N6-methyladenosine (m6A), the most abundant RNA modification in eukaryotic cells, exerts a critical influence on RNA function and gene expression. It has attracted considerable attention within the rapidly evolving field of epitranscriptomics. METTL3 is a key enzyme for m6A modification and is essential for maintaining normal m6A levels. High expression of METTL3 is closely associated with various cancers, including gastric cancer, liver cancer, and leukemia. Inhibiting METTL3 has shown potential in slowing cancer progression, thereby driving the development of METTL3 inhibitors. In this work, we summarize recent advancements in the development of METTL3 inhibitor, with a focus on medicinal chemistry strategies employed during discovery and optimization phases. We explore the application of structure-activity relationship (SAR) studies and protein-targeted degradation techniques, while addressing key challenges associated with their characterization and clinical translation. This review underscores the therapeutic potential of METTL3 inhibitors in modulating epitranscriptomic pathways and aims to offer perspectives for future research in this rapidly evolving field.

RNA modifications, collectively known as epitranscriptomic modifications, have emerged as critical regulators of gene expression, cellular adaptation, and therapeutic resistance. This review explores the pharmacological potential of targeting RNA modifications, including N6-methyladenosine (m6A) and 5-methylcytosine (m5C), as strategies to overcome drug resistance in cancer. We examine key regulatory enzymes, writers, erasers, and readers-and their roles in modulating RNA stability, translation, and splicing. Advances in combination therapies, integrating RNA modification modulators with conventional chemotherapies and immune checkpoint inhibitors, have shown promising outcomes in reversing multidrug resistance (MDR). Emerging RNA-targeting technologies, such as CRISPR/Cas13 systems and advanced RNA sequencing platforms, further enable precision manipulation of RNA molecules, opening new therapeutic frontiers. However, several challenges persist, including issues related to pharmacokinetics, acquired resistance, and the complexity of epitranscriptomic networks. This review underscores the need for innovative delivery systems, such as lipid nanoparticles and tissue-specific targeting strategies, and highlights the dynamic nature of RNA modifications in response to environmental and therapeutic stress. Ongoing research into non-coding RNA modifications and the interplay between epitranscriptomics and epigenetics offers exciting possibilities for developing novel RNA-targeting therapies. The continued evolution of RNA-based technologies will be crucial in advancing precision medicine, addressing drug resistance, and improving clinical outcomes across multiple diseases.

The impact of amino acids on tumor immunotherapy is gradually being uncovered. In this study, we screened various essential and non-essential amino acids and found that methionine enhances mRNA methylation and reduced the activation of Type I interferon pathway in bladder cancer. Through RNA sequencing, point mutations, MB49 mouse tumor models, and single-cell RNA sequencing, we demonstrated that high methionine levels elevate the expression of m6A reader YTHDF1, promoting the degradation of RIG-I, thereby inhibiting the RIG-I/MAVS-mediated IFN-I pathway and reducing the efficacy of tumor immunotherapy. Additionally, immunoprecipitation and mass spectrometry revealed that YTHDF1 binds to the eukaryotic translation initiation factor eIF5B, which acts on PD-L1 mRNA to enhance its translation and promote immune evasion. By intravesical administration of oncolytic bacteria VNP20009, we effectively depleted methionine locally, significantly prolonging mouse survival and enhancing immune cell infiltration and differentiation within tumors. Multiplex immunofluorescence assays in bladder cancer immunotherapy patients confirmed our findings. Our research elucidates two mechanisms by which methionine inhibits bladder cancer immunotherapy and proposes a targeted methionine depletion strategy that advances research while minimizing nutritional impact on patients.

METTL3 has been proven to play an important role in the proliferation of Esophageal squamous cell carcinoma (ESCC). In this study, we focused on investigating the therapeutic role and molecular mechanism of STM2457 in ESCC, which is a novel small-molecule inhibitor of METTL3. The effect of STM2457 on ESCC was evaluated using ESCC cell lines by the cell viability measurement, cloning formation assay, scratching assay, transwell assay, and flow cytometry techniques. Furthermore, the molecular mechanism study was employed to evaluate by RT-qPCR, Western blotting, proteomics analysis, comet assay, etc. Additionally, the anticancer effect of STM2457 was carried out by nude mice tumor xenograft in vivo. This study showed STM2457 could significantly inhibit the proliferation and migration of Eca109 and KYSE150 cells, which promoted G0/G1 phase arrest and apoptosis in a dose-dependent manners in vitro. Moreover, proteomics analysis suggested the important role of ATM in action mechanism of STM2457. Further studies showed that STM2457 may activate DNA damage response and the expression of ATM, p-ATM, p-Chk2, and γ-H2AX protein in ATM-Chk2 pathway. Intriguingly, ATM inhibitor CGK-733 and knocking down ATM significantly reduced the expression of ATM in Eca109 and KYSE150 cells treated with STM2457. Importantly, STM2457 significantly upregulated the expression of ATM and γ-H2AX protein and inhibited the growth of ESCC in vivo. Finally, STM2457 combined with PTX could also significantly inhibit the proliferation and migration ability of Eca109 and KYSE150 cells by targeting the ATM-mediated DDR pathway. In tumor-bearing nude mice model, STM2457 combined with Paclitaxel can inhibit the growth of ESCC and increased the expression of ATM and γ-H2AX protein. These findings revealed ATM-Chk2 pathway is a promising therapeutic target for STM2457 to effectively inhibit the proliferation of ESCC.

