The Role of N<sup>6</sup>-Methyladenosine in Inflammatory Diseases

Xu, Haojun; Lin, Changjie; Yang, Jinghan; Chen, Xi; Chen, Yingyu; Chen, Jianguo; Guo, Aizhen; Hu, Changmin

doi:https://doi.org/10.1155/2022/9744771

Oxidative Medicine and Cellular Longevity

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Review Article | Open Access

Volume 2022 | Article ID 9744771 | https://doi.org/10.1155/2022/9744771

The Role of N⁶-Methyladenosine in Inflammatory Diseases

Haojun Xu,^1,2Changjie Lin,^1,2Jinghan Yang,^1,2Xi Chen,^2,3Yingyu Chen,^2,3Jianguo Chen,^1,2Aizhen Guo ,^2,3,4and Changmin Hu¹

Academic Editor: Kai Wang

Received20 Sept 2022

Revised23 Nov 2022

Accepted23 Nov 2022

Published12 Dec 2022

Abstract

N⁶-Methyladenosine (m⁶A) is the most abundant epigenetic RNA modification in eukaryotes, regulating RNA metabolism (export, stability, translation, and decay) in cells through changes in the activity of writers, erasers, and readers and ultimately affecting human life or disease processes. Inflammation is a response to infection and injury in various diseases and has therefore attracted significant attention. Currently, extensive evidence indicates that m⁶A plays an essential role in inflammation. In this review, we focus on the mechanisms of m⁶A in inflammatory autoimmune diseases, metabolic disorder, cardio-cerebrovascular diseases, cancer, and pathogen-induced inflammation, as well as its possible role as targets for clinical diagnosis and treatment.

1. Introduction

With the increasing RNA modification mapping technique, hundreds of modifications have been found in RNA that, taken together, represent the posttranscriptional regulatory mechanisms. RNA modifications are responsible for regulating gene translation in a precise and detailed spatiotemporal manner. Among them, significant attention has been focused on methylation modification. N⁶-Methyladenosine (m⁶A) chemical modifications involve addition of an extra methyl to the adenylate 6-position N atom in a specific sequence (i.e., RRACH), and they are widely found distributed in mRNA and ncRNA [1]. m⁶A is the most abundant RNA modification in mammalian cells [2–4]. It is estimated that about 0.1%–0.4% of the adenosine in RNA carries an m⁶A modification, with each transcript normally containing one to three m⁶A-modified sites [4]. Additionally, the nucleotide fragments resulting from degradation of m⁶A-modified RNA also have a certain signaling effect and can activate the immune response [5]. Taken above, it can be concluded that m⁶A plays important roles in regulating all cell biological processes. Furthermore, m⁶A is involved in necrosis, apoptosis, and autophagy in cells, which can eventually lead to the development of inflammatory diseases [6].

Inflammation is a double-edged sword that is common in various diseases [7, 8]; on the one hand, inflammation fights infection or tissue damage [9, 10], and on the other hand, it could become excessive and cause autologous damage [11]. Recent extensive studies on autoimmune diseases, metabolic diseases, cardio-cerebrovascular diseases, and even cancer have indicated that inflammation contributes more to these diseases [12–15]. Moreover, m⁶A has an essential role in regulating inflammation [16–19]. Recent studies exploring the relationship between m⁶A and inflammation have resulted in novel insights. In this review, we summarize the mechanisms of m⁶A in several inflammatory diseases, as well as its possible role in exploring new therapies from the perspective of epigenetics.

2. An Overview of N⁶-Methyladenosine (m⁶A)

The participation of methylases (writers), demethylases (erasers), and reader proteins (readers) is required in m⁶A methylation. Methyl is added or removed by writers or erasers to regulate RNA methylation. Readers recognize alterations in methylation and then play regulatory functions in RNA stability, decay, translation, and nuclear output (Figure 1). Finally, m⁶A affects the course of cellular life and influences the occurrence and development of diseases.

2.1. Writers

N⁶-Methyladenosine methylation in adenosine is modified by highly conserved RNA methyltransferase complexes, including METTL3, METTL14, WTAP, RBM15, KIAA1429, METTL16, and ZC3H13. METTL3 and METTL14 contain SAM-binding motifs and form stable heterodimers [3, 20]. METTL3 acts as a catalytic subunit, while METTL14 recognizes RNA substrates [21]. At the same time, WTAP and KIAA1429 are responsible for the formation of the complex, and RBM15 is involved in the initial recruitment of the complex to the target site in mRNA [22]. As intensive research on m⁶A has been conducted, more novel methylases have been discovered, such as ZC3H13 and METTL16. Recent studies have shown that ZC3H13 bridges the gap between the aptamers RBM15 and WTAP [23], and METTL16 is an active m⁶A methyltransferase in human cells, which mainly methylates snRNA and intron sites in pre-mRNA [24]. Moreover, two independent studies discovered that rRNA was also subject to m⁶A modification. The METTL5–TRMT112 complex is responsible for human 18S rRNA m⁶A modification [25], while ZCCHC4 is involved in modification of 28S rRNA [26].

2.2. Erasers

N⁶-Methyladenosine methylation reversal has been found to be mainly mediated by two demethylases, FTO and ALKBH5. FTO was originally found to be associated with obesity and is the first m⁶A demethylase to be discovered in vitro, in early 2011 [27]. Mechanistically, FTO first oxidizes m⁶A to intermediate N⁶-hydroxymethyladenosine (hm⁶A), which is then converted to N⁶-formyladenosine (f⁶A) and, finally, into adenosine [28]. However, it has been reported that FTO can not only remove m⁶A methylation but also reverse m⁶Am modification with greater efficiency [29]. Shortly after this role of FTO was confirmed, the second mammalian m⁶A demethylase, ALKBH5, was identified [30]. Unlike FTO, ALKBH5 directly converts m⁶A to adenosine in the reverse reaction and without intermediates [31]. Interestingly, both FTO and ALKBH5 are Fe²⁺ and α-ketoglutarate-dependent dioxygenase and belong to the ALKBH family; it has been suggested that more ALKBH family proteins or other proteins with similar structures are involved in the demethylation process, resulting in more diverse means for regulating m⁶A methylation. With the development of structural biology, there may be numerous demethylases still waiting to be discovered.

2.3. Readers

The m⁶A reader protein is a major player in molecular functions, which mainly includes members of the YTH protein family, IGF2BPs, eIF3, hnRNPs, and Prrc2a. Different reader proteins are distributed in different locations in cells. Nuclear m⁶A readers include YTHDC1 and hnRNPs. Cytoplasmic m⁶A readers include YTHDF1/2/3, YTHDC2, and IGF2BP1/2/3. YTHDC1 recruits splicing factors SRSF3 to regulate the splicing of mRNA [32] as well as affect nuclear output, the decay of specific transcripts [33], and noncoding RNA-mediated gene silencing [34]. hnRNPA2B1 and hnRNPC are also the major reader proteins in the nucleus. hnRNPA2B1 regulated pre-mRNA splicing and promotes primary miRNA processing [35], while hnRNPC only influences pre-mRNA splicing [36, 37]. Moreover, there is a study which indicated that hnRNPG may also be the reader protein of m⁶A [38], which needed to be further confirmed. YTHDC2 mainly affects the translation efficiency of mRNA [39]. YTHDF1 improves translation efficiency by recruiting translation initiation factors in HeLa cells [21, 32]. However, the binding of YTHDF2 to mRNA accelerates mRNA degradation [40]. YTHDF3 regulates the translation or decay of mRNA depending on whether it interacts with YTHDF1 or YTHDF2 [21]. IGF2BPs enhance mRNA stability and translation [41]. Interestingly, IGF2BPs are also able to interact with ncRNA [42], but the regulatory mechanism needs to be further studied [35].

Additionally, eIF3 [43] and Prrc2a [44] are also essential readers. ELAVL1 [45] and G3BPs [46] have been found to repel the binding of m⁶A adenosine to stable mRNA, which may present more interesting competitive functions in the m⁶A reading process.

3. Inflammation

Inflammation is the basis of various physiological and pathological processes in humans and animals. Usually, inflammation is an autoadaptive response which is triggered by infection or tissue damage [47, 48]. Furthermore, new interdisciplinary disciplines such as “immune metabolism” have emerged.

3.1. Inflammation Initiation

According to the origin of inflammation, inflammatory substances can be divided into two categories: exogenous inducers and endogenous inducers. Exogenous inducers mainly include biological, physical, and chemical factors, while endogenous inducers mainly refer to autoantibodies that induce I–IV autoimmunity and cause varying degrees of inflammation. This in turn leads to the activation of inflammatory mediators.

Inflammatory mediators are molecules that play an important regulatory role in inflammation, and they are mainly derived from blood vessels and cells. Cytogenic inflammatory mediators mainly include vasoactive amines, arachidonic acid metabolites, leukocyte products, cytokines, and platelet activator. Plasma-derived inflammatory mediators mainly include kinin, complement, and the coagulation system.

Generally, inflammation can be classified as acute or chronic based on the course of the inflammation. The degree of inflammation varies according to the stage of a disease. For instance, inflammation is chronic from the beginning in some diseases such as atherosclerosis [49], obesity [50], and cancer [51]. However, acute and chronic inflammation can also coexist, which means that the inflammation is constantly recurring and recovery is difficult, such as in the case of rheumatoid arthritis (RA), multiple sclerosis (MS), and inflammatory bowel disease (IBD). Unfortunately, the mechanisms of these diseases remain unclear [51], but inflammation promotes their progression. Through increased research into inflammation, people have attempted to unravel the molecular mechanisms behind it.

3.2. Typical Inflammation Signaling Pathways

Abnormal inflammatory responses are being considered as a key factor in human disease. IL-6 is a pleiotropic proinflammatory cytokine, which is an important modular for the transition from acute phase to chronic phase of inflammation. Interestingly, IL-6/IL-6R/gp130 consists of a hexameric complex and activates three essential signaling pathways including MAPK, JAK/STAT3, and PI3K [52] (Figure 2). These pathways are closely associated with cancer, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, and Alzheimer’s disease. In route 1, JAK activates Ras/Raf and subsequently causes hyperphosphorylation of MAPK. In route 2, JAK induces phosphorylation of itself and activates STAT3. Route 3 is associated with the PI3K/PKB/AKT pathway, which contributes to the activation of NF-κB. Finally, multiple inflammatory factors are synthesized by target cells, such as TNF-α, IL-1β, NO, PGs, IL-6, IL-8, and PAF [9, 53], causing serious tissue damage.

4. The Role of m⁶A in Inflammatory Diseases

N⁶-Methyladenosine regulates the expression of inflammation-related mRNAs as well as ncRNA, thereby ultimately regulating inflammatory diseases. Recent studies have shown that m⁶A is closely linked with inflammation (Table 1).

