A bibliometric analysis of advances in N6‑methyladenosine research in colorectal cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally. Epigenetic regulation, especially N6-methyladenosine (m6A) RNA modification, plays a critical role in CRC development. Although molecular studies have linked m6A to CRC progression, comprehensive bibliometric assessments are scarce. We analyzed 230 publications from the Web of Science (2014–2024) using CiteSpace and VOSviewer. Highly cited studies emphasize regulators such as METTL3 and IGF2BP2 in stemness and metabolic reprogramming. A emerging trend is the integration of m6A with tumor immunotherapy, indicating a shift from basic research toward clinical translation. This evolution highlights new therapeutic opportunities in CRC.

Introduction

Colorectal cancer (CRC) is a gastrointestinal malignancy originating in the glandular tissue of the large intestine. In 2022, CRC was the third most commonly diagnosed cancer globally, with 1,926,118 new cases accounting for 9.6% of all cancers, behind only lung and breast cancers. It also ranked as the second leading cause of cancer death worldwide, resulting in 903,859 fatalities, which represented 9.3% of total cancer deaths. Between 2010 and 2019 in China, new CRC cases increased by 28.3% (95% UI: 20.2%-36.4%) and deaths rose by 22.1% (95% UI: 15.0%-29.2%) [1]. This rising trend has established CRC as a significant public health burden, causing substantial physical and psychological harm to patients and consuming considerable healthcare resources, alongside imposing a substantial economic burden [2]. The subtle early-stage symptoms and significant tumor heterogeneity of CRC contribute to diagnostic difficulties [3], often resulting in delayed diagnosis. Consequently, many early-onset CRC cases are diagnosed at advanced stages (III/IV), leading to increased mortality due to disease progression [4]. As early as 1988, Vogelstein et al. proposed the seminal “adenoma-carcinoma sequence” hypothesis, based on findings that the progressive accumulation of mutations drives colorectal tumorigenesis [5]. This model posits that the transition from benign adenoma to malignant carcinoma is driven by the sequential accumulation of mutations in tumor suppressor genes and oncogenes. However, accumulating evidence suggests that CRC progression involves not only the accumulation of genetic mutations but also the synergistic contribution of epigenetic alterations, which collectively drive tumorigenesis [6].

N6-methyladenosine (m6A) is the most prevalent, abundant, and conserved internal co-transcriptional modification in eukaryotic RNAs [7]. It exerts various functions in cells mainly through m6A methyltransferases (Writers), demethylases (Erasers), and m6A-binding proteins (Readers).m6A is deposited by Writers such as METTL3, METTL14, and METTL16, reversibly removed by Erasers such as FTO, and recognized by Readers including the YTH domain-containing protein family and the IGF2BP family proteins (IGF2BP1/2/3) [8]. Research on epigenetic modifications of m6A regulator proteins represents an emerging frontier in cancer biology [9]. In CRC, molecular-level studies of m6A have revealed its critical roles in driving proliferation and metastasis, as well as regulating key oncogenic signaling pathways. During the early stage of tumor metastasis, the m6A-reading protein PRRC2A was significantly up-regulated in CRC, promoting tumor growth and metastasis by stabilizing CSNK1E (CK1ε) mRNA to activate the WNT and YAP signaling pathways [10]. At the stage of tumor progression, METTL3-mediated m6A modification enhanced the stability of POU6F2-AS1, which was up-regulated in CRC, thereby promoting fatty acid synthesis and accelerating tumor proliferation by recruiting YBX1 to the FASN promoter [11]. m6A-modified circ-YAP encodes oncogenic YAP-220aa, a protein significantly elevated in CRC. This upregulation inhibits LATS1, promoting YAP nuclear translocation and establishing a positive feedback loop that drives liver metastasis [12].

Nevertheless, current research on m6A in CRC remains largely fragmented, dominated by individual case studies rather than systematic integrations of the field. It is imperative to conduct a comprehensive research that maps the intellectual landscape, pinpoints emerging trends, and steers future research toward the most promising directions and critical breakthroughs.Here, bibliometric analysis offers a powerful solution by systematically profiling bibliographic elements—such as authorship, geographic and institutional affiliations, journal metrics, and citation networks—across a body of literature [13]. This quantitative approach leverages large-scale scholarly data to minimize subjective bias through computational objectivity. Using visualization tools such as VOSviewer and CiteSpace, it enables topological mapping of knowledge domains, traces the evolution of research fronts over time, and identifies emerging interdisciplinary convergences with predictive potential. Ultimately, the analysis can help uncover novel therapeutic strategies targeting m6A modification for CRC treatment [14–15].

