
==== Front
Clin Epigenetics
Clin Epigenetics
Clinical Epigenetics
1868-7075
1868-7083
BioMed Central London

39261973
1736
10.1186/s13148-024-01736-5
Review
N6-methyladenosine (m6A) RNA modification in fibrosis and collagen-related diseases
Tan Man 12
Liu Siyi 12
Liu Lubin liulubin1975@126.com

12
1 https://ror.org/05pz4ws32 grid.488412.3 Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, No. 120, Longshan Road, Yubei District, Chongqing, China
2 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children, No. 120, Longshan Road, Yubei District, Chongqing, China
12 9 2024
12 9 2024
2024
16 1272 6 2024
26 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Fibrosis is an abnormal tissue healing process characterized by the excessive accumulation of ECM components, such as COL I and COL III, in response to tissue injury or chronic inflammation. Recent advances in epitranscriptomics have underscored the importance of m6A modification in fibrosis. m6A, the most prevalent modification in eukaryotic RNA, is catalyzed by methyltransferases (e.g., METTL3), removed by demethylases (e.g., FTO), and recognized by reader proteins (e.g., YTHDF1/2). These modifications are crucial in regulating collagen metabolism and associated diseases. Understanding the role of m6A modification in fibrosis and other collagen-related conditions holds promise for developing targeted therapies. This review highlights the latest progress in this area.

Keywords

N6-methyladenosine
Collagen
Fibroblast
α-Smooth muscle actin
http://dx.doi.org/10.13039/501100002865 Chongqing Municipal Science and Technology Bureau CSTB2023NSCQ-MSX0597 cstc2020jcyj-zdxmX0002 Tan Man Liu Lubin Chongqing Personnel Bureau2021XM2055 Tan Man issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Collagen is a crucial protein in the extracellular matrix (ECM) [1], providing essential structural support to various tissues and organs [2, 3]. Its metabolism involves a delicate balance between synthesis, assembly, and degradation. Dysregulation of collagen metabolism can lead to fibrosis, characterized by an excessive buildup of collagen and other matrix components in tissues. Fibrosis occurs as a response to tissue injury or chronic inflammation and can affect different organs in the body [4, 5].

In fibrosis, abnormal collagen synthesis and deposition play a central role. Activated fibroblasts and other cells increase collagen production, driven by signaling pathways like TGF-β [6] and CTGF [7]. Additionally, impaired collagen degradation contributes to fibrosis, resulting from an imbalanced ratio of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [8].

Epitranscriptomics is an emerging and crucial field in recent years, encompassing over 170 distinct post-transcriptional RNA modifications or editing events, which play important roles in the regulation of fibroblasts and fibrosis [9, 10], such as the liver [11], lungs [12], kidneys, and heart [13]. Among these modifications, N6-adenosine methylation, known as m6A modification, stands out as the most prevalent modification in eukaryotic RNA and was first reported in 1974 [14]. The m6A modification is catalyzed by the methyltransferase complex (comprising METTL3, METTL14, and WTAP as co-factors), removed by demethylases (such as FTO and ALKBH5), and recognized by reader proteins (e.g., YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3), dynamically regulating gene expression at the post-transcriptional level and contributing to the development of various diseases [15]. Recent research has shed light on the roles of m6A regulatory factors in fibrosis and collagen-related diseases.

Understanding the role of m6A modification in fibrosis and other collagen-related conditions holds significant promise for the development of targeted therapies. This review highlights the latest advancements and progress in this area.

Collagen metabolism and fibrosis

The extracellular matrix is a vital three-dimensional macromolecular network consisting of collagen proteins, proteoglycans/glycosaminoglycans, elastin proteins, fibronectin, laminin, and other glycoproteins [16]. It plays a crucial role in tissue remodeling and the regulation of cell behavior. Collagen, a protein with a triple-helix structure [17], is the predominant constituent of the ECM, making up approximately 30% of the total protein content in the human body [1]. Its main functions include providing elasticity, stability, and support to tissues [2]. There are 28 different types of collagen identified so far, with COL I, COL III, and COL V mainly produced by fibroblasts, while COL IV is primarily expressed by epithelial cells and endothelial cells. In some cases, cancer cells and tumor-associated macrophages can also produce collagen [18].

Fibrosis is an abnormal tissue healing process characterized by excessive accumulation of ECM components such as COL I and COL III in response to tissue injury or chronic inflammation. It can affect various organs, such as the liver, lungs, kidneys, and heart. Fibrosis disrupts tissue architecture and function, leading to organ dysfunction and organ failure. Tissue healing involves three stages: inflammation, proliferation, and remodeling [19]. Fibroblasts play a significant role in this process, transforming into myofibroblasts with contractile force during the proliferation stage and driving wound contraction during the remodeling stage [20, 21]. The proper transformation of fibroblasts to myofibroblasts and their subsequent apoptosis are crucial for appropriate tissue healing. However, under pathological conditions, this normal wound healing process is disrupted, resulting in persistent myofibroblast presence and ECM remodeling [22].

In the context of fibrosis, abnormal collagen synthesis and deposition play a central role. Fibrotic tissues exhibit increased collagen production by activated fibroblasts and other cell types. This enhanced collagen synthesis is triggered by various signaling pathways, such as TGF-β [6] and CTGF [7]. These pathways promote the expression of collagen genes and drive fibroblast-to-myofibroblast transition, characterized by increased contractility and collagen production.

Furthermore, the degradation of collagen is finely regulated through a delicate balance between MMPs and TIMPs [23]. MMPs play a primary role in the breakdown of collagen [24], and their activity is controlled by TIMPs to prevent excessive degradation of the connective tissue. TIMPs counteract the effects of MMPs by forming complexes with them, impeding their interaction with substrates, and thus, slowing down the process of collagen degradation [25]. In fibrosis, this balance between MMPs and TIMPs is disrupted, resulting in reduced collagen breakdown and increased accumulation [8].

The regulation of collagen metabolism and fibrosis is a complex and dynamic process involving various factors. m6A modification may play a role in regulating collagen metabolism at multiple stages. Gaining insights into the molecular mechanisms of both collagen metabolism and m6A modification offers promising potential for developing targeted therapies for fibrosis and collagen-related diseases.

m6A regulatory proteins

“writers” of m6A methyltransferase

The m6A methyltransferase complex comprises METTL3, METTL14, and the co-factor WTAP [26]. METTL3, recognized as the catalytic core of the methyltransferase in 1997 [27], is the pioneering "writer" responsible for transferring the methyl group from S-adenosylmethionine (SAM) to the adenosine residues of RNA. METTL14 serves as an RNA-binding platform, facilitating RNA substrate binding and enhancing the complex's integrity [28, 29]. In human cells, METTL3 and METTL14 form a 1:1 stoichiometric complex [30], which localizes in the cytoplasm and then translocates to the nucleus through a nuclear localization signal within METTL3, where it associates with WTAP [31]. Although WTAP lacks methyltransferase activity, it interacts with the METTL3-14 complex and plays a regulatory role in recruiting the m6A methyltransferase complex to mRNA targets [32].

"erasers" of m6A demethylase

The "erasers" of m6A demethylase function akin to an eraser, removing m6A modifications from RNA. The first reported m6A demethylase in eukaryotic cells is the Fat mass and obesity-associated protein (FTO) [33]. The second identified m6A demethylase is ALKBH5, which has been shown to regulate mRNA output and RNA metabolism by reducing m6A levels in nuclear speckles [34].