4.1. Inflammatory Autoimmune Disease

4.1.1. Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory neurological disorder that involves demyelinating and neurodegeneration. Typical pathological changes in MS involve scattered and distributed demyelinating plaques around the perivenular inflammatory injury, accompanied by glial fibrosis and axonal injury. There is a wide range of inflammatory infiltrates, mainly including T cells (mainly MHC class 1 restricted CD8+ T cells) and B cells, and oligodendrocyte and macrophages surround the core of a lesion [54].

Recently, studies have shown the modification of m⁶A methylation in cerebrospinal fluid that involves the development of multiple sclerosis. It has been reported that patients who suffered from MS usually have higher m⁶A methylase expression [55]. In addition, the m⁶A and expression levels of inflammation-related mRNA in the patients with relapsing remitting multiple sclerosis (RRMS) are significantly higher than those in progressive multiple sclerosis (PMS) [56]. To explore the role of m⁶A in nerve cells, Xu et al. [57] found that knocking out METTL14 in oligodendrocytes leads to hypomethylation of the mRNA of several transcription factors, growth factors, and histone modifiers. This disrupts the normal maturation and differentiation of oligodendrocytes and led to abnormal splicing of large amounts of transcripts that are significantly enriched in several inflammatory signaling pathways, such as the PI3K/AKT/mTOR, ERK/MAPK, IGF-1, Notch, and WNT signaling pathways [57] (Figure 3(a)).

4.1.2. Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by atopic chronic inflammation that is often associated with a variety of factors, such as food, the environment, and heredity [58], and includes ulcerative colitis (UC) and Crohn’s disease (CD) [59].

Numerous studies have shown an association between m⁶A and the mucosal immune microenvironment [16]; therefore, scholars have speculated that m⁶A also plays a critical role in IBD. By testing the clinical samples of CRC, researchers have found that METTL3 promotes cell proliferation through suppressing SOCS2 [60] and stabilizing CCNE1 in an m⁶A-dependent manner [61]. Also, METTL14 is essential for suppressing apoptosis in colonic epithelial cells through the NF-κB pathway [62]. The lack of METTL14 in T cells has been shown to induce spontaneous colitis in mice and is accompanied by severe inflammatory cell infiltration [63]. Therefore, abnormal cell proliferation, chronic inflammation, and antiapoptotic processes occur in intestinal cells where hypermethylation is observed, which may further aggravate IBD. Additionally, YTHDF1 promotes the expression of TRAF6 [64], and YTHDF1 knockout strongly inhibits WNT-driven regeneration and tumorigenesis [65, 66].

Recently, a comprehensive analysis of m⁶A in IBD was carried out. IGF2BP2, HNRNPA2B1, ZCCHC4, and EIF3I showed significantly different expression patterns in colon biopsy samples of patients with IBD [67]. Sebastian-delaCruz et al. [68] predicted that m⁶A also regulates genes associated with IBD, such as UBE2L3 and SLC22A4 in Crohn’s disease and TCF19, C6orf47, and SNAPC4 in ulcerative colitis. High expression of m⁶A-related phenotype genes, such as H2AFZ, is often accompanied by higher abundances of M1 macrophages, M0 macrophages, and naive B cells in IBD patients. This research has guided drug selection in the direction of m⁶A and provided ideas for improving responses to anti-TNF treatment [16]. However, experiments that confirm the diagnostic significance or therapeutic value of the m⁶A regulatory gene in IBD are lacking, and further research is still needed (Figure 3(b)).

4.1.3. Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a typical multisystem inflammatory autoimmune disease [69]. Normally, lupus nephritis (LN) is one of the most common severe organ manifestations of SLE, which is related to high mortality [70]. Neuropsychiatric lupus (NPSLE) occurs in 40–90% of SLE patients, and the damage of microglia may be the major damaged cell [71–73]. Actually, NPSLE is a major source of morbidity in the SLE population, and its mortality is second only to that of LN.

Single-cell transcriptomics analysis has shown that microglia in mice exhibit upregulation of multiple inflammatory genes, for which m⁶A plays an important role [74]. To explore the m⁶A mechanism of cell injury in SLE, researchers have found that METTL3 is an important writer that promotes LPS-induced microglia inflammation through the TRAF6/NF-κB pathway [75]. Moreover, METTL3 has been found to regulate the repair of corneal cell damage [76], while METTL14 exacerbates the progression of renal epithelial cell damage by downregulating Sirt1 [77]. m⁶A is supposed to be the protective factor in SLE. Other studies also confirmed that the expression levels of METTL3, METTL14, WTAP, FTO, ALKBH5, and YTHDF3 in patients with SLE are significantly downregulated [78, 79]. Downregulation of ALKBH5 in peripheral blood may be related to the pathogenesis of SLE, and scientists have observed a strong correlation between ALKBH5 expression and patient autoantibody levels as well as clinical features [78].

Studies have shown that YTHDF1 regulates KCNH6 in an m⁶A-dependent manner and affects the transition from lung fibroblasts to myofibroblasts [80]. YTHDF2 regulates the CircGARS–miR-19a–TNFAIP3 axis through a sponge mechanism, which mediates immune activation of NF-κB and ultimately promotes SLE progression [81]. IGFBP3 is an important biological marker of SLE disease, and it may indirectly inhibit the immune response by reducing the regulation of T cell and B cell activities, thus achieving therapeutic effects [82]. Interestingly, these studies may provide preliminary evidence for taking an epigenetic perspective in SLE targeted therapies, but there is still an urgent need for more detailed reports with clear evidence supporting targeting of m⁶A in SLE therapy (Figure 3(c)).

4.1.4. Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic disease primarily dominated by synovial inflammation that results in synovitis, synovial hypertrophy, and cartilage/bone destruction [83]. Eventual disease progression leads to multiorgan inflammatory damage, affecting the skin, lungs, heart, and/or eyes [83–85] with the development of the course of disease. However, the mechanism of RA is still unclear, and most researchers believe that this autoimmune disease is the result of a combination of epigenetic and genetic factors recently.

Based on single-cell sequencing and machine learning methods, some researchers have identified neuropeptide-related molecules with key regulatory activities in RA, and they have suggested that METTL3 downregulation and IGF2BP2 upregulation aggravate RA through GHR and NPR2 [19]. METTL3 knockdown decreased the percentage of apoptosis and, through the NF-κB pathway, the expression of inflammatory factors in chondrocytes that had been induced by IL-1β [86]. Furthermore, recent studies have shown that reductions in ALKBH5, FTO, and YTHDF2 may be key risk factors for patients who suffer from RA [87]. Moreover, m⁶A-modified noncoding RNA can also regulate the inflammatory response of chondrocytes, for instance, lncRNA_AC008 accelerates the exacerbation of inflammatory damage in chondrocytes through the miR-328-3p-AQP1/ANKH axis under the regulation of FTO [88]. Another important gene, BCL2, regulates chondrocyte’ apoptosis and autophagy in an YTHDF1-dependent manner [89].

Interestingly, Sarsasapogenin, as a representative anti-inflammatory traditional medicine, acts on the m⁶A methylation-modified gene TGM2 in the immune microenvironment of synovial tissue, regulating the cell cycle and reducing apoptosis, which can effectively alleviate the development of RA diseases [90]. However, as a global autoimmune disease, there is still no clear explanation of the actual mechanism of RA. It is hoped that studies on m⁶A could provide us with new directions for studying this disease (Figure 3(d)).

4.2. Inflammatory Metabolic Disorder

4.2.1. Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease, with a global prevalence of about 25% [91]. Mechanically, NAFLD is usually accompanied by inflammation and liver fibrosis [92], which progresses to hepatocellular carcinoma in severe cases.

METTL3 regulates hepatocyte ploidy, and METTL3 knockout results in global hypomethylation, which leads to a series of pathological features associated with NAFLD (e.g., hepatocyte ballooning, microsteatosis, polymorphic nucleus, and DNA damage) [93]. Knocking out METTL3 can effectively inhibit the mTOR and NF-κB signaling pathways, alleviating NAFLD and inflammation in mice [94]. Moreover, METTL3 and METTL14 have been shown to affect triglyceride and cholesterol production and lipid droplet accumulation through ACLY and SCD1 in vitro [95].

Since NAFLD and lipid metabolism are inextricably linked, FTO has also attracted attention in the study of NAFLD, where it reduces mitochondrial abundance and promotes hepatic fat accumulation in hepatocytes, which are hypomethylated [96]. Recent research has explored FTO-regulated hepatic lipid production through FASN. Knockdown of FTO decreased the expression of FASN, which inhibited de novo lipogenesis, thereby resulting in deficient lipid accumulation and induction of cellular apoptosis [97]. Hypermethylated rubicon mRNA is expressed and bound by YTHDF1, which increases its stability, with autophagy in the liver being ultimately inhibited, which leads to accumulation of lipid droplets [98]. YTHDF2 binds to PPARα, leading to alterations in the circadian rhythm, and mRNA stability is mediated to regulate lipid metabolism [99] (Figure 3(e)).

4.2.2. Obesity

Maintenance of homeostasis is essential to the proper operation of the body’s life activities, and extensive inflammation and stress occur when the body’s metabolism is disturbed. In obesity, excess adipose tissue can secrete more adipokines, such as leptin and interleukin. Excess interleukin promotes adipose tissue infiltration of immune cells, which leads to chronic low-grade inflammation and promotes insulin resistance [100, 101].

In a recent study, the demethylation activity of FTO was shown to be necessary for preadipocyte differentiation [102] and fat metabolism [103], and FTO was identified as an important bridge between obesity and m⁶A. FTO reduces apoptosis of fat cells by activating the JAK2/STAT3 signaling pathway [104]. Zfp217 activates FTO through interaction with YTHDF2 and preserves adipose differentiation [105]. Another study indicated that white-to-beige fat transition is promoted by HIF1A with hypermethylation mediated by FTO [106]. However, some researchers have reported that m⁶Am, instead of m⁶A, was the substrate of FTO. As FTO expression increased, the fatty acid-binding proteins FABP2 and FABP5 lost their m⁶Am modification, and their expression was downregulated [107]. Above all, characterizing the role of the FTO gene has greatly contributed to clarifying the mechanism of m⁶A in obesity.

With more in-depth research on obesity, more relationships between m⁶A and obesity have been discovered. METTL3 was also found to be an essential regulatory protein in obesity [108]. A recent study found that METTL3 inhibits adipocyte differentiation through the JAK1/STAT5/C/EBPβ pathway [109]. Additionally, WTAP and METTL14 have also been found to affect the differentiation of adipocytes [110]. Moreover, two SNPs in METTL3 were found to be associated with body mass index (BMI), and two SNPs in YTHDF3 are associated with gene expression [17]. Clinical studies have explored that curcumin promotes TRAF4 m⁶A methylation and its expression levels under the mediation of YTHDF1, which finally promotes PPARγ degradation through the ubiquitin proteasome pathway, thereby inhibiting lipogenesis [111]. However, details of the complex mechanisms by which m⁶A regulates obesity remain unclear (Figure 3(f)).