To advance m6A research in colorectal cancer (CRC), this study employed a bibliometric approach. We conducted a comprehensive analysis of the research landscape, encompassing publication trends, disciplinary distribution, key sources, and major contributors (including countries, institutions, and authors). Furthermore, through co-citation, keyword co-occurrence, and thematic map analyses, we mapped the field’s intellectual structure to identify its foundational knowledge, current research hotspots, and emerging frontiers, thereby pinpointing critical directions for future work.

Materials and methods

Data resource and literature search strategy

Literatures for this study were collected on the Web of Science Core Collection (wosCC), with the following search formula: TS=(Rectal Neoplasm* OR Rectal Tumor* OR Rectal Cancer* OR Rectum Neoplasm* OR Rectum Cancer* OR Cancer of the Rectum OR Cancer of Rectum OR Colorectal Neoplasm* OR Colorectal Tumor* OR Colorectal Cancer* OR Colorectal Carcinoma* OR Colonic Neoplasm* OR Colon Neoplasm* OR Cancer of Colon OR Colon Cancer* OR Cancer of the Colon OR Colonic Cancer*) AND TS=( m6A OR m(6)A OR N-6-methyladenosine OR N6 -methylation OR N-6 methylation ), restricted to English papers published between January 1, 2014 and November 23, 2024, with document types restricted to article, review article and early access.

Software for literature selection and paper extraction strategy

As the primary source for our literature retrieval, the WoSCC was searched using our predefined strategy, which yielded an initial cohort of 3388 articles. However, a preliminary assessment revealed that a significant proportion of the retrieved studies did not have m6A in CRC as their primary focus. To ensure the inclusion of only the most pertinent literature, all retrieved records underwent a manual screening against our eligibility criteria.

EndNote 21 was used to screen the literatures. The studies included for manual screening were required to have the interplay between m6A and CRC as their primary research focus. Consequently, any articles that discussed m6A or CRC in a cursory manner only, without establishing a direct investigative link between the two, were deemed ineligible and excluded. To improve the applicability of the study data, a two-step literature screening process was conducted, as shown in Fig. 1. Initially, 272 eligible articles were identified through an initial screening of titles and abstracts. Subsequently, a comprehensive full-text review confirmed the inclusion of 230 articles meeting the predefined criteria. After literature screening, all recorded data of the selected papers were downloaded from WosCC in EndNote Desktop format. All paper information, such as author name, source, institution, country, and keywords, was normalized according to the standard format.

Fig. 1.

Manual fine-screening using the literature management software Endnote eventually extracted a total of 230 papers closely related to the topic of m6A and colorectal cancer.

Software for bibliometric analysis and visualization analysis

Data analysis and visualization were performed using WPS Office (v6.6.0), CiteSpace (v6.3.R1), and VOSviewer (v1.6.19), with each software package serving specific methodological functions. CiteSpace serves as a specialized software application for bibliometric analysis, enabling visualization and analysis of intellectual structures within scientific domains. This Java-based platform is primarily applied to identify research frontiers, detect emerging trends, and map disciplinary evolution through co-citation networks and cluster analysis [16]. Network topology analysis employed two principal metrics: betweenness centrality and cluster validation indices. Betweenness centrality, quantifying a node’s bridging role by the proportion of shortest paths traversing, was visualized using purple annular rings for nodes exceeding the threshold of 0.1. Cluster robustness was evaluated through modularity (Q) and silhouette coefficients (S), where Q > 0.3 indicated significant community structure, and S > 0.7 indicated high-confidence clustering. All analytical procedures followed established bibliometric protocols.