"readers" of m6A modifications

"Readers" constitute a group of proteins that can recognize m6A modifications and regulate gene expression by influencing various biological processes, such as mRNA stability, splicing, structure, output, and translation efficiency [35]. Cytoplasmic m6A readers include YTHDF1/2/3, YTHDC2, and IGF2BP1/2/3. YTHDF1 enhances the translation of m6A methylated mRNA; while, YTHDF2 accelerates the degradation of m6A methylated mRNA. YTHDF3 collaborates with YTHDF1 and YTHDF2 to promote the metabolism of m6A methylated mRNA in the cytoplasm [36]. YTHDC2, located in nuclear speckles, preferentially binds to transcripts containing m6A modifications, leading to decreased mRNA abundance and increased translation efficiency through interactions with translation initiation and decay mechanisms [37]. Human insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) enhance mRNA stability by binding to target transcripts [38]. Nuclear m6A readers include YTHDC1, which interacts with splicing factors and nuclear export adapter protein SRSF3 to facilitate the transport of m6A-modified mRNA from the nucleus to the cytoplasm [39].

m6A modification in fibrotic diseases

Pulmonary fibrosis

Research related to pulmonary fibrosis is shown in Table 1. m6A levels increase in the lung tissues of patients with IPF and in mice with bleomycin (BLM)-induced fibrosis. This increase is attributed to elevated METTL3 expression. Silencing METTL3 reduces m6A levels and inhibits αSMA and COL I expression in TGF-β1-induced WI-38 cells. m6A modification, mediated by YTHDF1, regulates the fibroblast-to-myofibroblast transition (FMT) by modulating KCNH6 mRNA translation [41].Table 1 Pulmonary fibrosis

Diseases and cell types	Regulatory factors	Mechanisms	Functions	References	
Silica-induced mice	METTL3↑, ALKBH5, FTO, YTHDF1, YTHDF3↓	–	–	[40]	
Patients with IPF

BLM-induced mice

TGF-β1-induced WI-38

	METTL3↑	YTHDF1/KCNH6	Regulating the fibroblast-to-myofibroblast transition	[41]	
PM2.5-exposed mice

BEAS-2B

	METTL3↑, YTHDF2↑	miR-494-3p/YTHDF2/CDH1	Accelerating the progression of epithelial–mesenchymal transition and pulmonary fibrosis	[42]	
Silicosis patients

SiO2-induced mice

HPF-a, MRC-5

	METTL3↑	hsa_circ_0000672, hsa_circ_0005654, eIF4A3	METTL3 facilitates lung fibroblast activation, migration, and activity, contributing to SiO2-induced pulmonary fibrosis through circRNA m6A modification	[43]	
PM2.5-exposed mice

16HBE

	METTL3↑	YTHDF1, IGF2BP1/Nrf2	Activating the Nrf2 antioxidant signaling pathway. Knockdown of METTL3 increases αSMA expression after PM2.5 exposure	[44]	
Patients with pulmonary fibrosis

BLM-induced mice

	METTL3↓	–	–	[45]	
PM2.5-exposed mice

BEAS-2B

	ALKBH5↓	Atg13/ULK complex	The lack of ALKBH5 exacerbates PM2.5 exposure-induced autophagy, inflammation, and fibrosis	[46]	
SiO2-induced mice

TGF-β1-induced lung fibroblast

	ALKBH5↑	miR-320a-3p/FOXM1	Promoting silica-induced pulmonary fibrosis	[47]	
CB-induced rats

16HBE

	pri-miRNA-126 m6A↓	miRNA-126/DGCR8/PI3K/AKT/mTOR	Upregulating levels of pulmonary fibrosis markers, including αSMA, fibronectin, COL I, and hydroxyproline	[48]	

Another study, through immunohistochemical analysis, observed a decrease in METTL3 expression in both pulmonary fibrosis patients and in a BLM-induced pulmonary fibrosis model in mice [45].

PM 2.5

PM2.5 exposure increases METTL3 expression, leading to heightened m6A modification of CDH1 mRNA. Moreover, enhanced recognition of CDH1 mRNA m6A modification by YTHDF2 inhibits its transcription and promotes its degradation, ultimately accelerating the progression of epithelial–mesenchymal transition (EMT) and pulmonary fibrosis after PM2.5 exposure [42].

Another study suggests that the upregulation of METTL3 plays a protective role in PM2.5 exposure. PM2.5 exposure-induced METTL3 expression promotes YTHDF1/IGF2BP1-mediated recognition of m6A sites on Nrf2 mRNA, leading to enhanced Nrf2 translation and activation of the Nrf2 antioxidant signaling pathway. Knockdown of METTL3 increases αSMA expression after PM2.5 exposure [44].

Simultaneously, PM2.5 exposure downregulates ALKBH5 expression, which promotes m6A modification of Atg13 mRNA in BEAS-2B cells. This results in the upregulation of the ULK complex mediated by Atg13, promoting epithelial cell autophagy and inflammation under PM2.5 treatment. Consequently, the NF-κB/NLRP3 signaling pathway is activated, driving pulmonary fibrosis [46].

Silicosis

m6A-seq and RNA-seq analyses on silica-induced silicosis mice showed increased m6A levels and METTL3 expression; while, ALKBH5, FTO, YTHDF1, and YTHDF3 expression decreased. Furthermore, 307 genes showed high methylation; while, 52 genes exhibited hypomethylation, mainly enriched in pathways related to "phagosome," "antigen processing and presentation," and "apoptosis" [40].

In silicosis patients, SiO2-treated fibroblasts, and mice, METTL3 expression was found to increase. SiO2 induced m6A modification of hsa_circ_0000672 and hsa_circ_0005654 in lung fibroblasts through METTL3, and this process involved cooperation with eIF4A3. Consequently, lung fibroblast proliferation, migration, and activation were induced, ultimately leading to pulmonary fibrosis [43]

Additionally, upregulation of ALKBH5 in mice exposed to silica and TGF-β1-activated lung fibroblasts inhibited fibroblast activation. Mechanistically, ALKBH5 demethylated pri-miR-320a-3p, blocking its maturation process and preventing its regulation of fibrosis through FOXM1 mRNA 3'-UTR targeting. Furthermore, ALKBH5 could directly regulate FOXM1 in an m6A-dependent manner, promoting silica-induced pulmonary fibrosis [47].

Carbon black

In another study, the fibrosis-promoting factor, carbon black (CB), reduced the m6A modification of pri-miRNA-126 and its binding with the RNA-binding protein DiGeorge syndrome critical region gene 8 (DGCR8). This led to a decrease in mature miRNA-126 and activation of the PI3K/AKT/mTOR pathway, driving an increase in levels of pulmonary fibrosis markers, including αSMA, fibronectin, COL I, and hydroxyproline. [48]

Cardiac fibrosis

“writers” in cardiac fibrosis

Research related to cardiac fibrosis is shown in Table 2. In numerous studies, METTL3 has been consistently shown to play a promoting role in cardiac fibrosis. Upregulation of METTL3 was observed in human atrial fibrillation cardiac tissue [50–52], heart tissues of myocardial infarction mouse models [49, 51, 52], and TGFβ1-induced cardiac fibroblasts [49–52].Table 2 Cardiac fibrosis

Tissues and cell types	Regulatory factors	Mechanisms	Functions	References	
Myocardial infarction mice

TGF-β1-induced CF

	METTL3↑	–	Promoting proliferation and FMT and collagens accumulation	[49]	
Atrial fibrillation patients

Mice

TGF-β1-induced CF

	METTL3↑	YTHDF2/AR	Promoting glycolysis and cardiac fibroblast proliferation	[50]	
Atrial fibrillation patients

TAC/ISO-induced mice

TGF-β1-induced CF

	METTL3↑	IGFBP3	Silencing METTL3 can inhibit the activation of CFs and the degree of cardiac fibrosis	[51]	
Atrial fibrillation patients

ISO-induced mice

TGF-β1-induced CF

3T3

	METTL3↑	YTHDF2/GAS5/mitochondrial fission	Knockdown of METTL3/YTHDF2 improves ISO-induced cardiac fibrosis	[52]	
Myocardial infarction mice

HL1, AC16

	METTL3	TNC	Overexpression of METTL3 exacerbates post-myocardial infarction cardiac dysfunction and cardiac fibrosis	[53]	
Myocardial infarction mice