4.3. Inflammatory Cardio-Cerebrovascular Diseases

4.3.1. Ischemic Stroke

Ischemic stroke (IS) is one of the most harmful cardio-cerebrovascular diseases. Due to acute ischemia of brain tissue, nerve cells are hypoperfused, leading to local depletion of oxygen and glucose [112]. The infarction area undergoes the death of nerve cells, during which apoptosis and autophagy are the main pathological features [113–115].

Ischemia was first thought to be the only factor to cause tissue damage. However, through extensive review of cases of ischemic diseases, such as stroke and renal ischemic renal failure, scientists gradually discovered that ischemic reperfusion damage leads to more serious damage to tissues. The source of damage is mainly from free radicals and inflammation. Venous recombinant tissue plasminogen activators (rt-PA) are currently proven treatments for stroke, but they are only effective within three hours of a limited onset [116]. Therefore, there is an urgent need to explore new directions for treating IS. In an m⁶A transcriptome-wide map of an MCAO mouse model, 17 lncRNAs and 22 mRNAs with hypermethylation and 5 mRNAs and 3 lncRNAs with hypomethylation were found. The function of these altered m⁶A transcripts was found to be mainly enriched in inflammation, apoptosis, and brain damage [117]. They found that the expression of inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-18) and inflammatory enzymes (TRAF6 and NF-κB) is upregulated as the expression of METTL3 increases in microglia inflammation. Also, overexpression of METTL3 promotes activation of the TRAF6-NF-κB pathway in an m⁶A-dependent manner, and it inhibits inflammation [75]. Another study showed that in the I/R model, the overall m⁶A methylation level was upregulated, and there were significant differences in METTL3, FTO, and ALKBH5 [118, 119]. In a recent study, an oxygen glucose deprivation/reoxygenation (OGD/R) model was established successfully by inducing nerve cell injury, and the expression of Lnc-D63785 with hypermethylation decreased in a METTL3-dependent manner, which led to the accumulation of miR-422a and resulted in cell apoptosis in primary murine neurons [120]. Another study also showed that knocking down ALKBH5 can aggravate neuronal damage and demethylases ALKBH5/FTO coregulate m6A demethylation, resulting in neuronal apoptosis mediated by BCL-2 [118]. Therefore, it is speculated that demethylase also has a protective role in I/R damage and in preventing reperfusion damage [117]. This lays the foundation for the clinical application of m⁶A modification. miR-421-3p specifically targets YTHDF1 and inhibits translation of p65, suggesting a possible role for m⁶A in IS [121]. There is a complex regulatory network precisely regulating our circulatory system based on the extensive role of m⁶A methylation (Figure 3(g)).

4.3.2. Atherosclerosis

Atherosclerosis (AS) occurs due to the accumulation of cholesterol in vessel walls, and recent research has suggested that chronic inflammation may be the real cause of AS [122]. Arteries are divided into three layers, of which the innermost intima mainly consists of collagen fibers, elastin fibers, and a small number of smooth muscle cells. Under homeostatic conditions, endothelial monolayers do not attract the aggregation of leukocytes and lead to immune activation. When inflammatory cytokines or other cardiovascular risk factors are present, endothelial cells promote the adhesion of immune cells and induce inflammation [123].

HSP60 and LDL act as antigens in the development of the disease, causing cellular immunity and humoral immunity [124], while CD4⁺ T cells handle these antigens [125]. Study revealed that METTL14 targets mir-19a and facilitated the treatment of mature miR-19a, thus promoting the proliferation and invasion of atherosclerotic vascular endothelial cells [126]. Hypermethylation may be a risk factor for aggravating the inflammation of AS.

AS is the most extensive cardiovascular disease currently known, and surveys have shown that patients with other chronic inflammation disorders have a higher probability of developing AS [127]. Recently, a study showed that the expression of ZFAS1 with hypermethylation increases under the regulation of METTL14 [128], which activates the downstream ADAM10/RAB22A pathway in an epigenetic modification manner, and ultimately participates in the inflammatory process of vascular endothelial cells in AS [129]. In fact, numerous reports have revealed that AS is regulated by m⁶A modification, mainly based on inflammatory models of endothelial cells [126, 130], macrophages [131, 132], and smooth muscle cells [133, 134]. Although these studies aim to simulate what happens to patients with AS, they cannot truly reflect the conditions of AS patients. More clinical research is needed to explain the epigenetic mechanisms of AS pathogenesis (Figure 3(h)).

5. The Role of m⁶A in Inflammatory Cancer Microenvironments

Cancer has always been a difficult problem in the medical community. Extensive studies have showed that inflammatory microenvironments are associated with cancer progression or inhibition [135–139], and m⁶A provides new ideas for clinical diagnosis and treatment. Globally, liver cancer is the most frequent fatal malignancy [140]. Lung cancer is one of the most common malignant tumors and is the most frequently diagnosed fatal tumor type in China [141].

In human liver cancer, the expression of USP48 is downregulated, reducing the stability of SIRT6, which induces the occurrence of liver cancer. Recent studies have shown that METTL14 is involved in the stabilization of USP48, thereby hindering the occurrence of liver cancer tumors [142]. YTHDF2, as an important reading protein, is significantly downregulated in liver cancer cells and leads to severe inflammation, vascular reconstruction, and cancer metastasis. The deletion of YTHDF2 causes mRNA decay of IL-1β and HIF-2α. After using an HIF-2α inhibitor, the authors found that liver cancer was suppressed [143]. Additionally, FTO can also inhibit tumor growth by reducing TED2 mRNA stability [144] (Figure 4(a)).

Recently, researchers again confirmed that IL-6 can effectively construct the inflammatory microenvironment of lung adenocarcinoma liver metastasis in vitro, increasing the proliferation, metastasis, and EMT of lung adenocarcinoma cells [145–149]. Moreover, the authors found global RNA methylation increases and METTL3 activates the YAP1/TEAD signaling pathway. Another study showed that high expression of YTHDF2 and SUMO1 often suggests a poor prognosis for lung adenocarcinoma. Sumoylation of YTHDF2 can increase its ability to bind to m⁶A-modified mRNA to downregulate target gene expression, ultimately inducing cancer [150] (Figure 4(b)).

The relationship between cancer and inflammation is not a new idea, and as early as 1863, Verchow proposed the hypothesis that cancer may originate from inflammation [6]. Studies have documented that in the inflammatory microenvironment (Figure 4(c)), where inflammatory factors such as IL-1β and IL-6 are enriched (Figure 4(d)), tumor cells are more likely to proliferate, metastasize, and perform EMT [151]. The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can effectively reduce the risk of several types of cancer by 40–50%, such as colon cancer, which demonstrates the important impact of inflammation in the cancer process. Immunotherapy against the tumor inflammatory microenvironment has a significant curative effect on tumors with activation of inflammatory pathways, infiltration of active immune cells, and lack of matrix components [152]. Researchers have found that writers and erasers regulate malignant tumors in a reading protein-dependent manner, and they are mainly concentrated in inflammatory pathways [152, 153]. This provides new ideas for personalized treatment of tumors. For instance, IFITM3, as an important innate immune protein, may be associated with the microbiota and m⁶A. At the same time, IFITM3 is positively correlated with immunomodulators, tumor-infiltrating immune cells (TIIC), and cancer immune cycles [154].

In clinic, chemotherapy is a common cancer treatment (Figure 4(e)). Aseptic inflammation caused by chemotherapy is a serious negative effect, while ALKBH5 affects the progression of aseptic inflammation through epidermal modifications [155]. Above all, m⁶A plays an important role in not only the development of cancer but also in controlling the negative effects of chemotherapy. m⁶A may be a crucial mechanism in cancer, and further epigenetics research into cancer could lead to further breakthroughs in cancer treatments. Moreover, numerous preclinical studies indicated that m⁶A targeting therapy synchronizing with anti-PD1 therapy has shown tremendous potential.

6. The Role of m⁶A in Pathogen-Induced Inflammation

Extensive studies have shown that m⁶A plays a wide range of roles in pathogen-induced inflammation. METTL3 has attracted considerable attention. Overexpression of METTL3 can significantly reduce LPS-induced inflammation in macrophage [156]. METTL3 depletion inhibits YTHDF1- and YTHDF2-mediated degradation of NOD1 and RIPK2, which subsequently promotes LPS-induced inflammatory responses [157]. Another research demonstrated that LPS stimulation leads to upregulation of YTHDF2, and knockdown of YTHDF2 improves the stability of MAP2K4 and MAP4K4 and activates the MAPK and NF-κB signaling pathways [131].

In Salmonella typhimurium infection, YTHDF2 depletion promoted H3K27me3 demethylation of multiple inflammatory cytokines in the MAPK and NF-κB signaling pathways, such as IL-6 and IL-12B, and subsequently enhanced its transcription [158]. Moreover, cell injury induced by E. coli and S. aureus has also been proved to be associated with m⁶A modification, and differentially expressed genes are mainly enriched in inflammation, apoptosis, and autophagy [47, 159].

The role of m⁶A modification has also been found in fungi-induced inflammation. Fusarium solani-induced keratitis increased global m⁶A level and the expression of METTL3 in corneal stromal cell and mice, which ultimately activated the NF-κB signaling pathway [160].

Recently, researchers showed that METTL3 depletion in host cells simultaneously reduced m⁶A levels in both the host and SARS-CoV-2. The global hypomethylation in SARS-CoV-2 increased RIG-I and enhanced the expression of innate immune signaling pathways and inflammatory genes relatedly [161]. This may indicate that SARS-CoV-2 undergoes m⁶A modification through host m⁶A machinery and regulates its own activities [162].

Totally, it is widely acknowledged that m⁶A modification plays important roles in pathogen-induced inflammation.

7. Clinical Therapy Potential

Taken together, m⁶A has clinical therapeutic potential for the treatment of inflammatory disease. Recently, studies have discovered highly effective compounds that target m⁶A modification [163–165]. For instance, meclofenamic acid (MA) was directly identified as a specific inhibitor of FTO through screening [166]. The natural compound radicicol was proved to be a potent FTO inhibitor [167]. STM2457 is a highly potent and selective first-in-class catalytic inhibitor of METTL3, which can reduce acute myeloid leukemia (AML) growth [164]. Moreover, traditional medicines have also been found to be important m⁶A modulators [168–171]. Resveratrol and curcumin are natural phenolic compounds that increase YTHDF2 levels to maintain intestinal mucosal integrity, which has potential for IBD treatment [111, 172, 173]. Epigallocatechin gallate is a tea flavonoid, and it exerts a strong anti-inflammatory effect mainly by inhibiting FTO expression and enhancing YTHDF2 expression [174]. Saikosaponin, an extract of Bupleuri, also has anti-inflammatory activity, inhibiting FTO expression [175]. With the development of modern medicine, photoactivated compounds have been creatively constructed, such as a caged molecule activator of METTL3/14, photocaging substituent-linked MPCH [176]. This drug can be rapidly released by exogenous light and functions in vivo, and it is considered a breakthrough in m⁶A-targeted drugs, though its side effects still need to be strictly monitored.

