner, M.; et al. The Role of m6A/m-RNA Methylation in Stress Response Regulation. Neuron 2018, 99, 389–403.e9. [Google Scholar] [CrossRef] [PubMed]
  70. Roy, R.; Li, X.; Hou, S.; Fujiwara, Y.; Sukegawa, M.; Hong, W.; Oomoto, I.; Ito, H.; Joshi, K.; Fan, R.; et al. Schizophrenia and autism associated mutations and disrupted m6A signal by YTHDF1 cause defects in microtubule function and neurodevelopment. bioRxiv 2020. [Google Scholar] [CrossRef]
  71. Hastings, M.H. m6A mRNA methylation: A new circadian pacesetter. Cell 2013, 155, 740–741. [Google Scholar] [CrossRef] [PubMed][Green Version]
Epigenomes 09 00036 g001
Figure 1. RNA Methylation Dynamics in the Nervous System.
Figure 1. RNA Methylation Dynamics in the Nervous System.
Epigenomes 09 00036 g001
Table 1. The association of m6A RNA methylation/m6A regulators with psychiatric disorders.
Table 1. The association of m6A RNA methylation/m6A regulators with psychiatric disorders.
Psychiatric
Disorders		m6A Methylation/
m6A Regulators		Human/
Animal		Research
Findings		References
DepressionFTOHumanPolymorphisms linked to depression risk/protection[56]
FTO; ALKBH5Human, mouseReduced hippocampal FTO leads to depression-like behaviors; Reduced VTA FTO leads to higher stress susceptibility; circSTAG1 overexpression inhibits ALKBH5 translocation, resulting in reduced depressive-like behaviors [45]
Global m6AHumanSex-specific m6A changes: microtubule movement in[57]
vmPFCmales; neuronal projection in females
FTOHumanDecreased hippocampal FTO leads to MDD[58]
FTOMouseHippocampal Fto KD/KO leads to depression-like[58]
behaviors; Fto overexpression rescues; ADRB2 stimulation rescues
ALKBH5HumanDecreased peripheral blood ALKBH5 leads to MDD[58]
Global m6AHuman & AnimalAltered brain m6A linked to depression[59]
METTL3; METTL14RatAntidepressant-like effects; regulated depression/stress genes[60]
AnxietyFTOMouseFTO deficiency reduced anxiety- and depression-like behaviors[45]
disordersMETTL3MouseLoss of METTL3 increases fear generalization[45]
FTOMouse VTAFTO loss increases stress; overexpression protective[45]
FTO, global m6AMouse PFCFTO knockdown increases cued fear memory[45]
FTO, ALKBH5, global m6AMouseStress alters m6A regionally[61]
FTOMouseReduced FTO in anterior cingulate cortex increases anxiety[61]
FTO (global KO)MouseFTO (global KO) leads to anxiety[61]
METTL3; METTL14RatMETTL3/14 activation reduces anxiety-like behavior[60]
SchizophreniaZC3H13HumanPolymorphism associated with schizophrenia[56]
Global m6AHumanm6A level unchanged; slightly up in non-responders (not significant)[62]
FMRP (m6A reader)MouseFMRP loss leads to nuclear retention of m6A RNAs[63]
FMRP (m6A reader); MouseFMRP stabilizes m6A-marked RNAs;[64]
YTHDF2 FMRP loss leads to YTHDF2-driven decay
Bipolarm6AHumanDMR—EIF2B5/VWA5B2 (TTS) related to lithium response[65]
disorderm6AHumanDMR—RALGAPA1 (promoter/TSS) related to lithium response[65]
m6AHumanDMR—C2orf81 (exon) related to lithium response[65]
m6AHumanDMR—LINC01237 (intron) related to lithium response[65]
m6AHumanDMR—Intergenic sites related to lithium response[65]
METTL3/METTL14 activator compound CHMA1004RatCHMA1004 elicits anxiolytic-like effects[60]
vmPFC: ventral medial prefrontal cortex; VTA: ventral tegmental area; KD/KO: knockdown/knockout; MDD: major depressive disorder; DMR: differentially methylated region.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ngo, A.L.; Nguyen, L.; Gharavi Alkhansari, N.; Zhang, H. m6A RNA Methylation in Psychiatric Disorders: An Emerging Epitranscriptomic Axis. Epigenomes 2025, 9, 36. https://doi.org/10.3390/epigenomes9030036

AMA Style

Ngo AL, Nguyen L, Gharavi Alkhansari N, Zhang H. m6A RNA Methylation in Psychiatric Disorders: An Emerging Epitranscriptomic Axis. Epigenomes. 2025; 9(3):36. https://doi.org/10.3390/epigenomes9030036

Chicago/Turabian Style

Ngo, Ambrose Loc, Linda Nguyen, Niki Gharavi Alkhansari, and Huiping Zhang. 2025. "m6A RNA Methylation in Psychiatric Disorders: An Emerging Epitranscriptomic Axis" Epigenomes 9, no. 3: 36. https://doi.org/10.3390/epigenomes9030036

APA Style

Ngo, A. L., Nguyen, L., Gharavi Alkhansari, N., & Zhang, H. (2025). m6A RNA Methylation in Psychiatric Disorders: An Emerging Epitranscriptomic Axis. Epigenomes, 9(3), 36. https://doi.org/10.3390/epigenomes9030036

Article Metrics

Back to TopTop