TGF-β1-induced CF

	MetBil↑	METTL3 binding lncRNA	Enhancing collagen deposition and CFs proliferation	[54]	
Heart failure patients

Myocardial infarction pigs

Myocardial infarction mice

Rat primary CF

	FTO↓	–	Overexpression of FTO can reduce fibrosis and enhance angiogenesis	[55]	
Diabetic cardiomyopathy mice	FTO↓	–	Overexpression of FTO in DCM model mice improved cardiac function by reducing myocardial fibrosis and myocyte hypertrophy	[56]	
Myocardial infarction mice

CF

	FTO	Ang II/circCELF1/FTO/DKK2	FTO overexpression attenuates the upregulation of αSMA, COL I, and COL III induced by Ang II, inhibiting the progression of myocardial fibrosis	[57]	
Heart failure with preserved ejection fraction mice	m6A level↑, FTO↓, METTL3↑	–	Overexpression of FTO cancels out the benefits of exercise in HFpEF + EXT mice by promoting myocyte apoptosis, myocardial fibrosis and myocyte hypertrophy	[58]	
YTHDF2 KO mice, NRVM, ACM	YTHDF2	–	Knockdown of YTHDF2 results in cardiomyocyte growth and remodeling	[59]	
Diabetic cardiomyopathy mice

High glucose-induced CF

	Airn → IMP2↑	Airn/IMP2/p53	CF cell cycle arrest and reduced cardiac fibrosis	[60]	
Human PASMCs

Mice

	YTHDF1	Foxm1	Silencing of YTHDF1 alleviates pulmonary vascular changes and fibrosis	[61]	

From a mechanistic perspective, silencing METTL3 alleviated TGF-β1-induced cell proliferation, FMT, and collagen production in CFs, and reduced the m6A modification levels of fibrosis-related genes [49]. Additionally, METTL3 downregulates AR expression through an m6A-YTHDF2 dependent mechanism, promoting glycolysis and cardiac fibroblast proliferation, which ultimately leads to cardiac fibrosis [50]. Furthermore, silencing METTL3 has been observed to downregulate the expression of IGFBP3, inhibiting the activation of CFs and reducing the degree of cardiac fibrosis [51]. Moreover, METTL3 increases m6A methylation of GAS5, leading to YTHDF2 binding to GAS5 and inhibiting its expression, which further promotes CF proliferation, migration, and mitochondrial fission [52]. In addition to its fibrotic effects, METTL3 is also involved in cardiac fibrosis and myocardial cell apoptosis by increasing the m6A level of TNC mRNA [53].

Furthermore, in the heart tissues of the myocardial infarction mouse model and TGF-β1-induced CFs, the expression of MetBil (METTL3 binding lncRNA) is significantly increased. MetBil overexpression enhances collagen deposition and CFs proliferation [54].

“erasers” in cardiac fibrosis

FTO plays a protective role against myocardial fibrosis. In heart failure mammalian hearts and hypoxic cardiomyocytes, FTO expression is reduced, leading to increased RNA m6A levels and impaired myocardial contractile function. Increased FTO expression in heart failure mice selectively demethylates contractile transcripts in the heart, preventing their degradation, thus mitigating the ischemia-induced increase in m6A and the decline in cardiac contractile function. This, in turn, reduces fibrosis and enhances angiogenesis [55]. In the diabetic cardiomyopathy mouse model, there is an increase in m6A levels and a downregulation of FTO. FTO overexpression can improve cardiac function in diabetic cardiomyopathy mice by reducing myocardial fibrosis and cardiomyocyte hypertrophy [56]. circCELF1 upregulates the expression of FTO, reducing m6A modification on DKK2 mRNA, inhibiting the binding of miR-636 to DKK2, and promoting DKK2 expression, thereby inhibiting the progression of myocardial fibrosis [57].

However, in another study, FTO played a contrasting role: HFpEF + Exercise training (EXT) mice showed higher m6A levels and downregulated FTO levels. FTO overexpression promoted myocardial cell apoptosis, myocardial fibrosis, and cardiomyocyte hypertrophy, thereby counteracting the benefits of exercise in HFpEF + EXT mice [58].

“readers” in cardiac fibrosis

YTHDF2 deficiency results in declined cardiac function in elderly mice, exacerbating the cardiac dysfunction and increasing fibrosis induced by the pressure overload from TAC surgery [59].

lncRNA Airn binds to IMP2, protecting it from degradation. The retained IMP2 recognizes m6A modifications on p53 mRNA, leading to increased stability and protein expression. This reduces α-SMA and COL I expression in high glucose-induced CFs, thereby reducing cardiac fibrosis in diabetic mice. Silencing METTL3 decreases m6A modification on p53, resulting in reduced stability and downregulation of p53 mRNA in CFs [60].

Pulmonary arterial hypertension

YTHDF1 interacts with Foxm1 mRNA and upregulates Foxm1 protein levels by enhancing translation efficiency through an m6A-dependent mechanism. This promotes the proliferation of hypoxic pulmonary arterial smooth muscle cells (PASMC) and the expression of proliferation markers. Silencing YTHDF1 alleviates pulmonary vascular changes and fibrosis [61].

Hepatic fibrosis

Research related to hepatic fibrosis is shown in Table 3. In the study of hepatic fibrosis progression and reversal, dynamic analysis of m6A methylation profiles revealed that during hepatic fibrosis, m6A methylation differences are primarily enriched in processes related to oxidative stress and cytochrome metabolism, while in hepatic fibrosis reversal, they are mainly associated with immune response and apoptosis [62].Table 3 Hepatic fibrosis

Tissues and cell types	Regulatory factors	Mechanisms	Functions	References	
CCL4-induced mice	–	–	During hepatic fibrosis, m6A methylation differences are primarily enriched in processes related to oxidative stress and cytochrome metabolism	[62]	
CCL4-induced rats

THP-1/LX-2/293 T

Primary Kupffer cells and HSCs

	METTL3↑	NEAT1/Sp1/TGF-β1/Smad	METTL3 targets and enhances NEAT1 expression in macrophages, thereby promoting the proliferation and migration of HSCs and inducing the expression of fibrotic proteins	[63]	
CCL4-induced mice

KC, BMM

IFN-γ/LPS-induced macrophages

HEK293T, RAW264.7

	METTL3↑	MALAT1/PTBP1/USP8/TAK1	Stimulating pyroptosis and inflammation of macrophages exacerbates liver fibrosis	[64]	
METTL3 cKO mice

CCL4-induced mice

HSC

	METTL3	Lats2/Hippo/YAP	METTL3 knockout suppresses HSC activation and alleviates liver fibrosis	[65]	
CdCl2-induced mice

HSC

	METTL3↓	–	METTL3 overexpression in hepatocytes attenuates CdCl2-induced steatosis and liver fibrosis in mice, and ameliorates the CdCl2-induced cytotoxicity and activation of primary HSCs	[66]	
CORT-induced chickens

293 T

	METTL3↑	HSPs	Long-term exposure to CORT induces hepatic inflammation and fibrosis in chickens, while also leading to increased levels of various HSP mRNA and m6A methylation	[67]	
NASH rats

METTL14 cKO mice

LPS-induced KC

	METTL3↑, METTL14↑	LPS/NF-κB p65/METTL3/14/TGF-β1	Enhancing cap-independent translation of TGF-β1 exacerbates TGF-β1-mediated stellate cell activation, promoting the transition from NASH to liver fibrosis	[68]	
CCL4-induced mice

Primary HSCs

HSC-T6

	METTL3	ASIC1a/METTL3/DGCR8/miR-350/SPRY2/PI3K/KT and ERK pathways	Silencing of METTL3 reduces the expression of αSMA and COL I	[69]	
Patients with hepatoblastoma/cholestasis/biliary atresia

LX-2, primary HSC

	METTL3, METTL14, WTAP↑, ALKBH5↓	THY1	Overexpression of METTL3 and METTL14 promotes the expression of COL IA1, MMP2	[70]	
CHB patients