8. Future Prospects

Recently, many studies have shown that m⁶A is closely related to inflammation and can thus be considered a target for treatment. As an epigenetic modification found in various RNAs, m⁶A in ncRNA can represent a more precise target than those used in traditional medicine. With the development of high-throughput sequencing technology and MeRIP-seq, used in combination with GWAS and SNP analyses, it may be possible to gain more biological information about m⁶A modifications. Comprehensive studies of m⁶A have been beneficial for enhancing our understanding of inflammation.

Moreover, it is more efficient to develop m⁶A agonists or inhibitors for treating inflammation by characterizing the m⁶A profiles in different diseases, which could replace some traditional drugs that have extensive side effects, such as corticosteroids. In summary, m⁶A has the potential to become a prospective target in treatments for inflammation, but further confirmation is still needed.

Abbreviations

m⁶A:	N⁶-Methyladenosine
MS:	Multiple sclerosis
RRMS:	Relapsed-remission multiple sclerosis
PMS:	Progressive multiple sclerosis
IBD:	Inflammatory bowel disease
UC:	Ulcerative colitis
CD:	Crohn’s disease
SLE:	Systemic lupus erythematosus
RA:	Rheumatoid arthritis
NAFLD:	Nonalcoholic fatty liver disease
MeRIP-seq:	Methylated RNA immunoprecipitation sequencing
GWAS:	Genome-wide association study
SNP:	Single nucleotide polymorphism
LN:	Lupus nephritis
NPSLE:	Neuropsychiatric lupus
MA:	Meclofenamic acid
AML:	Acute myeloid leukemia.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Authors’ Contributions

Haojun Xu, Changjie Lin, and Jinghan Yang were responsible for writing—review and editing. Xi Chen, Yingyu Chen, Jianguo Chen, Aizhen Guo, and Changmin Hu were responsible for project administration and funding acquisition. All authors read and approved the final manuscript.

Acknowledgments

We thank the State Key Laboratory of Agricultural Microbiology of Huazhong Agricultural University for providing a platform to conduct this study. We thank Figdraw (http://www.figdraw.com) for the support. This research was funded by the National Natural Science Foundation of China (Nos. 32273087, 31972758, and 31101874). This work was supported by the Key Research and Development Program of Hubei Province (#2020BBA055) and the China Agricultural Research System (beef/yaks) of MOF and MARA (CARS-37).