Result

Analysis of publication trends

From January 2014 to November 2024, a total of 320 publications focusing on m6A modification in CRC have been indexed in the Web of Science database. This dataset consists of 211 original research articles (91.74%) and 19 review articles (8.26%), originating from 29 countries and 881 institutions globally. As illustrated in Fig. 2, the annual output of publications on m6A modification in CRC remained relatively low from 2014 to 2018, followed by a dramatic increase starting in 2019 that peaked in the early 2020s. Although a slight decline was observed between 2023 and 2024, the literature output over the past decade has shown an overall upward trend.

Fig. 2.

Annual publications related to m6A in CRC from 2014 through 2024

Country and institutional analysis

In the analysis with country as the unit of publication measurement, China ranked first in the number of publications, with 226 papers accounting for 70.40%, significantly outnumbering the United States (10 papers, 3.12%), Canada (4 papers, 1.25%), and Japan (4 papers, 1.25%) (Table 1; Fig. 3a). Furthermore, China recorded the highest number of citations and achieved a betweenness centrality of 1.88, substantially exceeding that of the United States (0.01). This indicates not only China’s extensive collaborative relationships with other countries in the field of CRC methylation research but also its central role within international cooperative networks.

Table 1.

Top 10 countries published literature related to m6A in CRC from 2014 to 2024

Rank	Countries	Count	Centrality	Years
1	PEOPLES R CHINA	226	1.88	2017
2	USA	10	0.01	2018
3	CANADA	4	0.01	2021
4	JAPAN	4	0	2014
5	BELGIUM	2	0	2021
6	FRANCE	2	0.47	2019
7	GERMANY	2	0	2021
8	PAKISTAN	1	0	2024
9	ITALY	1	0	2023
10	SINGAPORE	1	0	2023

In this table, count means the volume of a country’s scientific output in the field of research, with countries ranked according to count. Centrality is a measure of a country’s pivotal position and ability to intermediate in international cooperation networks. While the year is a time when the country first published a significant text in the research field. The data are derived by analyzing the raw data by CiteSpace

Fig. 3.

Visual maps of countries and institutions in the CiteSpace network related to m6A in CRC. (a) Analysis of countries collaborations. (b) Institutions cooperation analysis. Nodes represent countries or institutions and lines connect them. Nodes represent countries or institutions. The number of publications grows proportionally to the size of the nodes. The connecting lines between the nodes represent the partnership, and the thickness of the lines represents the strength of the partnership; the stronger the partnership, the thicker the lines. The color changes from purple to red from 2014 to 2024

Annual publications in this field have risen sharply since 2015, reflecting growing research interest and significant progress. The surge in paper volume (Fig. 2) coincides with a broader trend shown in the network visualization (Fig. 3a), highlighting China’s significant contribution to m6A research in CRC over the past decade. China’s leadership in this field is evidenced by its higher publication volume, centrality, citation frequency, and citation-to-publication ratio. Furthermore, the marked increase in China’s annual publications since 2016 marks a significant shift in the global research landscape of m6A.

The network visualization further highlights the collaborative nature of the research, in which countries such as France and China play a key role. These countries are interconnected with Belgium and Japan, highlighting the importance of international cooperation in advancing CRC research. In recent years, new countries such as Pakistan, Italy and Singapore have demonstrated that research efforts and knowledge exchange are spreading globally. The data table details country-specific publication counts and centrality metrics, complementing the visual findings. China and the United States initiated m6A research earliest, underscoring their pioneering contributions. Concurrently, the gradual rise in publications from countries such as Canada, Japan, and France demonstrates growing international engagement in exploring m6A’s role in CRC. Taken together, these data highlight a dynamic and evolving research landscape for m6A in CRC, characterized by significant contributions from leading countries and an expanding global network of collaborations. This trend is critical for advancing further understanding of the role of m6A in CRC and developing effective therapeutic strategies.

As shown in Table 2, Nanjing Medical University (NMU) ranked first with 24 publications (2014–2024), followed by Sun Yat-sen University (23 publications) and South China State Key Laboratory of Oncology (16 publications). Zhejiang University (14 publications) and Fudan University (12 publications) also made significant contributions. The strong links between Central South University, Sun Yat-sen University, and Zhejiang University are shown in the Institutional Collaboration Network diagram (Fig. 3b), indicating that these institutions drive productivity and partnerships. Since 2019, Chinese institutions have maintained sustained growth in publication output, whereas non-Chinese institutions show a more modest increase.