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of EP652 as an in vivo proof-of-concept compound. EP652 potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors.

The significance of m6A modifications in several biological processes has been increasingly recognized, particularly in the context of cancer. For instance, m6A modifications in gastric cancer (GC) have been significantly implicated in tumor progression, metastasis, and treatment resistance. GC is characterized by the differential expression of m6A regulators. High expression writers such as METTL3 and WTAP are associated with poor prognosis and aggressive clinical features. Conversely, low expression of METTL14 is linked to worse clinical outcomes, whereas elevated levels of demethylases, such as FTO and ALKBH5, correlate with better survival rates. These m6A regulators influence several cellular biological functions, including proliferation, invasion, migration, glycolysis, and chemotherapy resistance, thereby affecting tumor growth and therapeutic outcomes. The assessment of m6A modification patterns and the expression profiles of m6A-related genes hold substantial potential for improving the clinical diagnosis and treatment of GC. In this review, we provide an updated and comprehensive summary of the role of m6A modifications in GC, emphasizing their molecular mechanisms, clinical significance, and translational applications in developing novel diagnostic and therapeutic strategies.

N6-methyladenosine (m6A) methylation is the most prevalent and abundant internal modification of mRNAs and is catalyzed by the methyltransferase complex. Methyltransferase-like 3 (METTL3), the best-known m6A methyltransferase, has been confirmed to function as a multifunctional regulator in the reversible epitranscriptome modulation of m6A modification according to follow-up studies. Accumulating evidence in recent years has shown that METTL3 can regulate a variety of functional genes, that aberrant expression of METTL3 is usually associated with many pathological conditions, and that its expression regulatory mechanism is related mainly to its methyltransferase activity or mRNA posttranslational modification. In this review, we discuss the regulatory functions of METTL3 in various diseases, including metabolic diseases, cardiovascular diseases, and cancer. We focus mainly on recent progress in identifying the downstream target genes of METTL3 and its underlying molecular mechanisms and regulators in the above systems. Studies have revealed that the use of METTL3 as a therapeutic target and a new diagnostic biomarker has broad prospects. We hope that this review can serve as a reference for further studies.

m6A modification plays a vital role in gestational diabetes mellitus (GDM) progression. However, the role of METTL3 and differential m6A-modified circRNAs in GDMremainsto be investigated.

Placental tissue samples from GDM patients and normal controls (NC) were collected to measure changes in m6A modification levels. MeRIP-seq on placental tissue was performed to detect differential m6A-modified circRNAs.High glucose (HG)-treated JEG3 cells were used to establish the GDM cell model. Differentially expressed circRNAs levels in GDM and NC groups were measured by qRT-PCR. We knocked down METTL3 to study its function. Additionally, we conducted functional recovery experiments. Dot blot assay was utilized to assess changes in m6A levels. MeRIP-qPCR was performed to evaluate the effect of knocking down METTL3 on m6A modification of hsa_circ_0072380 in JEG3 cells.

Compared with the NC group, the GDM group exhibited increased levels of m6A modification and METTL3 expression. Differences in m6A modification of circRNAs exist between the GDM and NC groups. Hsa_circ_0000994, hsa_circ_0058733, and hsa_circ_0072380 were significantly down-regulated in the GDM group while hsa_circ_0036376, hsa_circ_0000471, and hsa_circ_0001173 showed no significant differences between two groups. HG treatment promoted METTL3 expression and m6A level of JEG3 cells, and inhibited cell proliferation, migration, and invasion abilities. Knocking down METTL3 reversed these effects. After HG treatment, hsa_circ_0072380 was significantly down-regulated. Knocking down METTL3 led to up-regulation of hsa_circ_0072380, while knocking down hsa_circ_0072380 restored the function of SiMETTL3. Additionally, knocking down METTL3 significantly reduced the m6A modification of hsa_circ_0072380.

METTL3 mediated m6A modification of hsa_circ_0072380 to regulate GDM progression.