References

H. Zhang, X. Shi, T. Huang et al., “Dynamic landscape and evolution of m⁶A methylation in human,” Nucleic Acids Research, vol. 48, pp. 6251–6264, 2020.
View at: Publisher Site | Google Scholar
K. R. Noon, E. Bruenger, and J. A. McCloskey, “Posttranscriptional modifications in 16S and 23S rRNAs of the archaeal hyperthermophile Sulfolobus solfataricus,” Journal of Bacteriology, vol. 180, pp. 2883–2888, 1998.
View at: Publisher Site | Google Scholar
D. Dominissini, S. Moshitch-Moshkovitz, S. Schwartz et al., “Topology of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq,” Nature, vol. 485, pp. 201–206, 2012.
View at: Publisher Site | Google Scholar
Y. Fu, D. Dominissini, G. Rechavi, and C. He, “Gene expression regulation mediated through reversible m⁶A RNA methylation,” Nature Reviews Genetics, vol. 15, pp. 293–306, 2014.
View at: Publisher Site | Google Scholar
A. Ogawa, C. Nagiri, W. Shihoya et al., “N⁶-methyladenosine (m⁶A) is an endogenous A3 adenosine receptor ligand,” Molecular Cell, vol. 81, pp. 659–674.e7, 2021.
View at: Publisher Site | Google Scholar
F. Balkwill and A. Mantovani, “Inflammation and cancer: back to Virchow?” The Lancet, vol. 357, pp. 539–545, 2001.
View at: Publisher Site | Google Scholar
S. C. Gupta, A. B. Kunnumakkara, S. Aggarwal, and B. B. Aggarwal, “Inflammation, a double-edge sword for cancer and other age-related diseases,” Frontiers in Immunology, vol. 9, p. 2160, 2018.
View at: Publisher Site | Google Scholar
D. Liu, Z. Zhong, and M. Karin, “NF-κB: a double-edged sword controlling inflammation,” Biomedicine, vol. 10, p. 1250, 2022.
View at: Publisher Site | Google Scholar
C. Liu, X. Tang, W. Zhang et al., “6-Bromoindirubin-3-oxime suppresses LPS-induced inflammation via inhibition of the TLR4/NF-κB and TLR4/MAPK signaling pathways,” Inflammation, vol. 42, pp. 2192–2204, 2019.
View at: Publisher Site | Google Scholar
S. J. Chen, C. Y. Zhang, D. Yu, C. J. Lin, H. J. Xu, and C. M. Hu, “Selenium alleviates inflammation in staphylococcus aureus-induced mastitis via MerTK-dependent activation of the PI3K/Akt/mTOR pathway in mice,” Biological Trace Element Research, vol. 200, pp. 1750–1762, 2022.
View at: Publisher Site | Google Scholar
C. K. Lin and B. I. Kazmierczak, “Inflammation: a double-edged sword in the response to Pseudomonas aeruginosa infection,” Journal of Innate Immunity, vol. 9, pp. 250–261, 2017.
View at: Publisher Site | Google Scholar
Q. Q. Huang and R. M. Pope, “The role of toll-like receptors in rheumatoid arthritis,” Current Rheumatology Reports, vol. 11, pp. 357–364, 2009.
View at: Publisher Site | Google Scholar
S. Devaraj, J. M. Yun, C. R. Duncan-Staley, and I. Jialal, “Low vitamin D levels correlate with the proinflammatory state in type 1 diabetic subjects with and without microvascular complications,” American Journal of Clinical Pathology, vol. 135, pp. 429–433, 2011.
View at: Publisher Site | Google Scholar
I. Jialal, H. Kaur, and S. Devaraj, “Toll-like receptor status in obesity and metabolic syndrome: a translational perspective,” The Journal of Clinical Endocrinology & Metabolism, vol. 99, pp. 39–48, 2014.
View at: Publisher Site | Google Scholar
W. Gao, Y. Xiong, Q. Li, and H. Yang, “Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics,” Frontiers in Physiology, vol. 8, p. 508, 2017.
View at: Publisher Site | Google Scholar
Y. Chen, J. Lei, and S. He, “M⁶A modification mediates mucosal immune microenvironment and therapeutic response in inflammatory bowel disease,” Frontiers in Cell and Developmental Biology, vol. 9, article 692160, 2021.
View at: Publisher Site | Google Scholar
T. Ronningen, M. B. Dahl, T. G. Valderhaug et al., “M⁶A regulators in human adipose tissue-depot-specificity and correlation with obesity,” Frontiers in Endocrinology, vol. 12, article 778875, 2021.
View at: Publisher Site | Google Scholar
W. L. Ke, Z. W. Huang, C. L. Peng, and Y. P. Ke, “M⁶A demethylase FTO regulates the apoptosis and inflammation of cardiomyocytes via YAP1 in ischemia-reperfusion injury,” Bioengineered, vol. 13, pp. 5443–5452, 2022.
View at: Publisher Site | Google Scholar
J. Xiao, X. Cai, R. Wang, W. Zhou, and Z. Ye, “Identification of synovial fibroblast-associated neuropeptide genes and m⁶A factors in rheumatoid arthritis using single-cell analysis and machine learning,” Disease Markers, vol. 2022, Article ID 5114697, 12 pages, 2022.
View at: Publisher Site | Google Scholar
K. D. Meyer, Y. Saletore, P. Zumbo, O. Elemento, C. E. Mason, and S. R. Jaffrey, “Comprehensive analysis of mRNA methylation reveals enrichment in 3 UTRs and near stop codons,” Cell, vol. 149, pp. 1635–1646, 2012.
View at: Publisher Site | Google Scholar
H. Shi, X. Wang, Z. Lu et al., “YTHDF3 facilitates translation and decay of N⁶-methyladenosine-modified RNA,” Cell Research, vol. 27, pp. 315–328, 2017.
View at: Publisher Site | Google Scholar
X. L. Ping, B. F. Sun, L. Wang et al., “Mammalian WTAP is a regulatory subunit of the RNA N⁶-methyladenosine methyltransferase,” Cell Research, vol. 24, pp. 177–189, 2014.
View at: Publisher Site | Google Scholar
J. Wen, R. Lv, H. Ma et al., “Zc3h13 regulates nuclear RNA m⁶A methylation and mouse embryonic stem cell self-renewal,” Molecular Cell, vol. 69, pp. 1028–1038.e6, 2018.
View at: Publisher Site | Google Scholar
K. E. Pendleton, B. Chen, K. Liu et al., “The U6 snRNA m⁶A methyltransferase METTL16 regulates SAM synthetase intron retention,” Cell, vol. 169, pp. 824–835.e14, 2017.
View at: Publisher Site | Google Scholar
C. Sepich-Poore, Z. Zheng, E. Schmitt et al., “The METTL5-TRMT112 N⁶-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation,” Journal of Biological Chemistry, vol. 298, article 101590, 2022.
View at: Publisher Site | Google Scholar
R. Pinto, C. B. Vågbø, M. E. Jakobsson et al., “The human methyltransferase ZCCHC4 catalyses N⁶-methyladenosine modification of 28S ribosomal RNA,” Nucleic Acids Research, vol. 48, pp. 830–846, 2020.
View at: Publisher Site | Google Scholar
G. Jia, Y. Fu, X. Zhao et al., “N⁶-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO,” Nature Chemical Biology, vol. 7, pp. 885–887, 2011.
View at: Publisher Site | Google Scholar
Y. Fu, G. Jia, X. Pang et al., “FTO-mediated formation of N⁶-hydroxymethyladenosine and N⁶-formyladenosine in mammalian RNA,” Nature Communications, vol. 4, p. 1798, 2013.
View at: Publisher Site | Google Scholar
J. Mauer, X. Luo, A. Blanjoie et al., “Reversible methylation of m⁶Am in the 5 cap controls mRNA stability,” Nature, vol. 541, pp. 371–375, 2017.
View at: Publisher Site | Google Scholar
G. Zheng, J. A. Dahl, Y. Niu et al., “ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility,” Molecular Cell, vol. 49, pp. 18–29, 2013.
View at: Publisher Site | Google Scholar
G. Zheng, J. A. Dahl, Y. Niu et al., “Sprouts of RNA epigenetics: the discovery of mammalian RNA demethylases,” RNA Biology, vol. 10, pp. 915–918, 2013.
View at: Publisher Site | Google Scholar
W. Xiao, S. Adhikari, U. Dahal et al., “Nuclear m⁶A reader YTHDC1 regulates mRNA splicing,” Molecular Cell, vol. 61, pp. 507–519, 2016.
View at: Publisher Site | Google Scholar
H. Shima, M. Matsumoto, Y. Ishigami et al., “S-Adenosylmethionine synthesis is regulated by selective N⁶-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1,” Cell Reports, vol. 21, pp. 3354–3363, 2017.
View at: Publisher Site | Google Scholar
D. P. Patil, C. K. Chen, B. F. Pickering et al., “m⁶A RNA methylation promotes XIST-mediated transcriptional repression,” Nature, vol. 537, pp. 369–373, 2016.
View at: Publisher Site | Google Scholar
C. R. Alarcón, H. Goodarzi, H. Lee, X. Liu, S. Tavazoie, and S. F. Tavazoie, “HNRNPA2B1 is a mediator of m⁶A-dependent nuclear RNA processing events,” Cell, vol. 162, pp. 1299–1308, 2015.
View at: Publisher Site | Google Scholar
J. Konig, K. Zarnack, G. Rot et al., “iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution,” Nature Structural & Molecular Biology, vol. 17, pp. 909–915, 2010.
View at: Publisher Site | Google Scholar
Z. Cienikova, F. F. Damberger, J. Hall, F. H. Allain, and C. Maris, “Structural and mechanistic insights into poly(uridine) tract recognition by the hnRNP C RNA recognition motif,” Journal of the American Chemical Society, vol. 136, no. 41, pp. 14536–14544, 2014.
View at: Publisher Site | Google Scholar
K. I. Zhou, H. Shi, R. Lyu et al., “Regulation of co-transcriptional pre-mRNA splicing by m⁶A through the low-complexity protein hnRNPG,” Molecular Cell, vol. 76, pp. 70–81.e9, 2019.
View at: Publisher Site | Google Scholar
S. Liao, H. Sun, and C. Xu, “YTH domain: a family of N⁶-methyladenosine (m⁶A) readers,” Genomics, Proteomics & Bioinformatics, vol. 16, pp. 99–107, 2018.
View at: Publisher Site | Google Scholar
X. Wang, Z. Lu, A. Gomez et al., “N⁶-Methyladenosine-dependent regulation of messenger RNA stability,” Nature, vol. 505, pp. 117–120, 2014.
View at: Publisher Site | Google Scholar
H. Huang, H. Weng, W. Sun et al., “Recognition of RNA N⁶-methyladenosine by IGF2BP proteins enhances mRNA stability and translation,” Nature Cell Biology, vol. 20, pp. 285–295, 2018.
View at: Publisher Site | Google Scholar
S. Wang, B. Chim, Y. Su et al., “Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3,” Genes & Development, vol. 33, no. 15-16, pp. 1048–1068, 2019.
View at: Publisher Site | Google Scholar
K. D. Meyer, D. P. Patil, J. Zhou et al., “5 UTR m⁶A promotes cap-independent translation,” Cell, vol. 163, pp. 999–1010, 2015.
View at: Publisher Site | Google Scholar
R. Wu, A. Li, B. Sun et al., “A novel m⁶A reader Prrc2a controls oligodendroglial specification and myelination,” Cell Research, vol. 29, pp. 23–41, 2019.
View at: Publisher Site | Google Scholar
Y. Wang, Y. Li, J. I. Toth, M. D. Petroski, Z. Zhang, and J. C. Zhao, “N⁶-Methyladenosine modification destabilizes developmental regulators in embryonic stem cells,” Nature Cell Biology, vol. 16, pp. 191–198, 2014.
View at: Publisher Site | Google Scholar
R. R. Edupuganti, S. Geiger, R. G. H. Lindeboom et al., “N⁶-Methyladenosine (m⁶A) recruits and repels proteins to regulate mRNA homeostasis,” Nature Structural & Molecular Biology, vol. 24, pp. 870–878, 2017.
View at: Publisher Site | Google Scholar
T. Li, C. Lin, Y. Zhu et al., “Transcriptome profiling of m⁶A mRNA modification in bovine mammary epithelial cells treated with Escherichia coli,” International Journal of Molecular Sciences, vol. 22, p. 6254, 2021.
View at: Publisher Site | Google Scholar
C. Lin, Y. Zhu, Z. Hao et al., “Genome-wide analysis of lncRNA in bovine mammary epithelial cell injuries induced by Escherichia Coli and staphylococcus aureus,” International Journal of Molecular Sciences, vol. 22, p. 9719, 2021.
View at: Publisher Site | Google Scholar
E. Galkina and K. Ley, “Immune and inflammatory mechanisms of atherosclerosis,” Annual Review of Immunology, vol. 27, pp. 165–197, 2009.
View at: Publisher Site | Google Scholar
C. Nathan, “Epidemic inflammation: pondering obesity,” Molecular Medicine, vol. 14, no. 7-8, pp. 485–492, 2008.