HSC

	METTL16↑	HLA-DPB1	Silencing METTL16 downregulates the m6A modification level of HLA-DPB1 mRNA, and is involved in the progression of fibrosis in chronic hepatitis B	[71]	
Patients with liver cirrhosis complicated with HCC treated with sorafenib monotherapy

Primary HSCs

CCL4-induced mice

	HSC ferroptosis → METTL4↑, FTO↓	YTHDF1/BECN1	HSC-specific inhibition of m6A modification could impair erastin-induced HSC ferroptosis in murine liver fibrosis	[72]	
CCL4-induced mice

Primary HSCs

	m6A↓, WTAP↓, ALKBH5↓, YTHDF1↓	–	Differentially expressed m6A genes are found to be closely correlated with processes such as the endoplasmic reticulum stress response, PPAR signaling pathway, and TGF-β signaling pathway

Decreased expression of WTAP was shown to promote HSC activation

	[73]	
CCL4-induced rats

TGF-β1-induced HSC

	WTAP ↑, AcSDKP → WTAP↓	AcSDKP/WTAP/Ptch1	AcSDKP inhibits CCl4-induced rat HSC apoptosis through the Hedgehog pathway	[74]	
CCL4 and olive oil (1:9) -induced mice

Primary HSCs, HSC-LX2

	DHA induces iron-ferroptosis → m6A level↑, FTO↓, YTHDF1↑	DHA/FTO/YTHDF1/BECN1	Overexpression of FTO reduces DHA-induced ferroptosis, and knocking down YTHDF1 can prevent DHA-induced HSC ferroptosis and exacerbate liver fibrosis in mice	[75]	
Patients with liver cirrhosis

CCL4-induced mice

HSC-T6, hepatocyte

	ALKBH5↓	YTHDF1/Drp1	ALKBH5 suppresses mitochondrial fission and HSC proliferation and migration by reducing Drp1 methylation in an m6A-YTHDF1-dependent manner	[76]	
Patients with liver cirrhosis

CCL4-induced mice

TGF-β1-induced HSC

	ALKBH5↓	PTCH1	Overexpression of ALKBH5 reduces HSCs proliferation and migration	[77]	
Patients received radiotherapy for intrahepatic tumor

RILF mice

HCC mice

LX2, THP-1, HSC

	Radiation → ALKBH5↑	YTHDF2/TIRAP/NF-κB pathway	ALKBH5 mediates monocyte recruitment and M2 polarization, promoting radiation-induced liver fibrosis and reducing hepatocellular carcinoma radiosensitivity	[78]	
CCL4-induced mice

JS1

	YTHDF1	Increase the stability of COL I A1 mRNA	Vitamin A-coupled YTHDF1 siRNA alleviates CCl4-induced liver fibrosis in mice through HSC-specific inhibition of collagen production	[79]	
Patients with liver cirrhosis

CCL4-induced mice

BDL-induced mice

LX-2, Primary HSCs

	YTHDF3↓	PRDX3/ROS/TGF-β1/Smad2/3	YTHDF3 specifically regulates PRDX3 translation and expression, inhibiting HSC activation, and ameliorating liver fibrosis	[80]	
CCL4-induced mice

Primary mouse HSCs, hepatocytes, and KCs

	YTHDC1↑, ZC3H13↑, FTO↓	NR1D1/DRP1S616/cGAS	Lowering m6A levels can reduce the expression of αSMA and COL I. DHA promotes the proteasomal degradation of YTHDC1, thereby restoring NR1D1 expression and alleviating liver fibrosis	[81]	

“writers” in hepatic fibrosis

Regarding the role of METTL3 in hepatic fibrosis, it is upregulated in lipopolysaccharide (LPS)-activated THP-1 macrophages and plays a role in promoting the expression of fibrotic proteins, such as COL I, α-SMA, and fibronectin, through the Sp1/TGF-β1/Smad signaling pathway [63]. Additionally, METTL3 is upregulated in the CCl4-induced mouse liver fibrosis model and IFN-γ/LPS-activated M1 macrophages, where it promotes macrophage pyroptosis and inflammation via the PTBP1/USP8/TAK1 axis by increasing MALAT1 levels through m6A modification, thereby exacerbating liver fibrosis [64]. Silencing METTL3 in HSCs leads to inhibited HSC activation and reduced liver fibrosis. Mechanistically, silencing METTL3 increases the stability and protein expression of Lats2 mRNA, which leads to increased YAP phosphorylation, inhibiting YAP nuclear translocation and ultimately resulting in decreased expression of pro-fibrotic genes [65].

In CdCl2-exposed mouse liver tissue, METTL3 expression decreases over time and correlates with the severity of liver injury. Liver-specific overexpression of METTL3 in mice attenuates CdCl2-induced hepatic steatosis and fibrosis; while, METTL3 overexpression improves CdCl2-induced cytotoxicity and activation of HSCs [66]. Long-term exposure to chronic corticosterone (CORT) induces hepatic inflammation and fibrosis in chickens and increases the levels of various heat shock proteins (HSPs) mRNA and m6A methylation [67].

In non-alcoholic steatohepatitis (NASH) rats and LPS-treated Kupffer cells (KCs), METTL3/METTL14 is upregulated; while, FTO is downregulated. After LPS stimulation, NF-κB p65 directly activates METTL3 and METTL14, promoting cap-independent translation of TGF-β1 through m6A modification in the 5′UTR region. This upregulates TGF-β1 and exacerbates TGF-β1-mediated stellate cell activation, promoting the transition from NASH to liver fibrosis [68]. Acid-sensitive ion channel 1a (ASIC1a) regulates the processing of miR-350 through METTL3-dependent m6A modification. Mature miR-350 targets SPRY2 and further promotes liver fibrosis through the PI3K/KT and ERK pathways [69].

In patients with biliary atresia, there is an increase in m6A levels, and the expression of METTL3, METTL14, and WTAP is upregulated; while, ALKBH5 is downregulated. The overexpression of METTL3 and METTL14 promotes the expression of COL1A1, MMP2, and THY1. THY1 may play a role in cholestatic fibrosis by interacting with the ITGAX/ITGB2 complex in bone marrow cells [70].

METTL16 is upregulated in the liver tissues of chronic hepatitis B (CHB) with severe fibrosis. Silencing METTL16 in HSCs downregulates the m6A modification level of HLA-DPB1 mRNA, and it is involved in the progression of fibrosis in CHB [71].

In Sorafenib, erastin, and RSL3-induced ferroptosis of HSCs, METTL4 expression is upregulated, and FTO is downregulated. YTHDF1 recognizes m6A binding sites and stabilizes BECN1 mRNA, triggering autophagy activation. Inhibition of m6A modification impairs erastin-induced ferroptosis in CCl4-induced liver fibrosis in mice and reverses the beneficial effect of erastin on liver fibrosis improvement [72].

The differentially expressed m6A genes in liver fibrosis mice are closely associated with processes such as the endoplasmic reticulum stress response, PPAR signaling pathway, and TGF-β signaling pathway. In liver fibrosis mice, the expression of WTAP, ALKBH5, and YTHDF1 is reduced. Decreased expression of WTAP leads to an increase in αSMA and COL I expression, promoting HSC activation and inducing the occurrence of liver fibrosis [73]. However, in another study, WTAP is highly expressed in liver fibrosis and it targets the 3'-UTR of Ptch1 mRNA to increase its stability. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) reduces the expression of WTAP and decreases the stability of Ptch1 mRNA, thereby exerting an anti-fibrotic effect [74].

“erasers” in hepatic fibrosis

FTO downregulation and consequent upregulation of m6A modification are essential for DHA-induced autophagy activation and HSC ferroptosis. YTHDF1 upregulation and FTO downregulation are involved in DHA-induced HSC ferroptosis by increasing the stability of BECN1 mRNA. Knocking down YTHDF1 can prevent this process, ultimately reducing the therapeutic effect of DHA on liver fibrosis [75].