Table 2.

Top 10 productive institutions related to m6A in CRC from 2014 to 2024

Rank	Organizations	Number of publications	Count of citations	Years
1	Nanjing Medical University	24	0.15	2019
2	Sun Yat Sen University	23	0.19	2019
3	State Key Lab Oncology South China	16	0.08	2019
4	Zhejiang University	14	0.18	2020
5	Fudan University	12	0.1	2020
6	Central South University	12	0.22	2019
7	Zhengzhou University	10	0.1	2019
8	Chinese Academy of Sciences	10	0.22	2021
9	China Medical University	9	0.06	2021
10	Guangzhou Medical University	8	0.1	2019

The analysis of m6A in CRC research institutions shows that the top 10 institutions in terms of the number of articles are all from China, with Nanjing Medical University (24 articles), Sun Yat Sen University (23 articles) and Zhejiang University (14 articles) ranking in the top three, showing that Chinese scientific research institutions have demonstrated significant academic dominance. In terms of geographical distribution, these institutions have formed a dual-center pattern with the Yangtze River Delta (YRD) and the Pearl River Delta (PRD) as the core, showing a strong regional agglomeration. The PRD region is represented by Sun Yat Sen University, State Key Lab Oncology South China, and Guangzhou Medical University, while the YRD region has a concentration of Nanjing Medical University, Zhejiang University, and Fudan University. The Yangtze River Delta region gathers advantageous institutions such as Nanjing Medical University, Zhejiang University and Fudan University. It is worth noting that these high-output institutions have significant advantages in academic resources, seven of which are medical universities and top research institutions such as Chinese Academy of Sciences, and all of them have been selected as China’s “double first-class” construction universities or have national research platforms.

Analysis of authors and co-authors

Table 3 lists the top 10 authors who published the most literature related to m6A modification in CRC in the past decade. The data show that Hao Wang (2022) published the most papers with 6 papers, followed by Huarong Chen (2021) and Wei Kang (2022) with 5 papers each. Jun Yu (2022), Jianning Zhai (2022) and Zhen Zhang (2021) tied for the third place with 4 papers each. According to the co-cited authors network (Fig. 4a) analysis, SIEGEL RL (0.3) and WANG X (0.27) were found to be the authors with the highest number of co-citations.

Table 3.

Top 10 authors related to m6A in CRC from 2014 to 2024

Rank	Author	Year	Number of publications	H-Index
1	Wang, Hao	2022	6	55
2	Chen, Huarong	2021	5	35
3	Kang, Wei	2022	4	47
4	Yu, Jun	2022	4	111
5	Zhai, Jianning	2022	4	11
6	Zhang, Zhen	2021	4	32
7	Bai, Jianan	2023	3	10
8	Ben, Shuai	2023	3	10
9	Chen, Danyu	2023	3	16
10	Chen, Jinhao	2023	3	10

Fig. 4.

CiteSpace network visualizations of co-cited authors and references about m6A in CRC. a Visualized network diagram of co-cited authors. b Network visualization of co-cited references. Co-cited authors or co-cited references are represented by nodes. Connecting lines between nodes indicate co-citation relationships. The node area increases with the number of co-citations. The colors represent different years, from 2014 to 2024, the color changes from purple to red

Analysis of co-cited literature

The co-cited literature network graph (Fig. 4B) consists of 280 nodes and 1344 links, with the time slice set to one year, covering the time period from 2014 to 2024. The most co-cited article was “METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma” by Lit T (2019), which was co-cited 83 times. “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries” by Sung H (2021) was co-cited 61 times. He LE (2019), “Functions of N6-Methyladenosine and Its Role in Cancer” was also one of the most co-cited papers with 42 times.

Figure 5 provides a temporal co-citation analysis of m6A in CRC research hotspots from 2014 to 2024. From the overall view of the image, “CRC” (cluster 0) is a persistent research focus, and the maximum frequency of nodes indicates a large number of papers cited throughout the time period. In terms of the different hotspots presented in each time period, the early research interest was mainly focused on “m6A methylation” (cluster 1) and “ALKBH5” (cluster 2), and their larger nodes and extensive connectivity evidenced that these two clusters gained greater research attention, from 2019 onwards. Further analysis reveals that the number of citations for “mettl14” (cluster 3) is significantly concentrated around 2020. In addition, the number of citations for “immunotherapy” (cluster 7) peaked around 2021, while “kiaa1429” (cluster 8) appeared at the end of the timeline, at a small but significant node, for the darkest color of its node indicates a hot spot for current research.