View at: Publisher Site | Google Scholar
A. Mantovani, P. Allavena, A. Sica, and F. Balkwill, “Cancer-related inflammation,” Nature, vol. 454, no. 7203, pp. 436–444, 2008.
View at: Publisher Site | Google Scholar
S. Kaur, Y. Bansal, R. Kumar, and G. Bansal, “A panoramic review of IL-6: structure, pathophysiological roles and inhibitors,” Bioorganic & Medicinal Chemistry, vol. 28, article 115327, 2020.
View at: Publisher Site | Google Scholar
X. Tang, C. Liu, T. Li et al., “Gambogic acid alleviates inflammation and apoptosis and protects the blood-milk barrier in mastitis induced by LPS,” International Immunopharmacology, vol. 86, article 106697, 2020.
View at: Publisher Site | Google Scholar
R. Dobson and G. Giovannoni, “Multiple sclerosis - a review,” European Journal of Neurology, vol. 26, pp. 27–40, 2019.
View at: Publisher Site | Google Scholar
S. J. Park and J. W. Choi, “Brain energy metabolism and multiple sclerosis: progress and prospects,” Archives of Pharmacal Research, vol. 43, no. 10, pp. 1017–1030, 2020.
View at: Publisher Site | Google Scholar
F. Ye, T. Wang, X. Wu, J. Liang, J. Li, and W. Sheng, “N⁶-Methyladenosine RNA modification in cerebrospinal fluid as a novel potential diagnostic biomarker for progressive multiple sclerosis,” Journal of Translational Medicine, vol. 19, no. 1, p. 316, 2021.
View at: Publisher Site | Google Scholar
H. Xu, Y. Dzhashiashvili, A. Shah et al., “M⁶A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination,” Neuron, vol. 105, no. 2, pp. 293–309.e5, 2020.
View at: Publisher Site | Google Scholar
J. D. Lewis, J. J. Deren, and G. R. Lichtenstein, “Cancer risk in patients with inflammatory bowel disease,” Gastroenterology Clinics of North America, vol. 28, no. 2, pp. 459–477, 1999.
View at: Publisher Site | Google Scholar
S. Deweerdt, “Genetics: clues in the code,” Nature, vol. 540, no. 7634, pp. S104–S105, 2016.
View at: Publisher Site | Google Scholar
J. Xu, Q. Chen, K. Tian et al., “M⁶A methyltransferase METTL3 maintains colon cancer tumorigenicity by suppressing SOCS2 to promote cell proliferation,” Oncology Reports, vol. 44, no. 3, pp. 973–986, 2020.
View at: Publisher Site | Google Scholar
W. Zhu, Y. Si, J. Xu et al., “Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m⁶A-dependent manner,” Journal of Cellular and Molecular Medicine, vol. 24, no. 6, pp. 3521–3533, 2020.
View at: Publisher Site | Google Scholar
T. Zhang, C. Ding, H. Chen et al., “M⁶A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB–mediated antiapoptotic pathway,” Science Advances, vol. 8, no. 12, article eabl5723, 2022.
View at: Publisher Site | Google Scholar
T. X. Lu, Z. Zheng, L. Zhang et al., “A new model of spontaneous colitis in mice induced by deletion of an RNA m⁶A methyltransferase component METTL14 in T cells,” Cellular and Molecular Gastroenterology and Hepatology, vol. 10, no. 4, pp. 747–761, 2020.
View at: Publisher Site | Google Scholar
X. Zong, X. Xiao, B. Shen et al., “The N⁶-methyladenosine RNA-binding protein YTHDF1 modulates the translation of TRAF6 to mediate the intestinal immune response,” Nucleic Acids Research, vol. 49, no. 10, pp. 5537–5552, 2021.
View at: Publisher Site | Google Scholar
B. Han, S. Yan, S. Wei et al., “YTHDF1-mediated translation amplifies Wnt-driven intestinal stemness,” EMBO Reports, vol. 21, no. 4, article e49229, 2020.
View at: Publisher Site | Google Scholar
X. M. Liu and S. B. Qian, “Linking m⁶A to wnt signaling,” EMBO Reports, vol. 21, no. 4, article e50097, 2020.
View at: Publisher Site | Google Scholar
K. Nie, J. Yi, Y. Yang et al., “A broad m⁶A modification landscape in inflammatory bowel disease,” Frontiers in Cell and Development Biology, vol. 9, article 782636, 2021.
View at: Publisher Site | Google Scholar
M. Sebastian-delaCruz, A. Olazagoitia-Garmendia, I. Gonzalez-Moro, I. Santin, K. Garcia-Etxebarria, and A. Castellanos-Rubio, “Implication of m⁶A mRNA methylation in susceptibility to inflammatory bowel disease,” Epigenomes, vol. 4, p. 16, 2020.
View at: Publisher Site | Google Scholar
M. Kiriakidou and C. L. Ching, “Systemic lupus erythematosus,” Annals of Internal Medicine, vol. 172, pp. ITC81–ITC96, 2020.
View at: Publisher Site | Google Scholar
N. Alforaih, L. Whittall-Garcia, and Z. Touma, “A review of lupus nephritis,” The Journal of Applied Laboratory Medicine, vol. 7, pp. 1450–1467, 2022.
View at: Publisher Site | Google Scholar
X. Han, T. Xu, C. Ding et al., “Neuronal NR4A1 deficiency drives complement-coordinated synaptic stripping by microglia in a mouse model of lupus,” Signal Transduction and Targeted Therapy, vol. 7, p. 50, 2022.
View at: Publisher Site | Google Scholar
A. Zarfeshani, K. R. Carroll, B. T. Volpe, and B. Diamond, “Cognitive impairment in SLE: mechanisms and therapeutic approaches,” Current Rheumatology Reports, vol. 23, p. 25, 2021.
View at: Publisher Site | Google Scholar
N. Schwartz, A. D. Stock, and C. Putterman, “Neuropsychiatric lupus: new mechanistic insights and future treatment directions,” Nature Reviews Rheumatology, vol. 15, pp. 137–152, 2019.
View at: Publisher Site | Google Scholar
Q. Li, S. Wen, W. Ye, S. Zhao, and X. Liu, “The potential roles of m⁶A modification in regulating the inflammatory response in microglia,” Journal of Neuroinflammation, vol. 18, p. 149, 2021.
View at: Publisher Site | Google Scholar
L. Wen, W. Sun, D. Xia, Y. Wang, J. Li, and S. Yang, “The m⁶A methyltransferase METTL3 promotes LPS-induced microglia inflammation through TRAF6/NF-κB pathway,” Neuroreport, vol. 33, pp. 243–251, 2020.
View at: Publisher Site | Google Scholar
Y. Dai, M. Cheng, S. Zhang et al., “METTL3-mediated m⁶A RNA modification regulates corneal injury repair,” Stem Cells International, vol. 2021, Article ID 5512153, 14 pages, 2021.
View at: Publisher Site | Google Scholar
Z. Lu, H. Liu, N. Song et al., “METTL14 aggravates podocyte injury and glomerulopathy progression through N⁶-methyladenosine-dependent downregulating of Sirt1,” Cell Death & Disease, vol. 12, p. 881, 2021.
View at: Publisher Site | Google Scholar
Q. Luo, B. Fu, L. Zhang, Y. Guo, Z. Huang, and J. Li, “Decreased peripheral blood ALKBH5 correlates with markers of autoimmune response in systemic lupus erythematosus,” Disease Markers, vol. 2020, Article ID 8193895, 11 pages, 2020.
View at: Publisher Site | Google Scholar
Q. Luo, J. Rao, L. Zhang et al., “The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus,” Molecular Genetics & Genomic Medicine, vol. 8, article e1298, 2020.
View at: Publisher Site | Google Scholar
J. X. Zhang, P. J. Huang, D. P. Wang et al., “M⁶A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation,” Molecular Therapy, vol. 29, no. 12, pp. 3436–3448, 2021.
View at: Publisher Site | Google Scholar
X. Zhao, R. Dong, L. Zhang et al., “N⁶-Methyladenosine-dependent modification of circGARS acts as a new player that promotes SLE progression through the NF-κB/A20 axis,” Arthritis Research & Therapy, vol. 24, p. 37, 2022.
View at: Publisher Site | Google Scholar
X. Zhao, L. Ge, J. Wang et al., “Exploration of potential integrated models of N⁶-methyladenosine immunity in systemic lupus erythematosus by bioinformatic analyses,” Frontiers in Immunology, vol. 12, article 752736, 2021.
View at: Publisher Site | Google Scholar
E. A. Littlejohn and S. U. Monrad, “Early diagnosis and treatment of rheumatoid arthritis,” Primary Care, vol. 45, pp. 237–255, 2018.
View at: Publisher Site | Google Scholar
A. Blum and M. Adawi, “Rheumatoid arthritis (RA) and cardiovascular disease,” Autoimmunity Reviews, vol. 18, pp. 679–690, 2019.
View at: Publisher Site | Google Scholar
B. Brandt, S. Rashidiani, A. Ban, and T. A. Rauch, “DNA methylation-governed gene expression in autoimmune arthritis,” International Journal of Molecular Sciences, vol. 20, p. 5646, 2019.
View at: Publisher Site | Google Scholar
Q. Liu, M. Li, L. Jiang, R. Jiang, and B. Fu, “METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte,” Biochemical and Biophysical Research Communications, vol. 516, pp. 22–27, 2019.
View at: Publisher Site | Google Scholar
Q. Luo, Y. Gao, L. Zhang et al., “Decreased ALKBH5, FTO, and YTHDF2 in peripheral blood are as risk factors for rheumatoid arthritis,” BioMed Research International, vol. 2020, Article ID 5735279, 9 pages, 2020.
View at: Publisher Site | Google Scholar
J. Yang, M. Zhang, D. Yang et al., “M⁶A-mediated upregulation of AC008 promotes osteoarthritis progression through the miR-328-3p–AQP1/ANKH axis,” Experimental & Molecular Medicine, vol. 53, no. 11, pp. 1723–1734, 2021.
View at: Publisher Site | Google Scholar
Y. He, W. Wang, X. Xu et al., “METTL3 inhibits the apoptosis and autophagy of chondrocytes in inflammation through mediating BCL2 stability via YTHDF1-mediated m⁶A modification,” Bone, vol. 154, article 116182, 2022.
View at: Publisher Site | Google Scholar
X. Lin, C. Tao, R. Zhang, M. Zhang, Q. Wang, and J. Chen, “N⁶-Methyladenosine modification of TGM2 mRNA contributes to the inhibitory activity of sarsasapogenin in rheumatoid arthritis fibroblast-like synoviocytes,” Phytomedicine, vol. 95, article 153871, 2022.
View at: Publisher Site | Google Scholar
M. S. Mundi, S. Velapati, J. Patel, T. A. Kellogg, B. K. Abu Dayyeh, and R. T. Hurt, “Evolution of NAFLD and its management,” Nutrition in Clinical Practice, vol. 35, pp. 72–84, 2020.
View at: Publisher Site | Google Scholar
X. Sun, W. Luo, X. Tan et al., “Increased plasma corticosterone contributes to the development of alcoholic fatty liver in mice,” American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 305, pp. G849–G861, 2013.
View at: Publisher Site | Google Scholar
J. M. Barajas, C. H. Lin, H. L. Sun et al., “METTL3 Regulates Liver Homeostasis, Hepatocyte Ploidy, and Circadian Rhythm-Controlled Gene Expression in Mice,” The American Journal of Pathology, vol. 192, no. 1, pp. 56–71, 2022.
View at: Publisher Site | Google Scholar
Y. Qin, B. Li, S. Arumugam et al., “M⁶A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity,” Cell Reports, vol. 37, no. 6, article 109968, 2021.
View at: Publisher Site | Google Scholar
Y. Yang, J. Cai, X. Yang et al., “Dysregulated m⁶A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma,” Molecular Therapy, vol. 30, pp. 2342–2353, 2022.
View at: Publisher Site | Google Scholar
H. Kang, Z. Zhang, L. Yu, Y. Li, M. Liang, and L. Zhou, “FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation,” Journal of Cellular Biochemistry, vol. 119, pp. 5676–5685, 2018.
View at: Publisher Site | Google Scholar
D. Sun, T. Zhao, Q. Zhang, M. Wu, and Z. Zhang, “Fat mass and obesity-associated protein regulates lipogenesis via m⁶A modification in fatty acid synthase mRNA,” Cell Biology International, vol. 45, pp. 334–344, 2021.
View at: Publisher Site | Google Scholar
Z. Peng, Y. Gong, X. Wang et al., “METTL3-m⁶A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease,” Molecular Therapy, vol. 30, pp. 932–946, 2022.
View at: Publisher Site | Google Scholar