In human fibrotic liver tissues and CCl4-induced mouse liver fibrosis, elevated m6A levels and decreased ALKBH5 expression are observed. ALKBH5 functions in a YTHDF1-dependent manner to inhibit mitochondrial fission, HSC proliferation, and migration by reducing Drp1 m6A modification. This regulatory process leads to a reduction in αSMA and COL I expression, contributing to improved liver fibrosis [76]. ALKBH5 is downregulated in both human and mouse liver fibrotic tissues. Its overexpression leads to reduced αSMA and COL I expression, decreased collagen protein accumulation, and interstitial fibrosis. ALKBH5's beneficial effects on liver fibrosis are achieved through m6A-dependent PTCH1 activation, inhibiting HSC activation [77].

ALKBH5 is upregulated in radiation-induced HSCs. It mediates m6A demethylation of toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) mRNA and regulates TIRAP expression in a YTHDF2-dependent manner, promoting HSC activation through the TIRAP/NF-κB pathway. ALKBH5 also regulates CCL5 secretion, facilitating monocyte recruitment and M2 polarization, further enhancing ALKBH5 expression and TIRAP/NF-κB pathway activation. Irradiated HSCs educate monocytes, leading to HSC activation and reduced HCC radiosensitivity through CCL20 secretion. Blocking the ALKBH5-CCR6 axis can alleviate radiation-induced liver fibrosis (RILF) and improve HCC radio sensitivity [78].

“readers” in hepatic fibrosis

A study suggests that DNA methylation (5mC) is essential for the initiation stage of HSC activation (myofibroblast transdifferentiation); while, m6A is crucial for the perpetuation stage of HSC activation (excessive ECM production). YTHDF1 enhances COL I A1 protein production by stabilizing its mRNA. Silencing YTHDF1 can alleviate CCl4-induced mouse liver fibrosis by inhibiting collagen synthesis [79].

YTHDF3 induces PRDX3 translation in an m6A-dependent manner, leading to the upregulation of PRDX3 expression. Through the mitochondrial reactive oxygen species (ROS)/TGF-β1/Smad2/3 pathway, it inhibits HSC activation, exerting a protective effect against liver fibrosis [80].

CCl4-induced liver fibrosis and primary HSCs exhibit elevated levels of methylation, increased expression of ZC3H13, and decreased expression of FTO. Lowering m6A levels can reduce the protein levels of αSMA and COL I, thus improving liver fibrosis. YTHDC1 is upregulated in CCl4-induced liver fibrosis and primary HSCs, promoting the degradation of nuclear receptor subfamily 1 group d member 1 (NR1D1) mRNA. The absence of NR1D1 inhibits phosphorylation of DRP1S616, leading to weakened mitochondrial fission function, increased mtDNA release, activation of the cGAS pathway, and promotion of liver fibrosis progression. DHA alleviates liver fibrosis by promoting the proteasomal degradation of YTHDC1 in activated HSCs, restoring NR1D1 expression [81].

Renal fibrosis

“writers” in renal fibrosis

Research related to renal fibrosis is shown in Table 4. In renal fibrosis, the UUO mouse model shows decreased m6A levels and reduced METTL3/METTL14 expression; while, FTO is upregulated. Differentially methylated genes are mainly associated with the TGFβ signaling pathway (downregulated genes) and the axon signaling pathway (upregulated genes) [82]. However, another study using the UUO model found that METTL3 upregulation increased pri-miR-21 m6A modification, promoting miRNA-21-5p maturation. This triggered the SPRY1/ERK/NF-κB pathway, driving inflammation and the development of obstructive renal fibrosis. And HNRNPA2B1 may be involved in recognizing m6A modifications in pri-miR-21 and facilitating the maturation of miR-21-5p [83].Table 4 Renal fibrosis

Tissues and cell types	Regulatory factors	Mechanisms	Functions	References	
UUO mice	m6A level↓, METTL3↓, METTL14↓, FTO↑	–	Differentially methylated genes are mainly associated with the TGFβ signaling pathway (downregulated genes) and the axon signaling pathway (upregulated genes)	[82]	
UUO mice

HK2

	METTL3↑	HNRNPA2B1/miR-21-5p/SPRY1/ERK/NF-kB	Driving inflammation and the development of obstructive renal fibrosis	[83]	
UUO mice

V40 MES13

	METLL3	AI662270/METTL3/CTGF	Activating interstitial fibroblasts and driving renal fibrosis	[84]	
Patients with obstructive nephropathy

UUO mice

TGF-β1-induced HK2

	METTL3↑, METTL14↑, WTAP↑	MALAT1/miR-145/FAK	Inhibiting METTL3 can attenuate TGF-β1-induced EMT and decrease αSMA expression	[85]	
Patients with diabetic nephropathy

UN/HFD/STZ-induced mice

HG-induced SV40-MES-13

	High glucose → METTL3↓	YTHDF1/NDS2	Overexpression of METTL3 alleviates renal impairment and renal fibrosis in DN	[86]	
Diabetic kidney disease

STZ-induced mice

HG-induced HK2

	METTL14	TUG1/MAPK1	Knockdown of METTL14 or overexpression of TUG1 protects diabetic kidney disease (DKD) mice from renal lesions and renal fibrosis induced by STZ	[87]	
Renal tubular-specific Atg7-deficient and SQSTM1-deficient mice

canagliflozin-induced mice, UUO mice

TGF-β1-induced HK2

	canagliflozin → FTO↓	SQSTM1/autophagy/STAT6	FTO overexpression weakens the impact of canagliflozin on autophagy induction and eliminates the protective effect of canagliflozin against renal fibrosis	[88]	
Patients with tubulointerstitium fibrosis

Renal tubular-specific Kcnk5 knockout mice

Fto knockdown mice

UUO/UIR mice

HK2

	FTO↑	Kcnk5/TASK-2	Blocking FTO can weaken cell cycle arrest and renal fibrosis	[89]	
UUO mice

TGF-β1-induced HK-2, TGF-β1-induced HKC-8

	FTO↑	GAS5	Knocking down FTO inhibits the TGF-β1 and UUO-induced EMT and inflammatory response, leading to a decrease in αSMA and COL1 expression	[90]	
UUO mice, URI mice

TGF-β1-induced HK2

	ALKBH5↓	genistein/ALKBH5/Snail	ALKBH5 knockdown enhanced the mesenchymal phenotype marker αSMA and snail expression	[91]	
Alkbh5fl/flKspCre mice IRI mice

mRTECs

	ALKBH5	IGF2BP2/CCL28/Treg/inflammatory cell axis	Inhibiting ALKBH5 can prevent ischemia–reperfusion-induced AKI and fibrosis	[92]	
CKD patients

UUO mice

SV40-MES-13

	YTHDF1↑	YAP	Knocking down YTHDF1 alleviates the progression of renal fibrosis	[93]	

Long noncoding RNA AI662270 promotes the transcriptional stage of CTGF expression by recruiting METTL3 to the CTGF promoter and depositing m6A modifications on nascent mRNA. This activation of CTGF drives the activation of interstitial fibroblasts and promotes renal fibrosis [84]. TGF-β1 treatment upregulates METTL3, METTL14, and WTAP in HK2 cells. Inhibiting METTL3 reduces MALAT1 expression and contributes to DHA's anti-fibrotic effect against TGF-β1-induced renal fibrosis through the MALAT1/miR-145/FAK axis [85]. High glucose treatment in mouse mesangial cells (SV40-MES-13) results in decreased m6A levels and downregulation of METTL3 expression. Overexpression of METTL3 enhances the stability of Nuclear receptor-binding SET domain protein 2 (NSD2) mRNA through YTHDF1, promoting its expression. Consequently, this alleviates kidney impairment and renal fibrosis in diabetic nephropathy [86].