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m6A methyl transferase activity. We have explored PROTACs targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes degradation of METTL3 with a DC50 value of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 is capable of reversing differentiation and possesses anti-proliferative effects surpassing the small molecule inhibitors on MOLM-13 cells. Notably, we first present that METTL3 degrader significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effects of KH12 were further confirmed in patient-derived organoids (PDOs). This study offers therapeutic potentials of targeted degradation of METTL3 against GC implicated with non-catalytic function of METTL3 as well as against AML.

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. N6-methyladenosine (m6A) modification is the most prominent epigenetic modification of eukaryotic mRNAs, and methyltransferase-like 3 (METTL3), a core component of the methyltransferase complex, catalyzes m6A modification. The results of previous studies indicate that the expression level of METTL3 is significantly elevated in gastric cancer tissues and cells. In addition, fluctuations in m6A levels induced by METTL3 are closely associated with the malignant progression of tumors as well as the poor prognosis of patients with gastric cancer. In this review, we focus on the potential mechanism of METTL3 in gastric cancer, and through our analysis, we suggest that targeting METTL3 could be a new therapeutic tool for treating GC.

CircRNAs have been demonstrated to play a crucial role in regulating the growth and progression of various cancers, including hepatocellular carcinoma (HCC). Nevertheless, the circRNA's expression pattern and function in HCC need more investigation.

Bioinformatics techniques were used to identify differentially expressed circRNAs in HCC. CircASH2L expression in HCC tissues was assessed through qRT-PCR and ISH analysis. To assess circASH2L's impact on HCC progression, a variety of experiments were carried out both in vitro and in vivo, such as CCK8, colony formation, EdU assay, flow cytometry, transwell assay, and xenograft mouse model. Various experimental techniques including qRT-PCR, dual luciferase reporter assay, FISH, RNA pull-down, and RIP experiments were utilized to evaluate the relationship between circASH2L, miR-525-3p, and MTUS2. Additionally, experiments were conducted to explore the impact of m6A modification on circASH2L expression, including RNA stability assay, m6A RNA immunoprecipitation assay (MeRIP), and Co-IP experiments.

We found that circASH2L was downregulated in HCC tissues and the downregulation of circASH2L was significantly correlated with malignant characteristics as well as poor overall survival of patients with HCC. CircASH2L was found to inhibit cells growth, migration and invasion as well as tumorigenesis and metastasis in vivo. Mechanistically, we established that circASH2L directly interacted with miR-525-3p to enhance MTUS2 expression, subsequently leading to tumor suppression. Moreover, the influence of circASH2L on tumor suppression was attenuated by increasing miR-525-3p levels, and MTUS2 was recognized as an essential intermediary in circASH2L-induced tumor suppression. Additionally, N6-methyladenosine (m6A) modification was identified in circASH2L. Our data suggested that METTL3 was responsible for mediating m6A methylation of circASH2L, ultimately regulating circASH2L expression through the promotion of its degradation. These findings collectively highlight the role of circASH2L as a tumor suppressor through a unique circASH2L/miR-525-3p/MTUS2 axis, shedding light on the significance of m6A modification in regulating circASH2L function.

The work emphasizes circASH2L as a promising therapeutic target for treating HCC, offering new insights into the role of circRNAs in HCC development.

Mitochondria have a complete and independent genetic system with necessary biological energy for cancer occurrence and persistence. Mitochondrial RNA (mt-RNA) methylation, as a frontier in epigenetics, has linked to cancer progression with growing evidences. This review has comprehensively summarized detailed mechanisms of mt-RNA methylation in regulating cancer proliferation, metastasis, and immune infiltration from the mt-RNA methylation sites, biological significance, and its methyltransferases. The mt-RNA methylation also plays a very significant role via epigenetic crosstalk between nucleus and mitochondria. Importantly, the unique structures and functional characteristics of mt-RNA methyltransferases and the potential targeting treatment drugs for cancer are also analyzed. Revealing human mt-RNA methylation regulatory system and the relationship with cancer will contribute to identifying potential biomarkers and therapeutic targets for precise prevention, detection, intervention and treatment in the future.

Cancer development is thought to be closely related to aberrant epigenetic regulation, aberrant expression of specific non-coding RNAs (ncRNAs), and tumor microenvironment (TME). The m6A methylation is one of the most abundant RNA modifications found in eukaryotes, and it can determine the fate of RNA at the post-transcriptional level through a variety of mechanisms, which affects important biological processes in the organism. The m6A methylation modification is involved in RNA processing, regulation of RNA nuclear export or localisation, RNA degradation and RNA translation. This process affects the function of mRNAs and ncRNAs, thereby influencing the biological processes of cancer cells. TME accelerates and promotes cancer generation and progression during tumor development. The m6A methylation interacting with ncRNAs is closely linked to TME formation. Mutual regulation and interactions between m6A methylation and ncRNAs in TME create complex networks and mediate the progression of various cancers. In this review, we will focus on the interactions between m6A modifications and ncRNAs in TME, summarising the molecular mechanisms by which m6A interacts with ncRNAs to affect TME and their roles in the development of different cancers. This work will help to deepen our understanding of tumourigenesis and further explore new targets for cancer therapy.