X. Zhong, J. Yu, K. Frazier et al., “Circadian clock regulation of hepatic lipid metabolism by modulation of m⁶A mRNA methylation,” Cell Reports, vol. 25, no. 7, pp. 1816–1828.e4, 2018.
View at: Publisher Site | Google Scholar
U. Kintscher, M. Hartge, K. Hess et al., “T-lymphocyte infiltration in visceral adipose tissue,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 7, pp. 1304–1310, 2008.
View at: Publisher Site | Google Scholar
D. B. Ballak, R. Stienstra, C. J. Tack, C. A. Dinarello, and J. A. van Diepen, “IL-1 family members in the pathogenesis and treatment of metabolic disease: focus on adipose tissue inflammation and insulin resistance,” Cytokine, vol. 75, pp. 280–290, 2015.
View at: Publisher Site | Google Scholar
M. Zhang, Y. Zhang, J. Ma et al., “The demethylase activity of FTO (fat mass and obesity associated protein) is required for preadipocyte differentiation,” PLoS One, vol. 10, article e0133788, 2015.
View at: Publisher Site | Google Scholar
J. Yao, D. Wu, C. Zhang et al., “Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation,” Nature Immunology, vol. 22, pp. 1268–1279, 2021.
View at: Publisher Site | Google Scholar
Z. Shen, P. Liu, Q. Sun et al., “FTO inhibits UPR(mt)-induced apoptosis by activating JAK2/STAT3 pathway and reducing m⁶A level in adipocytes,” Apoptosis, vol. 26, pp. 474–487, 2021.
View at: Publisher Site | Google Scholar
T. Song, Y. Yang, H. Wei et al., “Zfp217 mediates m⁶A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation,” Nucleic Acids Research, vol. 47, pp. 6130–6144, 2019.
View at: Publisher Site | Google Scholar
R. Wu, Y. Chen, Y. Liu et al., “M⁶A methylation promotes white-to-beige fat transition by facilitating Hif1a translation,” EMBO Reports, vol. 22, article e52348, 2021.
View at: Publisher Site | Google Scholar
M. S. Ben Haim, Y. Pinto, S. Moshitch-Moshkovitz et al., “Dynamic regulation of N⁶,2-O-dimethyladenosine (m⁶Am) in obesity,” Nature Communications, vol. 12, p. 7185, 2021.
View at: Publisher Site | Google Scholar
G. Luo, J. Chen, and Z. Ren, “Regulation of methylase METTL3 on fat deposition,” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, vol. 14, pp. 4843–4852, 2021.
View at: Publisher Site | Google Scholar
Y. Yao, Z. Bi, R. Wu et al., “METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPbeta pathway via an m⁶A-YTHDF2-dependent manner,” The FASEB Journal, vol. 33, pp. 7529–7544, 2019.
View at: Publisher Site | Google Scholar
M. Kobayashi, M. Ohsugi, T. Sasako et al., “The RNA methyltransferase complex of WTAP, METTL3, and METTL14 regulates mitotic clonal expansion in adipogenesis,” Molecular and Cellular Biology, vol. 38, pp. e00116–e00118, 2018.
View at: Publisher Site | Google Scholar
Y. Chen, R. Wu, W. Chen et al., “Curcumin prevents obesity by targeting TRAF4-induced ubiquitylation in m⁶A-dependent manner,” EMBO Reports, vol. 22, no. 5, article e52146, 2021.
View at: Publisher Site | Google Scholar
P. Deb, S. Sharma, and K. M. Hassan, “Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis,” Pathophysiology, vol. 17, pp. 197–218, 2010.
View at: Publisher Site | Google Scholar
M. D. Ginsberg, “Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis lecture,” Stroke, vol. 34, pp. 214–223, 2003.
View at: Publisher Site | Google Scholar
P. Mergenthaler, U. Dirnagl, and A. Meisel, “Pathophysiology of stroke: lessons from animal models,” Metabolic Brain Disease, vol. 19, pp. 151–167, 2004.
View at: Publisher Site | Google Scholar
E. Sekerdag, I. Solaroglu, and Y. Gursoy Ozdemir, “Cell death mechanisms in stroke and novel molecular and cellular treatment options,” Current Neuropharmacology, vol. 16, pp. 1396–1415, 2018.
View at: Publisher Site | Google Scholar
M. Fisher and J. L. Saver, “Future directions of acute ischaemic stroke therapy,” The Lancet Neurology, vol. 14, pp. 758–767, 2015.
View at: Publisher Site | Google Scholar
A. K. Chokkalla, S. L. Mehta, T. Kim, B. Chelluboina, J. Kim, and R. Vemuganti, “Transient focal ischemia significantly alters the m⁶A epitranscriptomic tagging of RNAs in the brain,” Stroke, vol. 50, pp. 2912–2921, 2019.
View at: Publisher Site | Google Scholar
K. Xu, Y. Mo, D. Li et al., “N⁶-Methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury,” Therapeutic Advances in Chronic Disease, vol. 11, 2020.
View at: Publisher Site | Google Scholar
D. Yi, Q. Wang, Y. Zhao et al., “Alteration of N⁶-methyladenosine mRNA methylation in a rat model of cerebral ischemia–reperfusion injury,” Frontiers in Neuroscience, vol. 15, p. 164, 2021.
View at: Publisher Site | Google Scholar
S. Xu, Y. Li, J. P. Chen et al., “Oxygen glucose deprivation/re-oxygenation-induced neuronal cell death is associated with Lnc-D63785 m⁶A methylation and miR-422a accumulation,” Cell Death & Disease, vol. 11, p. 816, 2020.
View at: Publisher Site | Google Scholar
L. Zheng, X. Tang, M. Lu et al., “MicroRNA-421-3p prevents inflammatory response in cerebral ischemia/reperfusion injury through targeting m⁶A reader YTHDF1 to inhibit p65 mRNA translation,” International Immunopharmacology, vol. 88, article 106937, 2020.
View at: Publisher Site | Google Scholar
Z. Fu, E. Zhou, X. Wang et al., “Oxidized low-density lipoprotein-induced microparticles promote endothelial monocyte adhesion via intercellular adhesion molecule 1,” American Journal of Physiology. Cell Physiology, vol. 313, no. 5, pp. C567–C574, 2017.
View at: Publisher Site | Google Scholar
P. Libby, “The changing landscape of atherosclerosis,” Nature, vol. 592, pp. 524–533, 2021.
View at: Publisher Site | Google Scholar
G. K. Hansson and P. Libby, “The immune response in atherosclerosis: a double-edged sword,” Nature Reviews Immunology, vol. 6, pp. 508–519, 2006.
View at: Publisher Site | Google Scholar
G. K. Hansson, A. K. Robertson, and C. Soderberg-Naucler, “Inflammation and atherosclerosis,” Annual Review of Pathology, vol. 1, pp. 297–329, 2006.
View at: Publisher Site | Google Scholar
B. Y. Zhang, L. Han, Y. F. Tang et al., “METTL14 regulates m⁶A methylation-modified primary miR-19a to promote cardiovascular endothelial cell proliferation and invasion,” European Review for Medical and Pharmacological Sciences, vol. 24, pp. 7015–7023, 2020.
View at: Publisher Site | Google Scholar
G. K. Hansson and A. Hermansson, “The immune system in atherosclerosis,” Nature Immunology, vol. 12, pp. 204–212, 2011.
View at: Publisher Site | Google Scholar
L. Chen, H. Yao, J. Y. Hui et al., “Global transcriptomic study of atherosclerosis development in rats,” Gene, vol. 592, pp. 43–48, 2016.
View at: Publisher Site | Google Scholar
C. Gong, Y. Fan, and J. Liu, “METTL14 mediated m⁶A modification to LncRNA ZFAS1/ RAB22A: a novel therapeutic target for atherosclerosis,” International Journal of Cardiology, vol. 328, p. 177, 2021.
View at: Publisher Site | Google Scholar
D. Jian, Y. Wang, L. Jian et al., “METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N⁶-methyladeosine modifications,” Theranostics, vol. 10, no. 20, pp. 8939–8956, 2020.
View at: Publisher Site | Google Scholar
R. Yu, Q. Li, Z. Feng, L. Cai, and Q. Xu, “M⁶A reader YTHDF2 regulates LPS-induced inflammatory response,” International Journal of Molecular Sciences, vol. 20, no. 6, p. 1323, 2019.
View at: Publisher Site | Google Scholar
M. Guo, R. Yan, Q. Ji et al., “IFN regulatory factor-1 induced macrophage pyroptosis by modulating m⁶A modification of circ_0029589 in patients with acute coronary syndrome,” International Immunopharmacology, vol. 86, article 106800, 2020.
View at: Publisher Site | Google Scholar
J. Lin, Q. Zhu, J. Huang, R. Cai, and Y. Kuang, “Hypoxia promotes vascular smooth muscle cell (VSMC) differentiation of adipose-derived stem cell (ADSC) by regulating METTL3 and paracrine factors,” Stem Cells International, vol. 2020, Article ID 2830565, 11 pages, 2020.
View at: Publisher Site | Google Scholar
B. Zhu, Y. Gong, L. Shen et al., “Total Panax notoginseng saponin inhibits vascular smooth muscle cell proliferation and migration and intimal hyperplasia by regulating WTAP/p16 signals via m⁶A modulation,” Biomedicine & Pharmacotherapy, vol. 124, article 109935, 2020.
View at: Publisher Site | Google Scholar
S. Geula, S. Moshitch-Moshkovitz, D. Dominissini et al., “M⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation,” Science, vol. 347, no. 6225, pp. 1002–1006, 2015.
View at: Publisher Site | Google Scholar
S. Wang, C. Sun, J. Li et al., “Roles of RNA methylation by means of N⁶-methyladenosine (m⁶A) in human cancers,” Cancer Letters, vol. 408, pp. 112–120, 2017.
View at: Publisher Site | Google Scholar
D. Dai, H. Wang, L. Zhu, H. Jin, and X. Wang, “N⁶-Methyladenosine links RNA metabolism to cancer progression,” Cell Death & Disease, vol. 9, no. 2, p. 124, 2018.
View at: Publisher Site | Google Scholar
Y. Pan, P. Ma, Y. Liu, W. Li, and Y. Shu, “Multiple functions of m⁶A RNA methylation in cancer,” Journal of Hematology & Oncology, vol. 11, p. 48, 2018.
View at: Publisher Site | Google Scholar
D. C. Hinshaw and L. A. Shevde, “The tumor microenvironment innately modulates cancer progression,” Cancer Research, vol. 79, pp. 4557–4566, 2019.
View at: Publisher Site | Google Scholar
D. Anwanwan, S. K. Singh, S. Singh, V. Saikam, and R. Singh, “Challenges in liver cancer and possible treatment approaches,” Biochimica Et Biophysica Acta. Reviews on Cancer, vol. 1873, article 188314, 2020.
View at: Publisher Site | Google Scholar
F. R. Hirsch, G. V. Scagliotti, J. L. Mulshine et al., “Lung cancer: current therapies and new targeted treatments,” The Lancet, vol. 389, pp. 299–311, 2017.
View at: Publisher Site | Google Scholar
L. Du, Y. Li, M. Kang et al., “USP48 is upregulated by Mettl14 to attenuate hepatocellular carcinoma via regulating SIRT6 stabilization,” Cancer Research, vol. 81, pp. 3822–3834, 2021.
View at: Publisher Site | Google Scholar
J. Hou, H. Zhang, J. Liu et al., “YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma,” Molecular Cancer, vol. 18, no. 1, p. 163, 2019.
View at: Publisher Site | Google Scholar
Z. X. Rong, Z. Li, J. J. He et al., “Downregulation of fat mass and obesity associated (FTO) promotes the progression of intrahepatic cholangiocarcinoma,” Frontiers in Oncology, vol. 9, p. 369, 2019.
View at: Publisher Site | Google Scholar
H. Weng, H. Huang, H. Wu et al., “METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m⁶A modification,” Cell Stem Cell, vol. 22, no. 2, pp. 191–205.e9, 2018.
View at: Publisher Site | Google Scholar
R. Su, L. Dong, C. Li et al., “R-2HG exhibits anti-tumor activity by targeting FTO/m⁶A/MYC/CEBPA signaling,” Cell, vol. 172, no. 1-2, pp. 90–105.e23, 2018.
View at: Publisher Site | Google Scholar
K. J. Yoon, F. R. Ringeling, C. Vissers et al., “Temporal control of mammalian cortical neurogenesis by m⁶A methylation,” Cell, vol. 171, pp. 877–889.e17, 2017.
View at: Publisher Site | Google Scholar
F. Yu, J. Wei, X. Cui et al., “Post-translational modification of RNA m⁶A demethylase ALKBH5 regulates ROS-induced DNA damage response,” Nucleic Acids Research, vol. 49, pp. 5779–5797, 2021.