Fig. 5.

Timeline view of co-cited references related to m6A in CRC. The position of the node on the horizontal axis represents the time when the reference first appeared, and the size of the node is positively correlated with the number of times the reference was cited. Lines between nodes represent co-citation relationships. The deep red indicates that it is closer to 2024, and a purple color indicates that it is closer to 2014.Clusters with redder colors and larger nodes contain more publications, indicating that the cluster’s issues are hot topics in the field

Among the top ten most co-cited documents (Table 4), there were six research papers, three reviews and one observastional study, published centrally in 2018–2021.Studies in 2018 identified the IGF2BP protein family as novel m6A-reading proteins capable of specifically recognizing GG(m6A)C sequences and enhancing the stability and translational efficiency of target gene mRNAs, laying the molecular foundation for subsequent studies [17]. In 2019, several studies established the core regulatory mechanisms of m6A modifications in CRC, including the regulation of SOX2 expression by METTL3 through the m6A-IGF2BP2-dependent pathway, which in turn affects tumor stem cell properties, as well as the negative regulatory effect of the m6A reader YTHDF3 on the oncogenic lncRNA GAS5 [18, 19]. By 2020, studies have further expanded to multiple levels of the m6A regulatory network, not only discovering that METTL3 promotes tumor metabolic reprogramming through activation of key genes of glycolysis (HK2, GLUT1), but also revealing the oncogenic mechanism of METTL14 in down-regulating the expression of SOX4 and the oncogenic lncRNA XIST through the YTHDF2-dependent pathway. Together, these studies have constructed a dynamic m6A “writer-eraser-reader” regulatory network, which plays an important role in CRC progression by affecting the expression of oncogenes (e.g., MYC, SOX2) and tumor suppressor gene (e.g., GAS5) [17, 20, 21]. In 2021, it has been found that the high expression of m6A-related molecules such as METTL3 and low expression of METTL14 have been proved to have significant prognostic value, and therapeutic strategies targeting the m6A regulatory pathway (e.g., the METTL3-m6A-GLUT1-mTORC1 axis) show promising prospects for application, providing a new direction for precision treatment of CRC [22].

Table 4.

The top 10 most co-cited documents related to m6A in CRC from 2014 to 2024

Rank	Co-cited reference	Year	Counts	Citations
1	Li T, 2019, MOL CANCER, V18, P0, DOI 10.1186/s12943-019-1038-7	2019	83	0.08
2	Sung H, 2021, CA-CANCER J CLIN, V71, P209, DOI 10.3322/caac.21660	2021	61	0
3	He LE, 2019, MOL CANCER, V18, P0, DOI 10.1186/s12943-019-1109-9	2019	42	0.02
4	Huang HL, 2018, NAT CELL BIOL, V20, P285, DOI 10.1038/s41556-018-0045-z	2018	39	0.07
5	Shen CQ, 2020, MOL CANCER, V19, P0, DOI 10.1186/s12943-020-01190-w	2020	36	0.05
6	Chen XX, 2020, MOL CANCER, V19, P0, DOI 10.1186/s12943-020-01220-7	2020	36	0.05
7	Yang X, 2020, MOL CANCER, V19, P0, DOI 10.1186/s12943-020-1146-4	2020	35	0.05
8	Chen HR, 2021, GASTROENTEROLOGY, V160, P1284, DOI 10.1053/j.gastro.2020.11.013	2021	32	0.03
9	Chen XY, 2019, MOL CANCER, V18, P0, DOI 10.1186/s12943-019-1033-z	2019	32	0.01
10	Ni W, 2019, MOL CANCER, V18, P0, DOI 10.1186/s12943-019-1079-y	2019	30	0.06

Notably, our co-citation analysis showed that 7 of the 10 most frequently co-cited papers on the role of m6A in CRC were published in Molecular Cancer, highlighting the journal’s pivotal role in this area of research. These high-impact studies focused on m6A methyltransferases (e.g., METTL3/METTL14) and their role in CRC progression, metastasis, and chemoresistance. This concentration not only indicates a maturing research paradigm, but also raises the possibility of thematic saturation in certain areas (e.g., METTL3-mediated mechanisms). Researchers entering this field are recommend to use these basic studies to identify consensus findings while prioritizing under-explored aspects to avoid duplication and drive innovation.