The most common epigenetic modification of messenger RNAs (mRNAs) is N6-methyladenosine (m6A), which is mainly located near the 3' untranslated region of mRNAs, near the stop codons, and within internal exons. The biological effect of m6A is dynamically modulated by methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). By controlling post-transcriptional gene expression, m6A has a significant impact on numerous biological functions, including RNA transcription, translation, splicing, transport, and degradation. Hence, m6A influences various physiological and pathological processes, such as spermatogenesis, oogenesis, embryogenesis, placental function, and human reproductive system diseases. During gametogenesis and embryogenesis, genetic material undergoes significant changes, including epigenomic modifications such as m6A. From spermatogenesis and oogenesis to the formation of an oosperm and early embryogenesis, m6A changes occur at every step. m6A abnormalities can lead to gamete abnormalities, developmental delays, impaired fertilization, and maternal-to-zygotic transition blockage. Both mice and humans with abnormal m6A modifications exhibit impaired fertility. In this review, we discuss the dynamic biological effects of m6A and its regulators on gamete and embryonic development and review the possible mechanisms of infertility caused by m6A changes. We also discuss the drugs currently used to manipulate m6A and provide prospects for the prevention and treatment of infertility at the epigenetic level.

The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.

Solute carrier (SLC) 38 family, responsible for trans-membrane transport of neutral amino acids, plays a role in the proliferation, invasion, and metastasis of cancer cells, but its role in gastric cancer (GC) progression remains unclear. This study aimed to explore the biological effects of SLC38A7 and its regulatory mechanisms in GC. RNA expression data, tumor tissue specimens, and GC cell lines were used for bioinformatics and experimental analyses. Cell Counting Kit-8 assay, wound healing assay, and Transwell invasion assay were used to evaluate cell viability, migration, and invasion, respectively. Oxidative phosphorylation, mitochondrial membrane potential, and expression of the critical proteins in the mitochondrial respiratory chain were assayed using extracellular flux analysis, flow cytometry, and Western blot, respectively. RNA immunoprecipitation assay was used to explore the mechanisms of N6-methyladenosine (m6A) methylation. SLC38A7 was upregulated in GC tissue and cell lines. SLC38A7 silencing suppressed cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in cancer cells. SLC38A7 overexpression had the opposite biological effects. Interactions between SLC38A7 and methyltransferase like 3 (METTL3) or insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were detected. SLC38A7 mRNA stability was maintained by METTL3-IGF2BP2 axis in an m6A-dependent manner. Our results suggest that SLC38A7, stabilized by METTL3 and IGF2BP2-mediated m6A methylation, enhances cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in GC, highlighting its role as a potential therapeutic target for GC.

Methyltransferase-like protein is a ubiquitous enzyme-like protein in the human body, with binding domains for nucleic acids, proteins and other small molecules, and plays an important role in a variety of biological behaviours in normal organisms and diseases, characterised by the presence of a methyltransferase-like structural domain and a structurally conserved SAM-binding domain formed by the seven-stranded β-fold structure in the center of the protein. With the deepening of research, the METTL protein family has been found to be abnormally expressed in a variety of tumor diseases, and the clarification of its relationship with tumor diseases can be used as a molecular therapeutic target and has an important role in the prognosis of tumors. In this paper, we review the structure, biological process, immunotherapy, drug-targeted therapy, and markers of the METTL protein family to provide new ideas for the diagnosis and treatment of tumors.

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. High expression of the mitotic kinase BUB1 has been shown to be associated with the development of many cancers, but the role of BUB1 in GC is still unclear. The current study aimed to investigate the role of BUB1 in GC.

BUB1 inhibitor, siRNA or BUB1 overexpression plasmid-mediated functional studies were performed in vitro and in vivo to explore the oncogenic role of BUB1 in GC. The expression of BUB1 and FGF18 in GC tumor samples was determined by IHC staining. RNA-seq, Western blot, MeRIP-qPCR and Co-IP assays were used to investigate the molecular mechanisms by which BUB1 regulates GC progression.

Knockdown of BUB1 significantly inhibited the proliferation and metastasis of GC cells in vitro and in vivo. Moreover, overexpression of BUB1 significantly promoted the proliferation, migration and invasion of GC cells. High expression of BUB1 and FGF18 in GC tissues predicted poor prognosis in GC patients. Mechanistically, BUB1 interacted with METTL3 and induced m6A modification of TRAF6 mRNA, further activating the NF-κB/FGF18 axis in GC cells.