View at: Publisher Site | Google Scholar
L. P. Vu, Y. Cheng, and M. G. Kharas, “The biology of m⁶A RNA methylation in normal and malignant hematopoiesis,” Cancer Discovery, vol. 9, pp. 25–33, 2019.
View at: Publisher Site | Google Scholar
G. Hou, X. Zhao, L. Li et al., “SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m⁶A-modified mRNAs,” Nucleic Acids Research, vol. 49, no. 5, pp. 2859–2877, 2021.
View at: Publisher Site | Google Scholar
A. D. Garg, A. Kaczmarek, O. Krysko, P. Vandenabeele, D. V. Krysko, and P. Agostinis, “ER stress-induced inflammation: does it aid or impede disease progression?” Trends in Molecular Medicine, vol. 18, pp. 589–598, 2012.
View at: Publisher Site | Google Scholar
Y. Zhang, K. Zhang, H. Gong et al., “Links between N⁶-methyladenosine and tumor microenvironments in colorectal cancer,” Frontiers in Cell and Development Biology, vol. 10, article 807129, 2022.
View at: Publisher Site | Google Scholar
T. Li, P. S. Hu, Z. Zuo et al., “METTL3 facilitates tumor progression via an m⁶A-IGF2BP2-dependent mechanism in colorectal carcinoma,” Molecular Cancer, vol. 18, no. 1, p. 112, 2019.
View at: Publisher Site | Google Scholar
Y. Cai, W. Ji, C. Sun et al., “Interferon-induced transmembrane protein 3 shapes an inflamed tumor microenvironment and identifies immuno-hot tumors,” Frontiers in Immunology, vol. 12, article 704965, 2021.
View at: Publisher Site | Google Scholar
J. Zhao, D. X. Han, C. B. Wang, and X. L. Wang, “Zbtb7b suppresses aseptic inflammation by regulating m⁶A modification of IL6 mRNA,” Biochemical and Biophysical Research Communications, vol. 530, no. 1, pp. 336–341, 2020.
View at: Publisher Site | Google Scholar
J. Wang, S. Yan, H. Lu, S. Wang, and D. Xu, “METTL3 attenuates LPS-induced inflammatory response in macrophages via NF-κB signaling pathway,” Mediators of Inflammation, vol. 2019, Article ID 3120391, 8 pages, 2019.
View at: Publisher Site | Google Scholar
Y. Cai, R. Yu, Y. Kong, Z. Feng, and Q. Xu, “METTL3 regulates LPS-induced inflammatory response via the NOD1 signaling pathway,” Cellular Signalling, vol. 93, article 110283, 2022.
View at: Publisher Site | Google Scholar
C. Wu, W. Chen, J. He et al., “Interplay of m⁶A and H3K27 trimethylation restrains inflammation during bacterial infection,” Science Advances, vol. 6, article eaba0647, 2020.
View at: Google Scholar
H. Xu, C. Lin, T. Li et al., “N⁶-Methyladenosine-modified circRNA in the bovine mammary epithelial cells injured by Staphylococcus aureus and Escherichia coli,” Frontiers in Immunology, vol. 13, article 873330, 2022.
View at: Publisher Site | Google Scholar
H. Tang, L. Huang, and J. Hu, “Inhibition of the m6A methyltransferase METTL3 attenuates the inflammatory response inFusarium solani-induced keratitis via the NF-κB signaling pathway,” Investigative Ophthalmology & Visual Science, vol. 63, no. 11, p. 2, 2022.
View at: Publisher Site | Google Scholar
N. Li, H. Hui, B. Bray et al., “METTL3 regulates viral m⁶A RNA modification and host cell innate immune responses during SARS-CoV-2 infection,” Cell Reports, vol. 35, no. 6, article 109091, 2021.
View at: Publisher Site | Google Scholar
X. Zhang, H. Hao, L. Ma et al., “Methyltransferase-like 3 modulates severe acute respiratory syndrome coronavirus-2 RNA N⁶-methyladenosine modification and replication,” mBio, vol. 12, article e0106721, 2021.
View at: Publisher Site | Google Scholar
M. Cully, “Chemical inhibitors make their RNA epigenetic mark,” Nature Reviews Drug Discovery, vol. 18, pp. 892–894, 2019.
View at: Publisher Site | Google Scholar
E. Yankova, W. Blackaby, M. Albertella et al., “Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia,” Nature, vol. 593, no. 7860, pp. 597–601, 2021.
View at: Publisher Site | Google Scholar
J. Gu, J. Xu, Q. You, and X. Guo, “Recent developments of small molecules targeting RNA m⁶A modulators,” European Journal of Medicinal Chemistry, vol. 196, article 112325, 2020.
View at: Publisher Site | Google Scholar
Y. Huang, J. Yan, Q. Li et al., “Meclofenamic acid selectively inhibits FTO demethylation of m⁶A over ALKBH5,” Nucleic Acids Research, vol. 43, no. 1, pp. 373–384, 2015.
View at: Publisher Site | Google Scholar
R. Wang, Z. Han, B. Liu et al., “Identification of natural compound radicicol as a potent FTO inhibitor,” Molecular Pharmaceutics, vol. 15, pp. 4092–4098, 2018.
View at: Publisher Site | Google Scholar
L. Zhang, J. Song, L. Kong et al., “The strategies and techniques of drug discovery from natural products,” Pharmacology & Therapeutics, vol. 216, article 107686, 2020.
View at: Publisher Site | Google Scholar
J. C. Zhong, X. B. Li, W. Y. Lyu, W. C. Ye, and D. M. Zhang, “Natural products as potent inhibitors of hypoxia-inducible factor-1α in cancer therapy,” Chinese Journal of Natural Medicines, vol. 18, pp. 696–703, 2020.
View at: Publisher Site | Google Scholar
Y. R. Leng, M. H. Zhang, J. G. Luo, and H. Zhang, “Pathogenesis of NASH and promising natural products,” Chinese Journal of Natural Medicines, vol. 19, pp. 12–27, 2021.
View at: Publisher Site | Google Scholar
L. J. Deng, W. Q. Deng, S. R. Fan et al., “M⁶A modification: recent advances, anticancer targeted drug discovery and beyond,” Molecular Cancer, vol. 21, no. 1, p. 52, 2022.
View at: Publisher Site | Google Scholar
Z. Gan, W. Wei, J. Wu et al., “Resveratrol and curcumin improve intestinal mucosal integrity and decrease m⁶A RNA methylation in the intestine of weaning piglets,” ACS Omega, vol. 4, pp. 17438–17446, 2019.
View at: Publisher Site | Google Scholar
A. P. Singh, R. Singh, S. S. Verma et al., “Health benefits of resveratrol: evidence from clinical studies,” Medicinal Research Reviews, vol. 39, pp. 1851–1891, 2019.
View at: Publisher Site | Google Scholar
R. Wu, Y. Yao, Q. Jiang et al., “Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m⁶A-YTHDF2-dependent manner,” International Journal of Obesity, vol. 42, pp. 1378–1388, 2018.
View at: Publisher Site | Google Scholar
X. Li, X. Li, N. Huang, R. Liu, and R. Sun, “A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins,” Phytomedicine, vol. 50, pp. 73–87, 2018.
View at: Publisher Site | Google Scholar
L. Lan, Y. J. Sun, X. Y. Jin, L. J. Xie, L. Liu, and L. Cheng, “A light-controllable chemical modulation of m⁶A RNA methylation,” Angewandte Chemie (International Ed. in English), vol. 60, pp. 18116–18121, 2021.
View at: Publisher Site | Google Scholar
X. Zhang, X. Li, H. Jia, G. An, and J. Ni, “The m⁶A methyltransferase METTL3 modifies PGC-1alpha mRNA promoting mitochondrial dysfunction and oxLDL-induced inflammation in monocytes,” The Journal of Biological Chemistry, vol. 297, article 101058, 2021.
View at: Publisher Site | Google Scholar
Z. Li, Q. Xu, N. Huangfu, X. Chen, and J. Zhu, “METTL3 promotes oxLDL-mediated inflammation through activating STAT1 signaling,” Journal of Clinical Laboratory Analysis, vol. 36, article e24019, 2022.
View at: Publisher Site | Google Scholar
L. Jiang, X. Liu, X. Hu et al., “METTL3-mediated m⁶A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy,” Molecular Therapy, vol. 30, no. 4, pp. 1721–1740, 2022.
View at: Publisher Site | Google Scholar
Z. Feng, Q. Li, R. Meng, B. Yi, and Q. Xu, “METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells,” Journal of Cellular and Molecular Medicine, vol. 22, no. 5, pp. 2558–2568, 2018.
View at: Publisher Site | Google Scholar
E. Liu, L. Lv, Y. Zhan et al., “METTL3/N⁶-methyladenosine/ miR-21-5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF-κB pathway activation,” Journal of Cellular and Molecular Medicine, vol. 25, no. 16, pp. 7660–7674, 2021.
View at: Publisher Site | Google Scholar
W. Sang, S. Xue, Y. Jiang et al., “METTL3 involves the progression of osteoarthritis probably by affecting ECM degradation and regulating the inflammatory response,” Life Sciences, vol. 278, article 119528, 2021.
View at: Publisher Site | Google Scholar
S. X. Li, W. Yan, J. P. Liu, Y. J. Zhao, and L. Chen, “Long noncoding RNA SNHG4 remits lipopolysaccharide-engendered inflammatory lung damage by inhibiting METTL3 - mediated m⁶A level of STAT2 mRNA,” Molecular Immunology, vol. 139, pp. 10–22, 2021.
View at: Publisher Site | Google Scholar
L. Yang, G. Wu, Q. Wu, L. Peng, and L. Yuan, “METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice,” Cell Death Discovery, vol. 8, p. 62, 2022.
View at: Publisher Site | Google Scholar
Z. Xie, W. Yu, G. Zheng et al., “TNF-α-mediated m⁶A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis,” Nature Communications, vol. 12, no. 1, p. 5373, 2021.
View at: Publisher Site | Google Scholar
M. Li, L. Deng, and G. Xu, “METTL14 promotes glomerular endothelial cell injury and diabetic nephropathy via m⁶A modification of alpha-klotho,” Molecular Medicine, vol. 27, p. 106, 2021.
View at: Publisher Site | Google Scholar
H. Jiang, K. Cao, C. Fan, X. Cui, Y. Ma, and J. Liu, “Transcriptome-wide high-throughput m⁶A sequencing of differential m⁶A methylation patterns in the human rheumatoid arthritis fibroblast-like synoviocytes cell line MH7A,” Journal of Inflammation Research, vol. 14, pp. 575–586, 2021.
View at: Publisher Site | Google Scholar
P. K. Dubey, M. Patil, S. Singh et al., “Increased m⁶A-RNA methylation and FTO suppression is associated with myocardial inflammation and dysfunction during endotoxemia in mice,” Molecular and Cellular Biochemistry, vol. 477, pp. 129–141, 2022.
View at: Publisher Site | Google Scholar
G. Chen, Q. Zhao, B. Yuan et al., “ALKBH5-modified HMGB1-STING activation contributes to radiation induced liver disease via innate immune response,” International Journal of Radiation Oncology • Biology • Physics, vol. 111, pp. 491–501, 2021.
View at: Publisher Site | Google Scholar
R. Bechara, N. Amatya, R. D. Bailey et al., “The m⁶A reader IMP2 directs autoimmune inflammation through an IL-17- and TNFα-dependent C/EBP transcription factor axis,” Science Immunology, vol. 6, no. 61, article eabd1287, 2021.
View at: Publisher Site | Google Scholar
X. Wang, Y. Ji, P. Feng et al., “The m⁶A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPAR γ,” Advanced Science, vol. 8, article 2100209, 2021.
View at: Publisher Site | Google Scholar
L. Yang, J. Fu, X. Han et al., “Hsa_circ_0004287 inhibits macrophage-mediated inflammation in an N⁶-methyladenosine-dependent manner in atopic dermatitis and psoriasis,” The Journal of Allergy and Clinical Immunology, vol. 149, pp. 2021–2033, 2022.
View at: Publisher Site | Google Scholar
A. Olazagoitia-Garmendia, L. Zhang, P. Mera et al., “Gluten-induced RNA methylation changes regulate intestinal inflammation via allele-specific XPO1 translation in epithelial cells,” Gut, vol. 71, no. 1, pp. 68–76, 2022.
View at: Publisher Site | Google Scholar
C. Mapperley, L. N. van de Lagemaat, H. Lawson et al., “The mRNA m⁶A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function,” The Journal of Experimental Medicine, vol. 218, no. 3, article e20200829, 2021.
View at: Publisher Site | Google Scholar

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