Keyword co-occurrence and cluster analysis

Based on CiteSpace’s keyword centrality and citation count analysis (Table 5), it can be seen that the most influential keywords in the recent literature include “colorectal cancer”, “expression”, “m6A modification”, “messenger RNA”, and “metastasis”. These keywords had high citation counts and centrality scores, indicating that they played a pivotal role in the research discussion at the time.

Table 5.

The top 10 most co-cited journals related to m6A in CRC from 2014 to 2024

Rank	Cited journal	Year	Number of publications	Count of citations	IF/JCR partition
1	MOL CANCER	2019	189	0.06	27.7/Q1
2	CELL	2014	158	0.04	45.6/Q1
3	NATURE	2017	153	0.05	50.5/Q1
4	CA-CANCER J CLIN	2017	140	0.09	521.6/Q1
5	NUCLEIC ACIDS RES	2019	126	0.02	16.7/Q1
6	CANCER RES	2014	121	0.1	12.5/Q1
7	NAT COMMUN	2019	121	0.06	14.7/Q1
8	CELL RES	2019	115	0.02	28.2/Q1
9	CANCER CELL	2019	111	0.02	48.8/Q1
10	ONCOGENE	2014	108	0.05	6.9/Q1

As shown in Fig. 6a, a visual representation of the keyword network within the m6A modification domain in CRC studies illuminates the interconnections between topics and the areas of research focus. The network shows three distinct clusters, each representing a unique aspect of research. The red cluster consists primarily of terms related to cellular processes and molecular mechanisms, such as “metastasis” and “m6A,” indicating a focus on cell behavior and gene modification. The blue cluster centers on “cell biology” and “angiogenesis,” highlighting research on cellular and vascular aspects of cancer progression. The green cluster with terms such as “n6-methyladenosine” and “alkbh5” emphasizes the role of epigenetic modifications in cancer development.

Fig. 6.

The analysis of keyword co-occurrence. a A network of keywords. Node size indicates the counts of publications. Different colors represent different clusters. b The overlay visualization map of keywords. The circle size shows the number of publications; The circle colors represent the average published year

To explore the future direction of research with m6A in CRC, we plotted a visualization overlay based on the average publication year (Fig. 6b). Purple nodes indicate earlier appearing keywords and yellow nodes indicate more recent keywords. It was found that early research in the field focused on topics in the red cluster, but projects in the green and blue clusters gradually received more attention over time. Specifically, keywords such as “alkbh5”, “genetics & heredity”, “noncoding RNA”, “metabolism”, and “angiogenesis” have a relatively late average publication year and a low average frequency of occurrence, and may be the next hotspot in the future.

During the analysis, we also constructed a network diagram to visualize the keyword clusters, as shown in Fig. 7. The graph reveals the important clusters that appeared as the focus of research in a given time frame. Notably, “m6A modification” (cluster 2), and “demethylase” (cluster 0) were identified as prominent areas of interest. In addition, “cancer progression” (cluster 1), “Colorectal Cancer” (cluster 6) and “Clinical Applications” (cluster 5) were also highlighted as research areas.

Fig. 7.

Keyword clusters of m6A in CRC. Different colors represent different clusters. Each dot represents a keyword and the number on the node represents the cluster to which the keyword belongs. The line segments between the points represent two keywords with co-occurrence relationships. The blocks of corresponding colors represent the extent of each cluster in the network space

Discussion

Building on the aforementioned results, we find the keyword co-occurrence analysis (Fig. 6a) outlined four major research areas in the m6A-CRC field, which align with the distinct thematic clusters identified in the visualization (Figs. 6b and 7). The following section will discuss key research hotspots and emerging frontiers in m6A methylation within CRC.