Our results confirmed that BUB1 acts as a positive regulator of GC cell proliferation and metastasis by activating the TRAF6/NF-κB/FGF18 pathway through METTL3-mediated m6A methylation. Targeting the BUB1/METTL3/TRAF6/NF-κB/FGF18 axis might be a novel diagnostic and therapeutic strategy in GC.

Methyltransferase-like 3 (METTL3) is an RNA methyltransferase that catalyzes the N6 -methyladenosine (m6A) modification of mRNA in eukaryotic cells. Past studies have shown that METTL3 is highly expressed in various cancers and is closely related to tumor development. Therefore, METTL3 inhibitors have received widespread attention as effective treatments for different types of tumors. This study proposes a hybrid high-throughput virtual screening (HTVS) protocol that combines structure-based methods with geometric deep learning-based DeepDock algorithms. We identified unique skeleton inhibitors of METTL3 from our self-built internal database. Among them, compound C3 showed significant inhibitory activity on METTL3, and further molecular dynamics simulations were performed to provide more details about the binding conformation. Overall, our research demonstrates the effectiveness of hybrid virtual algorithms, which is of great significance for understanding the biological functions of METTL3 and developing treatment methods for related diseases.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in western countries. Evidence has indicated the significant role of the androgen receptor (AR) as the main driving factor in controlling the development of PCa, making androgen receptor inhibition (ARI) therapy a pivotal management approach. In addition, AR independent signaling pathways also contribute to PCa progression. One such signaling pathway that has garnered our attention is N6-Methyladenosine (m6A) signaling, which refers to a chemical modification on RNA with crucial roles in RNA metabolism and disease progression, including PCa. It is important to comprehensively summarize the role of each individual m6A regulator in PCa development and understand its interaction with AR signaling. This review aims to provide a thorough summary of the involvement of m6A regulators in PCa development, shedding light on their upstream and downstream signaling pathways. This summary sets the stage for a comprehensive review that would benefit the scientific community and clinical practice by enhancing our understanding of the biology of m6A regulators in the context of PCa.

Hepatocellular carcinoma (HCC) is a highly aggressive cancer with a poor prognosis. The molecular mechanisms underlying its development remain unclear. Recent studies have highlighted the crucial role of RNA modifications in HCC progression, which indicates their potential as therapeutic targets and biomarkers for managing HCC. In this review, we discuss the functional role and molecular mechanisms of RNA modifications in HCC through a review and summary of relevant literature, to explore the potential therapeutic agents and biomarkers for diagnostic and prognostic of HCC. This review indicates that specific RNA modification pathways, such as N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N1-methyladenosine, are erroneously regulated and are involved in the proliferation, autophagy, innate immunity, invasion, metastasis, immune cell infiltration, and drug resistance of HCC. These findings provide a new perspective for understanding the molecular mechanisms of HCC, as well as potential targets for the diagnosis and treatment of HCC by targeting specific RNA-modifying enzymes or recognition proteins. More than ten RNA-modifying regulators showed the potential for use for the diagnosis, prognosis and treatment decision utility biomarkers of HCC. Their application value for HCC biomarkers necessitates extensive multi-center sample validation in the future. A growing number of RNA modifier inhibitors are being developed, but the lack of preclinical experiments and clinical studies targeting RNA modification in HCC poses a significant obstacle, and further research is needed to evaluate their application value in HCC treatment. In conclusion, this review provides an in-depth understanding of the complex interplay between RNA modifications and HCC while emphasizing the promising potential of RNA modifications as therapeutic targets and biomarkers for managing HCC.

Breast cancer (BC) is a highly prevalent malignancy worldwide, with complex pathogenesis and treatment challenges. Research reveals that methyltransferase-like 3 (METTL3) is widely involved in the pathogenesis of several tumors through methylation of its target RNAs, and its role and mechanisms in BC are also extensively studied. In this review, we aim to provide a comprehensive interpretation of available studies and elucidate the relationship between METTL3 and BC. This review suggests that high levels of METTL3 are associated with the pathogenesis, poor prognosis, and drug resistance of BC, suggesting METTL3 as a potential diagnostic or prognostic biomarker and therapeutic target. Collectively, this review provides a comprehensive understanding of how METTL3 functions through RNA methylation, which provides a valuable reference for future fundamental studies and clinical applications.

The tumor-associated microbiota plays a vital role in cancer development. Accumulating evidence shows that Fusobacterium nucleatum (Fn) participates in the progression of multiple tumor types. However, the underlying mechanisms remain unclear.

This study examined the expression of methyltransferase-like protein 3 (METTL3) during Fn infection and elucidated the function and pathway of Fn-induced m6A methylation in esophageal squamous cell carcinoma (ESCC).