METTL14 reduces the stability of TUG1 mRNA by increasing its m6A modification, thereby inhibiting TUG1 expression. TUG1, in turn, interacts with LIN28B, leading to the inactivation of the MAPK1/ERK signaling pathway. Knockdown of METTL14 or overexpression of TUG1 protects diabetic kidney disease (DKD) mice from renal damage and renal fibrosis induced by streptozotocin (STZ) [87].

“erasers” in renal fibrosis

Canagliflozin increases m6A levels in HK2 cells while reducing FTO expression. FTO overexpression weakens the effect of canagliflozin on autophagy induction, leading to decreased stability of SQSTM1 mRNA. Deletion of SQSTM1 abolishes the protective effect of canagliflozin against renal fibrosis. Therefore, canagliflozin combats renal lipotoxicity and interstitial fibrosis through the m6A-modified SQSTM1/autophagy/STAT6 axis [88]. In UUO kidneys, the expression of FTO, METTL3, and METTL14 increases, while ALKBH5 expression decreases. In kidneys subjected to unilateral ischemia–reperfusion (UIR) and TGF-β1-treated HK-2 cells, FTO expression is elevated. In vivo and in vitro blocking of FTO can reduce the upregulation of Kcnk5, encoding TWIK-related acid-sensitive K+ channel-2 (TASK-2), cell cycle arrest, and renal fibrosis. TASK-2 is upregulated through FTO-mediated Kcnk5 demethylation and is activated by intracellular alkalization, leading to reduced intracellular K+ concentration, G2/M cell cycle arrest, and exacerbation of renal fibrosis [89]. FTO expression increases in TGF-β1-treated HK-2 and HKC-8 cells, as well as in UUO mouse kidney tissues. FTO suppresses the expression of lncRNA GAS5 by reducing its m6A modification. Knockdown of FTO inhibits TGF-β1 and UUO-induced EMT and inflammatory response, resulting in reduced expression of αSMA and COL I [90].

In the UUO model, the total m6A level increases; while, ALKBH5 expression decreases. Knocking down ALKBH5 suppresses E-cadherin expression and promotes αSMA and Snail levels. Genistein improves renal fibrosis by restoring ALKBH5 expression and regulating EMT [91]. Another study found that inhibiting ALKBH5 increases the m6A modification of CCL28 mRNA, leading to enhanced stability of CCL28 through recognition by IGF2BP2. This upregulates CCL28 levels, recruiting Tregs (regulatory T cells), which protect the kidneys from inflammation and immune cell infiltration. As a result, inhibiting ALKBH5 has a protective effect against ischemia–reperfusion-induced acute kidney injury (AKI) and fibrosis [92].

“readers” in renal fibrosis

YTHDF1 is highly expressed in human fibrotic kidneys and upregulated in fibrotic mouse kidneys induced by UUO, high-dose folic acid administration, or the unilateral ischemia–reperfusion injury (IRI). Knocking down YTHDF1 in cultured cells induced by TGF-β treatment and UUO mouse models alleviates the progression of renal fibrosis. This effect is likely mediated by YTHDF1's regulation of Yes-associated protein (YAP) [93].

Retinal

During the process of laser-induced choroidal neovascularization and subretinal fibrosis in mice, METTL3 is upregulated in retinal pigment epithelial (RPE) cells. METTL3 enhances the stability of HMGA2 mRNA through m6A modification, leading to an increase in HMGA2 protein expression. This activation of HMGA2 induces the transcription factor SNAIL, promoting EMT. However, silencing METTL3 effectively reduces subretinal fibrosis in the retina [94].

In patients with proliferative vitreoretinopathy (PVR), the expression of METTL3 is reduced in retinal pigment epithelial cells. The expression of METTL3 is downregulated in ARPE-19 cells after EMT. Overexpression of METTL3 inhibits cell proliferation and weakens the ability of TGFβ1 to induce EMT by modulating the Wnt/β-catenin pathway. Intravitreal injection of cells overexpressing METTL3 delays the occurrence of PVR [95].

High glucose upregulates the m6A modification level of PARP1 mRNA in human retinal microvascular endothelial cells (hRMECs) and downregulates YTHDF2. Overexpression of YTHDF2 reduces the expression of Poly (ADP-ribose) polymerase 1 (PARP1) in hRMECs in an m6A-dependent manner, enhances hRMEC viability, and prevents glucose-induced inflammation, fibrosis, and angiogenesis [96].

Oral

In Oral submucous fibrosis (OSF) tissues, there is an increase in m6A modification levels. Arecoline promotes the expression of METTL3 and METTL14 through TGFβ signaling. Silencing METTL14 reverses the effects of arecoline on Hacat cell proliferation and apoptosis by inhibiting MYC m6A modification and reducing TIMP1 expression [97].

m6A modification in non-fibrotic collagen-related diseases

Osteoarthrosis

m6A modification promotes intervertebral disc degeneration [98] and osteoarthritis [99, 100], and enhances chondrocyte differentiation [101] and osteoblast differentiation [102].

In degenerative human endplate cartilage tissue, m6A levels are increased. Mechanical tension stimulation increases METTL3-mediated m6A levels in human endplate chondrocytes. METTL3 mediates m6A modification of SOX9 mRNA and disrupts the stability of SOX9 mRNA, leading to the inhibition of downstream COL II α1 expression. Suppression of METTL3 expression in endplate cartilage can alleviate mechanical imbalance-induced intervertebral disc degeneration [98].

In ATDC5 chondroprogenitor cells treated with IL-1β, m6A levels and METTL3 expression increase. Silencing METTL3 reduces IL-1β-induced cell apoptosis, levels of inflammatory cytokines, and NF-κB signaling in chondrocytes. METTL3 silencing promotes extracellular matrix degradation by reducing MMP13 and COL X expression, and increasing aggrecan and COL II expression [99]. Similarly, IL-1β stimulation in C28/I2 chondrocyte cell line results in increased m6A levels and METTL3 expression, along with decreased ALKBH5 expression. Overexpression of ALKBH5 downregulates IL-1β-induced MMP13 and COL X expression, while upregulating COL II and aggrecan expression [100].

METTL3, METTL14, and m6A modification levels are increased in synovium-derived mesenchymal stem cells (SMSCs) during chondrogenic differentiation. Knockdown of METTL3 inhibits chondrogenic differentiation, downregulates SOX9, ACAN, and COL II α1, and increases MMP3, MMP13, and GATA3 expression [101]. METTL3-mediated m6A methylation of LncRNA MIR99AHG increases the expression of Osterix, COL I α1, bone sialoprotein, and RUNX2 by targeting miR-4660, enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) [102].

Skin

In the mouse model of bleomycin-induced scleroderma, the differentially m6A-hypermethylated mRNAs were most significantly associated with growth hormone synthesis, secretion, and action, insulin secretion, and amphetamine addiction. On the other hand, the differentially m6A-hypomethylated mRNAs were most significantly associated with rheumatoid arthritis, Toll-like receptor signaling pathway, and amoebiasis [103]. In keloid tissue, m6A modification was decreased, and the expression of m6A demethylase FTO was increased. FTO overexpression in skin fibroblasts stimulated fibroblast migration and increased the expression of COL I α1 and α-SMA. FTO upregulates COL I α1 expression by regulating its m6A modification and stabilizing mRNA, thus promoting keloid formation. [104]. m6A sequencing and RNA sequencing revealed that differentially methylated m6A-related genes were associated with fibrosis-related pathways in hyperplastic scars compared to normal skin. Highly methylated genes were mainly related to the P13K-Akt signaling pathway, focal adhesion, and ECM-receptor interaction. On the other hand, lowly methylated genes were mainly associated with the MAPK signaling pathway and the NF-κB signaling pathway [105].