m6A methylation and translation: its Lmpact on CRC cell biology (Cluster 1 -red)

m6A methylation is a key epigenetic modification that significantly impacts CRC development and progression by affecting tumor metabolism, signaling pathways, and gene regulation. This modification is dynamically regulated by methyltransferases (e.g., METTL3/METTL14), demethylases (e.g., FTO/ALKBH5), and binding proteins (e.g., YTHDF1/IGF2BP2), which collectively affect RNA stability, translation, and splicing [23–24]. Figure 6 A illustrates this interaction and shows that the association is particularly strong between translation and CRC. In CRC, m6A methylation has been shown to regulate key oncogenic and tumor suppressor pathways. For example, METTL14-mediated m6A modification promotes YTHDF2-dependent SOX4 mRNA degradation, and inhibition of METTL14 decreases the m6A modification of SOX4, thereby increasing its expression and exacerbating the process of SOX4-induced epithelial-mesenchymal transition (EMT) [25–26]. EMT activates SOX4-mediated PI3K/Akt signaling cascade, thereby promoting CRC metastasis. In addition, METTL3 enhances the translation of CTNNB1 (β-catenin) mRNA through the m6A-YTHDF1 mechanism, which promotes β-catenin protein accumulation and drives the activation of the Wnt/β-catenin pathway [27]. These findings underscore the critical role of m6A in regulating gene expression at the translational level and highlight potential therapeutic nodes, such as targeting the METTL14-ZFP14-STAT3 or METTL3-YTHDF1-β-catenin axes to impede metastasis [28].

m6A methylation and oncology: exploring its role in CRC development (Cluster 2 - Yellow)

CRC development is a multistep, multistage process critically regulated by m6A modification. As illustrated in Fig. 6A, this interaction is particularly prominent during CRC invasion and metastasis. A key regulator in this process is the m6A reader IGF2BP2, which has emerged as a definitive research hotspot due to its central role in post-transcriptional regulation [29]. IGF2BP2 recognizes and binds m6A-modified transcripts, enhancing the stability of oncogenic mRNAs such as HMGA1 and CDC27. It promotes CRC cell migration and invasion through direct stabilization of HMGA1 mRNA, often in complex with other molecules like DHX9 and LINC00460. Furthermore, circ_0000775 recruits IGF2BP2 to stabilize CDC27 mRNA, facilitating epithelial-mesenchymal transition (EMT). IGF2BP2 overexpression is correlated with poor prognosis and chemoresistance [30], underscoring its dual potential as a prognostic biomarker and a therapeutic target. These findings highlight IGF2BP2 as a master orchestrator of pro-oncogenic signals and emphasize the need to elucidate its precise mechanisms in different CRC subtypes and develop targeted inhibitors disrupting its RNA-binding activity in CRC.

m6A methylation and angiogenesis: unveiling new mechanisms in CRC (Cluster 3 - Blue)

m6A methylation promotes angiogenesis in CRC and affects tumor growth and metastasis. ALKBH5 inhibits mutant p53-driven CRC progression by demethylating the lncRNA CARMN. YTHDF2/YTHDF3 recognize and degrade m6A-modified CARMN, which inhibits angiogenesis and tumor metastasis via the miR-5683/FGF2 axis [31]. In contrast, FTO (m6A demethylase), which is highly expressed in tumor-associated fibroblasts (CAFs), promotes CRC neovascularization by decreasing the m6A modification of pro-angiogenic factors such as VEGFA and EGR1, enhancing their mRNA stability [32]. These findings highlight the dual role of m6A methylation in CRC angiogenesis, where its dynamic regulation by ALKBH5 and FTO in different cellular contexts either suppresses or promotes tumor progression, offering potential therapeutic targets for modulating the tumor microenvironment.

m6A methylation and lmmunotherapy: potential biomarkers and targets (Cluster 4 - Green)