The abundance of Fn in patient tissues was determined by qPCR. Western blot, qRT-PCR, and immunohistochemistry were performed to measure METTL3 expression in cells and tissues. METTL3 function was evaluated in vitro by colony formation and cell migration assays. MeRIP-qPCR was performed to determine the relationship between METTL3 and c-Myc. In addition, the half-lives of genes that are downstream of METTL3 were determined with RNA stability assays.

Fn was enriched in hepatocellular carcinoma (HCC), breast cancer (BRCA), ESCC, and colorectal cancer (CRC) tumor tissues. METTL3 expression was positively associated with Fn abundance in ESCC tissues. Fn could survive and proliferation as well as increase METTL3 expression in ESCC, HCC, CRC, and BRCA cells. Moreover, METTL3 overexpression promoted ESCC cells proliferation, migration in vivo and in vitro. Mechanistically, Intracellular Fn infection increases METTL3 transcription. METTL3 promoted c-Myc mRNA methylation in the 3'-untranslated Region (3'-UTR) and enhanced its mRNA stability in a YTH N6-Methyladenosine RNA binding protein 1(YTHDF1)-dependent manner, which contributes to Fn induced ESCC proliferation and metastasis.

This study indicates that intracellular Fn infection promotes ESCC development and metastasis, and eradicating Fn infection may be a promising strategy for treating ESCC.

N6-methyladenosine (m6A) is the predominant post-transcriptional RNA modification in eukaryotes and plays a pivotal regulatory role in various aspects of RNA fate determination, such as mRNA stability, alternative splicing, and translation. Dysregulation of the critical m6A methyltransferase METTL3 is implicated in tumorigenesis and development. Here, this work showed that METTL3 is upregulated in gastric cancer tissues and is associated with poor prognosis. METTL3 methylates the A2318 site within the coding sequence (CDS) region of STAT5A. IGF2BP2 recognizes and binds METTL3-mediated m6A modification of STAT5A through its GXXG motif in the KH3 and KH4 domains, leading to increased stability of STAT5A mRNA. In addition, both METTL3 and IGF2BP2 are positively correlated with STAT5A in human gastric cancer tissue samples. Helicobacter pylori infection increased the expression level of METTL3 in gastric cancer cells, thereby leading to the upregulation of STAT5A. Functional studies indicated that STAT5A overexpression markedly enhances the proliferation and migration of GC cells, whereas STAT5A knockdown has inhibitory effects. Further nude mouse experiments showed that STAT5A knockdown effectively inhibits the growth and metastasis of gastric cancer in vivo. Moreover, as a transcription factor, STAT5A represses KLF4 transcription by binding to its promoter region. The overexpression of KLF4 can counteract the oncogenic impact of STAT5A. Overall, this study highlights the crucial role of m6A in gastric cancer and provides potential therapeutic targets for gastric cancer.

Influenza A virus (IAV) is a negative-sense single-stranded RNA virus that causes acute lung injury and acute respiratory distress syndrome, posing a serious threat to both animal and human health. N6-methyladenosine (m6A), a prevalent and abundant post-transcriptional methylation of RNA in eukaryotes, plays a crucial regulatory role in IAV infection by altering viral RNA and cellular transcripts to affect viral infection and the host immune response. This review focuses on the molecular mechanisms underlying m6A modification and its regulatory function in the context of IAV infection and the host immune response. This will provide a better understanding of virus-host interactions and offer insights into potential anti-IAV strategies.

METTL3, a primary methyltransferase catalyzing the RNA N6-methyladenosine (m6A) modification, has been identified as an oncogene in several cancer types and thus nominated as a potentially effective target for therapeutic inhibition. However, current options using this strategy are limited. In this study, we targeted protein-protein interactions at the METTL3-METTL14 binding interface to inhibit complex formation and subsequent catalysis of the RNA m6A modification. Among candidate peptides, RM3 exhibited the highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed a stapled peptide inhibitor (RSM3) with enhanced peptide stability and formation of the α-helical secondary structure required for METTL3 interaction. Functional and transcriptomic analysis in vivo indicated that RSM3 induced upregulation of programmed cell death-related genes while inhibiting cancer-promoting signals. Furthermore, tumor growth was significantly suppressed while apoptosis was enhanced upon RSM3 treatment, accompanied by increased METTL3 degradation, and reduced global RNA methylation levels in two in vivo tumor models. This peptide inhibitor thus exploits a mechanism distinct from other small-molecule competitive inhibitors to inhibit oncogenic METTL3 activity. Our findings collectively highlight the potential of targeting METTL3 in cancer therapies through peptide-based inhibition of complex formation and proteolytic degradation.