Cancer

The role of m6A varies in different types of tumors. In U87 and U251 cells, METTL3 reduces the methylation level of COL IV α1, upregulates its expression, and stimulates the malignant development of glioblastoma [106]. In lung cancer, cancer-associated fibroblasts (CAFs) derived from lung squamous cell carcinoma (LUSC) upregulate the m6A modification of COL X α1 by increasing METTL3 expression, stabilizing COL X α1 expression, promoting LUSC cell proliferation, and inhibiting apoptosis-induced oxidative stress [107]. Silencing METTL3 can upregulate the expression of COL III α1 chain by increasing m6A levels, ultimately promoting the metastasis of triple-negative breast cancer tumor cells [108]. lncRNA NIFK-AS1 is highly expressed in HCC tissues and cells, and this upregulation is dependent on METTL3-mediated m6A methylation. NIFK-AS1 affects HCC progression through the NIFK-AS1/miR-637/AKT1 axis, regulating MMP7 and MMP9 expression. Knockdown of NIFK-AS1 inhibits HCC cell proliferation, colony formation, migration, and invasion [109]. In prostate cancer tissues, however, METTL3 is highly expressed and can regulate the expression of integrin β1 (ITGB1) through m6A modification, thereby affecting the binding of ITGB1 to COL I and promoting prostate cancer bone metastasis。 [110]

Cerebrovascular

Downregulation of m6A reader protein proline-rich coiled-coil 2B (PRRC2B) mediates selective splicing of COL XIIα1 chain in an m6A-dependent manner and regulates the decay of MMP14 and ADAM metallopeptidase domain 19 (ADAM19) mRNA in an m6A-independent manner, promoting hypoxia-induced endothelial cell migration. Conditional knockout of PRRC2B in endothelial cells enhances hypoxia-induced vascular remodeling and cerebral blood flow redistribution, thereby alleviating hypoxia-induced cognitive decline [111].

Conclusion and perspectives

In recent years, RNA epigenetics, particularly m6A modification, has emerged as a prominent research area. Among more than 100 different RNA modifications, m6A stands out as the most abundant in eukaryotic cells. This dynamic and reversible modification is meticulously controlled by "writers" and "erasers," while "readers" play a crucial role in its recognition and functionality. The significance of m6A modification in regulating collagen metabolism across various diseases cannot be overstated. This comprehensive review aims to provide an overview of the functions and mechanisms of m6A modification in organ fibrotic diseases and non-fibrotic collagen-related conditions. While the majority of research has focused on the core methyltransferase METTL3, there have been some investigations into other methyltransferases and demethylases, albeit with fewer studies dedicated to m6A readers.

In summary, the field of m6A regulation in collagen metabolism holds tremendous potential for further exploration. Recent advances have been made in elucidating the role of m6A in collagen regulation; however, many aspects of m6A modulators in collagen-related diseases remain unexplored, necessitating further inquiry.

Future research should prioritize the following areas: 1. Investigating the roles of other m6A methyltransferases and demethylases in collagen metabolism and their impact on collagen-related diseases. 2. Exploring the functions of various m6A readers and their contributions to collagen regulation. 3. Unraveling the intricate molecular mechanisms by which m6A modification regulates collagen synthesis, deposition, and degradation. 4. Developing potential therapeutic interventions targeting m6A modification for treating collagen-related diseases.

In conclusion, ongoing investigations into m6A modification in collagen metabolism offer promising directions for future research. Sustained efforts in this area will undoubtedly deepen our understanding of the regulatory mechanisms of m6A in collagen-related diseases and open up new possibilities for therapeutic applications.

Abbreviations

m6A N6-methyladenosine

ECM Extracellular matrix

TGF-β Transforming growth factor beta

αSMA α-Smooth muscle actin

CTGF Connective tissue growth factor

MMPs Matrix metalloproteinases

TIMPs Tissue inhibitors of metalloproteinases

METTL Methyltransferase like

WTAP Wilms’ tumor 1-associated protein

FTO Fat mass and obesity-associated protein

ALKBH5 AlkB homolog 5

YTHDF1/2/3 YTH domain-containing family protein

YTHDC1/2 YTH domain-containing protein

IGF2BPs Human insulin-like growth factor 2 mRNA-binding proteins

COL Collagen

SAM S-adenosylmethionine

SRSF3 Serine/arginine-rich splicing factor 3

IPF Idiopathic pulmonary fibrosis

BLM Bleomycin

FMT Fibroblast-to-myofibroblast transition

KCNH6 Potassium channel, voltage gated Kcnh6

CDH1 Cadherin 1

EMT Epithelial–mesenchymal transition

Nrf2 Nuclear factor erythroid 2-related factor 2

Atg13 Autophagy-related 13

ULK Unc-51 like autophagy activating kinase

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3 NOD-like receptor protein 3

eIF4A3 Eukaryotic translation initiation factor 4A3

FOXM1 Forkhead box M1

CB Carbon black

DGCR8 DiGeorge syndrome critical region gene 8

CF Cardiac fibrosis

TAC Tacrolimus

ISO Isoproterenol

GAS5 Growth arrest-specific 5

TNC Tenascin C

CELF1 CUGBP Elav-like family member 1

DKK2 Dickkopf WNT signaling pathway inhibitor 2

HFpEF Heart failure with preserved ejection fraction

EXT Exercise training

IMP2 Insulin-like growth factor 2 mRNA-binding protein 2

PASMC Pulmonary arterial smooth muscle cells

LPS Lipopolysaccharide

Sp1 Specificity protein 1

Smad Sma and Mad related proteins

PTBP1 Polypyrimidine tract-binding protein 1

USP8 Ubiquitin-specific protease 8

TAK1 TGF-β activated kinase 1

MALAT1 Metastasis-associated lung adenocarcinoma transcript 1

HSC Hepatic stellate cells

Lats2 Large tumor suppressor kinase 2

YAP Yes-associated protein

CORT Chronic corticosterone

HSPs Heat shock proteins

NASH Non-alcoholic steatohepatitis

KCs Kupffer cells

ASIC1a Acid-sensitive ion channel 1a

SPRY2 Sprouty RTK signaling antagonist 2

PI3K/KT Phosphoinositide 3-kinase/protein kinase B

ERK Extracellular signal-regulated kinase

THY1 Thy-1 cell surface antigen

ITGAX Integrin αX

ITGB2 Integrin β2

CHB Chronic hepatitis B

HLA-DPB1 Major histocompatibility complex, class II, DP beta 1

BECN1 Beclin 1

PPAR Peroxisome proliferator-activated receptor

AcSDKP N-acetyl-seryl-aspartyl-lysyl-proline

PTCH1 Patched 1

TIRAP Toll-interleukin 1 receptor domain-containing adaptor protein

RILF Radiation-induced liver fibrosis

PRDX3 Peroxiredoxin 3

ROS Reactive oxygen species

ZC3H13 Zinc finger CCCH-type containing 13

NR1D1 Nuclear receptor subfamily 1 group D member 1

DRP1S616 Dynamin-related protein 1 serine 616

cGAS Cyclic GMP-AMP synthase

UUO Unilateral ureteral obstruction

SPRY1 Sprouty RTK signaling antagonist 1

ERK Extracellular signal-regulated kinase

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells

HNRNPA2B1 Heterogeneous nuclear ribonucleoprotein A2/B1

NSD2 Nuclear receptor-binding SET domain protein 2

TUG1 Taurine upregulated gene 1

MAPK1 Mitogen-activated protein kinase 1

DKD Diabetic kidney disease

STZ Streptozotocin

SQSTM1 Sequestosome 1

UIR Unilateral ischemia–reperfusion

TASK-2 TWIK-related acid-sensitive K+ channel-2

AKI Acute kidney injury

IRI Ischemia–reperfusion injury

YAP Yes-associated protein

RPE Retinal pigment epithelial

HMGA2 High mobility group AT-Hook 2

PVR Proliferative vitreoretinopathy

PARP1 Poly(ADP-ribose) polymerase 1

hRMECs Human retinal microvascular endothelial cells

OSF Oral submucous fibrosis

MYC MYC proto-oncogene, BHLH transcription factor

SOX9 SRY-box transcription factor 9

SMSC Synovium-derived mesenchymal stem cells

GATA3 GATA binding protein 3

RUNX2 Runt-related transcription factor 2

BMSCs Bone marrow mesenchymal stem cells

CAFs Cancer-associated fibroblasts

LUSC Lung squamous cell carcinoma

ITGB1 Integrin β1

PRRC2B Proline-rich coiled-coil 2B

ADAM19 ADAM metallopeptidase domain 19

Author contributions

M Tan contributed to development of protocol, data collection, data analysis, and manuscript writing. Sy Liu contributed to data collection. Lb Liu contributed to concept, development of protocol, and manuscript editing.