The immune system plays a critical role in tumorigenesis and cancer progression [33]. Notably, tumor immunotherapy aims to reactivate and sustain the tumor-immune cycle, thereby restoring anti-tumor immunity and enabling tumor control or eradication [34–35]. Increasing evidence indicates that m6A RNA modification serves as a key regulatory mechanism within the tumor immune microenvironment of CRC. For example, YTHDF1 binds to m6A sites on CXCL1 mRNA to enhance its translation and secretion, activating the CXCL1/CXCR2 axis, recruiting myeloid-derived suppressor cells (MDSCs), suppressing T-cell function, and ultimately compromising anti-tumor immunity [36–37]. In contrast, ALKBH5 upregulates Axin2 expression through demethylation-mediated mRNA stabilization, which inhibits Wnt signaling and induces DKK1 secretion, thereby remodeling the immunosuppressive microenvironment [38]. Additionally, m6A modification influences tumor metabolism: FTO, an m6A eraser, enhances the stability of JUNB and CEBPB mRNAs by reducing their m6A levels, leading to upregulation of glycolytic enzymes (e.g., LDHA, HK2) and increased lactate production [39]. The resulting acidic microenvironment impairs CD8⁺ T-cell function and promotes immune evasion. Collectively, these mechanisms underscore the therapeutic potential of targeting m6A modification to counteract immunosuppression in CRC immunotherapy.

The strong clustering of keywords related to immunotherapy reflects a paradigm shift in the field toward clinical translation. Mechanistically, m6A modifications profoundly shape the immune landscape by regulating immunomodulatory genes and tumor antigens. Thus, profiling the “m6A signature” in CRC may help predict responses to immune checkpoint inhibitors. Moreover, targeting m6A regulators offers a promising strategy to synergize with existing immunotherapies and overcome resistance, highlighting a innovative avenue for combination therapy development in CRC.

Research gaps and future perspectives

Despite the wealth of basic mechanistic research identified in our keyword clustering analysis (e.g., clusters dominated by ‘IGF2BP2’, ‘METTL3’, ‘proliferation’), our bibliometric mapping reveals a conspicuous scarcity of studies transitioning these findings into clinical applications. Notably, terms such as ‘biomarker’, ‘prognostic model’, ‘liquid biopsy’, or ‘clinical trial’ are significantly underrepresented among high-frequency keywords, highlighting a critical translational gap. This disparity suggests that the field is still in its early translational phase. The transition from mechanistic understanding to clinical utility remains a primary challenge. Future research must prioritize the validation of m6A-related biomarkers (e.g., reader proteins like IGF2BP2 or specific m6A-modified transcripts) in large, multi-center patient cohorts to assess their diagnostic, prognostic, and predictive value for immunotherapy response.

Our analysis confirms the striking dominance of Chinese institutions in the output of m6A-related CRC research. This leadership may be attributed to a unique advantage in accessing large, well-characterized patient cohorts [12], which positions China as a key driver in defining the global agenda for m6A research in CRC. However, this geographical concentration also presents a potential risk for academic homogeneity. A lack of diverse geographical and ethnic perspectives could limit the generalizability of findings. For instance, m6A modifier mutations or expression patterns may vary across populations, and their value as biomarkers needs validation in diverse genetic backgrounds beyond East Asian cohorts. Therefore, a key future direction lies in fostering large-scale international collaborations. Integrating data from Western, European, and other populations will be essential to validate the universal applicability of m6A-based discoveries and accelerate their global clinical adoption.

Limitations

This study was limited to retrieving literature from WoSCC. Due to potential issues with the completeness of citation data, other databases, such as Scopus and PubMed, were not included. Relying on a single database may result in a slight deviation of the results of the study from reality. Therefore, the potential impact of these limitations should be carefully considered when interpreting and applying the results of this study. In future studies, the inclusion of additional databases or literature resources could allow for a more comprehensive analysis.

Conclusion

This study provides a comprehensive analysis of the current state of colorectal cancer m6A methylation research between 2014 and 2024. Since 2019, m6A methylation has received increasing attention in CRC. China has made important contributions in this field. Countries should actively create opportunities for exchange and cooperation to promote balanced regional academic development. The molecular mechanisms of methylation modification, their impact on CRC development, and their implications for immunotherapy represent an emerging hotspot and a promising area for future research.

Author contributions

All the authors were involved in the design of the study or in the explanation of the data. LD wrote the first draft of the manuscript. BY and WC contributed to the methodology. LS contributed to proof read the article. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the National Natural Science Foundation of China (82560611), Academic Enhancement Support Program of Hainan Medical University (XSTS2025019, XSTS2025194).

Data availability

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.

Declarations

Ethics approval and consent to participate

Ethics are not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.