Prostate cancer (PCa) affects males of all racial and ethnic groups, and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to the late detection of the disease. PCa affects middle‑aged males between the ages of 45 and 60 years, and is the highest cause of cancer‑associated mortality in Western countries. As the most abundant and common mRNA modification in higher eukaryotes, N6‑methyladenosine (m6A) is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recent studies have found that abnormal expression levels of various m6A regulators significantly affect the development and progression of various types of cancer, including PCa. The present review discusses the influence of m6A regulatory factors on the pathogenesis and progression of PCa through mRNA modification based on the current state of research on m6A methylation modification in PCa. It is considered that the treatment of PCa with micro‑molecular drugs that target the epigenetics of the m6A regulator to correct abnormal m6A modifications is a direction for future research into current diagnostic and therapeutic approaches for PCa.

The methylation of adenosine base at the nitrogen-6 position is referred to as "N6-methyladenosine (m6A)" and is one of the most prevalent epigenetic modifications in eukaryotic mRNA and noncoding RNA (ncRNA). Various m6A complex components known as "writers," "erasers," and "readers" are involved in the function of m6A. Numerous studies have demonstrated that m6A plays a crucial role in facilitating communication between different cell types, hence influencing the progression of diverse physiological and pathological phenomena. In recent years, a multitude of functions and molecular pathways linked to m6A have been identified in the osteogenic, adipogenic, and chondrogenic differentiation of bone mesenchymal stem cells (BMSCs). Nevertheless, a comprehensive summary of these findings has yet to be provided. In this review, we primarily examined the m6A alteration of transcripts associated with transcription factors (TFs), as well as other crucial genes and pathways that are involved in the differentiation of BMSCs. Meanwhile, the mutual interactive network between m6A modification, miRNAs, and lncRNAs was intensively elucidated. In the last section, given the beneficial effect of m6A modification in osteogenesis and chondrogenesis of BMSCs, we expounded upon the potential utility of m6A-related therapeutic interventions in the identification and management of human musculoskeletal disorders manifesting bone and cartilage destruction, such as osteoporosis, osteomyelitis, osteoarthritis, and bone defect.

N6-methyladenosine (m6A) is considered to be the most common and abundant epigenetics modification in messenger RNA (mRNA) and noncoding RNA. Abnormal modification of m6A is closely related to the occurrence, development, progression, and prognosis of cancer. m6A regulators have been identified as novel targets for anticancer drugs. Natural products, a rich source of traditional anticancer drugs, have been utilized for the development of m6A-targeting drugs. Here, we review the key role of m6A modification in cancer progression and explore the prospects and structural modification mechanisms of natural products as potential drugs targeting m6A modification for cancer treatment.

The tumor microenvironment (TME) is a heterogeneous ecosystem comprising cancer cells, immune cells, stromal cells, and various non-cellular components, all of which play critical roles in controlling tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), the core component of N 6-methyladenosine (m6A) writer, is frequently associated with abnormalities in the m6A epitranscriptome in different cancer types, impacting both cancer cells and the surrounding TME. While the impact of METTL3 on cancer cells has been extensively reviewed, its roles in TME and anti-cancer immunity have not been comprehensively summarized. This review aims to systematically summarize the functions of METTL3 in TME, particularly its effects on tumor-infiltrating immune cells. We also elaborate on the underlying m6A-dependent mechanism. Additionally, we discuss ongoing endeavors towards developing METTL3 inhibitors, as well as the potential of targeting METTL3 to bolster the efficacy of immunotherapy.

N6-methyladenosine (m6A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses m6A modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions.

Although the exact cause of inflammatory bowel disease (IBD) is still unknown, there is a lot of evidence to support the notion that it results from a combination of environmental factors, immune system issues, gut microbial changes, and genetic susceptibility. In recent years, the role of epigenetics in the pathogenesis of IBD has drawn increasing attention. The regulation of IBD-related immunity, the preservation of the intestinal epithelial barrier, and autophagy are all significantly influenced by epigenetic factors. The most extensive epigenetic methylation modification of mammalian mRNA among them is N6-methyladenosine (m6A). It summarizes the general structure and function of the m6A regulating factors, as well as their complex effects on IBD by regulating the intestinal mucous barrier, intestine mucosal immunity, epidermal cell death, and intestinal microorganisms.This paper provides key insights for the future identification of potential new targets for the diagnosis and treatment of IBD.

Senescence is the underlying mechanism of organism aging and is robustly regulated at the post-transcriptional level. This regulation involves the chemical modifications, of which the RNA methylation is the most common. Recently, a rapidly growing number of studies have demonstrated that methylation is relevant to aging and aging-associated diseases. Owing to the rapid development of detection methods, the understanding on RNA methylation has gone deeper. In this review, we summarize the current understanding on the influence of RNA modification on cellular senescence, with a focus on mRNA methylation in aging-related diseases, and discuss the emerging potential of RNA modification in diagnosis and therapy.

Tumor angiogenesis plays vital roles in the growth and metastasis of cancer. RNA methylation is one of the most common modifications and is widely observed in eukaryotes and prokaryotes. Accumulating studies have revealed that RNA methylation affects the occurrence and development of various tumors. In recent years, RNA methylation has been shown to play an important role in regulating tumor angiogenesis. In this review, we mainly elucidate the mechanisms and functions of RNA methylation on angiogenesis and progression in several cancers. We then shed light on the role of RNA methylation-associated factors and pathways in tumor angiogenesis. Finally, we describe the role of RNA methylation as potential biomarker and novel therapeutic target.

Thyroid cancer (TC) is the most predominant malignancy of the endocrine system, with steadily growing occurrence and morbidity worldwide. Although diagnostic and therapeutic methods have been rapidly developed in recent years, the underlying molecular mechanisms in the pathogenesis of TC remain enigmatic. The N6-methyladenosine(m6A) RNA modification is designed to impact RNA metabolism and further gene regulation. This process is intricately regulated by a variety of regulators, such as methylases and demethylases. Aberrant m6A regulators expression is related to the occurrence and development of TC and play an important role in drug resistance. This review comprehensively analyzes the effect of m6A methylation on TC progression and the potential clinical value of m6A regulators as prognostic markers and therapeutic targets in this disease.

The METTL3/14 complex is an important RNA N6-Methyladenosine (m6A) methyltransferase in organisms, and the abnormal METTL3/14 complex activity is associated with the pathogenesis and various cancers. Sensitive detection of METTL3/14 complex is essential to tumor pathogenesis study, cancer diagnosis, and anti-cancer drug discovery. However, traditional methods for METTL3/14 complex assay suffer from poor specificity, costly antibodies, unstable RNA substrates, and low sensitivity. Herein, we construct a single quantum dot (QD)-based förster resonance energy transfer (FRET) biosensor for sensitive detection of METTL3/14 complex activity. In the presence of METTL3/14 complex, it catalyzes the methylation of adenine in the substrate probe, leading to the formation of m6A that protects the substrate probes from MazF-mediated cleavage. The hybridization of methylated DNA substrate with biotinylated capture probe initiates polymerization reaction to obtain a biotinylated double-stranded DNA (dsDNA) with the incorporation of numerous Cy5 fluorophores. Subsequently, the Cy5-incorporated dsDNA can self-assembly onto the 605QD surface to form the 605QD-dsDNA-Cy5 nanostructure, causing FRET between 605QD donor and Cy5 acceptor. This biosensor has excellent sensitivity with a limit of detection (LOD) of 3.11 × 10-17 M, and it can measure the METTL3/14 complex activity in a single cell. Moreover, this biosensor can be used to evaluate the METTL3/14 complex kinetic parameters and screen potential inhibitors. Furthermore, it can differentiate the METTL3/14 complex expression in healthy human tissues and breast cancer patient tissues, providing a powerful tool for cancer pathogenesis study, clinical diagnosis, prognosis monitoring, and drug discovery.

Oxaliplatin is a widely used chemotherapy drug for patients with advanced colorectal cancer (CRC); however, frequent drug resistance limits its therapeutic efficacy in patients. Here, this work identifies cyclin-dependent kinase 1 (CDK1) as a critical contributor to oxaliplatin resistance via in vitro and in vivo CRISPR/Cas9 screening. CDK1 is highly expressed in oxaliplatin-resistant cells and tissues due to the loss of N6-methyladenosine modification. Genetic and pharmacological blockade of CDK1 restore the susceptibility of CRC cells to oxaliplatin in vitro and in cell/patient-derived xenograft models. Mechanistically, CDK1 directly binds to and phosphorylates Acyl-CoA synthetase long-chain family 4 (ACSL4) at S447, followed by recruitment of E3 ubiquitin ligase UBR5 and polyubiquitination of ACSL4 at K388, K498, and K690, which leads to ACSL4 protein degradation. Reduced ACSL4 subsequently blocks the biosynthesis of polyunsaturated fatty acid containing lipids, thereby inhibiting lipid peroxidation and ferroptosis, a unique iron-dependent form of oxidative cell death. Moreover, treatment with a ferroptosis inhibitor nullifies the enhancement of CRC cell sensitivity to oxaliplatin by CDK1 blockade in vitro and in vivo. Collectively, the findings indicate that CDK1 confers oxaliplatin resistance to cells by suppressing ferroptosis. Therefore, administration of a CDK1 inhibitor may be an attractive strategy to treat patients with oxaliplatin-resistant CRC.