Funding

Chongqing Natural Science Foundation (Grant numbers CSTB2023NSCQ-MSX0597). Author M Tan has received research support from Chongqing Science and Technology Commission. Chongqing Postdoctoral Science Special Foundation (Grant numbers 2021XM2055). Author M Tan has received research support from Chongqing Personnel Bureau. Chongqing Municipal Bureau of Science and Technology Natural Science Foundation (Grant numbers cstc2020jcyj-zdxmX0002). Author LB Liu has received research support from Chongqing Science and Technology Commission.

Availability of data and materials

No datasets were generated or analyzed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

No ethical approval is required.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Karamanos NK Theocharis AD Piperigkou Z A guide to the composition and functions of the extracellular matrix FEBS J 2021 288 24 6850 6912 10.1111/febs.15776 33605520
Karamanos NK, Theocharis AD, Piperigkou Z, et al. A guide to the composition and functions of the extracellular matrix. FEBS J. 2021;288(24):6850–912.33605520 10.1111/febs.15776
2. Kirkness MW Lehmann K Forde NR Mechanics and structural stability of the collagen triple helix Curr Opin Chem Biol 2019 53 98 105 10.1016/j.cbpa.2019.08.001 31606538
Kirkness MW, Lehmann K, Forde NR. Mechanics and structural stability of the collagen triple helix. Curr Opin Chem Biol. 2019;53:98–105.31606538 10.1016/j.cbpa.2019.08.001
3. Kong W Lyu C Liao H Du Y Collagen crosslinking: effect on structure, mechanics and fibrosis progression Biomed Mater 2021 16 6 062005 10.1088/1748-605X/ac2b79
Kong W, Lyu C, Liao H, Du Y. Collagen crosslinking: effect on structure, mechanics and fibrosis progression. Biomed Mater. 2021;16(6):062005.10.1088/1748-605X/ac2b79
4. Henderson NC Rieder F Wynn TA Fibrosis: from mechanisms to medicines Nature 2020 587 7835 555 566 10.1038/s41586-020-2938-9 33239795
Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555–66.33239795 10.1038/s41586-020-2938-9
5. Weiskirchen R Weiskirchen S Tacke F Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications Mol Asp Med 2019 65 2 15 10.1016/j.mam.2018.06.003
Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications. Mol Asp Med. 2019;65:2–15.10.1016/j.mam.2018.06.003
6. Frangogiannis N Transforming growth factor-β in tissue fibrosis J Exp Med 2020 217 3 e20190103 10.1084/jem.20190103 32997468
Frangogiannis N. Transforming growth factor-β in tissue fibrosis. J Exp Med. 2020;217(3):e20190103.32997468 10.1084/jem.20190103
7. Ramazani Y Knops N Elmonem MA Connective tissue growth factor (CTGF) from basics to clinics Matrix Biol 2018 68–69 44 66 10.1016/j.matbio.2018.03.007 29574063
Ramazani Y, Knops N, Elmonem MA, et al. Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol. 2018;68–69:44–66.29574063 10.1016/j.matbio.2018.03.007
8. Zhao X Chen J Sun H Zhang Y Zou D New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP–ECM interaction Cell Biosci 2022 12 1 117 10.1186/s13578-022-00856-w 35897082
Zhao X, Chen J, Sun H, Zhang Y, Zou D. New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP–ECM interaction. Cell Biosci. 2022;12(1):117.35897082 10.1186/s13578-022-00856-w
9. Ilieva M Uchida S Epitranscriptomics in fibroblasts and fibrosis Am J Physiol Cell Physiol 2022 322 6 C1110 C1116 10.1152/ajpcell.00121.2022 35508185
Ilieva M, Uchida S. Epitranscriptomics in fibroblasts and fibrosis. Am J Physiol Cell Physiol. 2022;322(6):C1110–6.35508185 10.1152/ajpcell.00121.2022
10. Xue T Qiu X Liu H Epigenetic regulation in fibrosis progress Pharmacol Res 2021 173 105910 10.1016/j.phrs.2021.105910 34562602
Xue T, Qiu X, Liu H, et al. Epigenetic regulation in fibrosis progress. Pharmacol Res. 2021;173: 105910.34562602 10.1016/j.phrs.2021.105910
11. Yang L Liu Y Sun Y Huang C Li J Wang Y New advances of DNA/RNA methylation modification in liver fibrosis Cell Signal 2022 92 110224 10.1016/j.cellsig.2021.110224 34954394
Yang L, Liu Y, Sun Y, Huang C, Li J, Wang Y. New advances of DNA/RNA methylation modification in liver fibrosis. Cell Signal. 2022;92: 110224.34954394 10.1016/j.cellsig.2021.110224
12. Xu L Zhou L Yan C Li L Emerging role of N6-methyladenosine RNA methylation in lung diseases Exp Biol Med (Maywood) 2022 247 20 1862 1872 10.1177/15353702221128564 36278325
Xu L, Zhou L, Yan C, Li L. Emerging role of N6-methyladenosine RNA methylation in lung diseases. Exp Biol Med (Maywood). 2022;247(20):1862–72.36278325 10.1177/15353702221128564
13. Li X Yang Y Chen S Zhou J Li J Cheng Y Epigenetics-based therapeutics for myocardial fibrosis Life Sci 2021 271 119186 10.1016/j.lfs.2021.119186 33577852
Li X, Yang Y, Chen S, Zhou J, Li J, Cheng Y. Epigenetics-based therapeutics for myocardial fibrosis. Life Sci. 2021;271: 119186.33577852 10.1016/j.lfs.2021.119186
14. Desrosiers R Friderici K Rottman F Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells Proc Natl Acad Sci U S A 1974 71 10 3971 3975 10.1073/pnas.71.10.3971 4372599
Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci U S A. 1974;71(10):3971–5.4372599 10.1073/pnas.71.10.3971
15. Maldonado López A Capell BC The METTL3-m(6)A epitranscriptome: dynamic regulator of epithelial development, differentiation, and cancer Genes (Basel) 2021 12 7 1019 10.3390/genes12071019 34209046
Maldonado López A, Capell BC. The METTL3-m(6)A epitranscriptome: dynamic regulator of epithelial development, differentiation, and cancer. Genes (Basel). 2021;12(7):1019.34209046 10.3390/genes12071019
16. Theocharis AD Skandalis SS Gialeli C Karamanos NK Extracellular matrix structure Adv Drug Deliv Rev 2016 97 4 27 10.1016/j.addr.2015.11.001 26562801
Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev. 2016;97:4–27.26562801 10.1016/j.addr.2015.11.001
17. Li X Zhang Q Yu SM Li Y The chemistry and biology of collagen hybridization J Am Chem Soc 2023 145 20 10901 10916 10.1021/jacs.3c00713 37158802
Li X, Zhang Q, Yu SM, Li Y. The chemistry and biology of collagen hybridization. J Am Chem Soc. 2023;145(20):10901–16.37158802 10.1021/jacs.3c00713
18. Xu S Xu H Wang W The role of collagen in cancer: from bench to bedside J Transl Med 2019 17 1 309 10.1186/s12967-019-2058-1 31521169
Xu S, Xu H, Wang W, et al. The role of collagen in cancer: from bench to bedside. J Transl Med. 2019;17(1):309.31521169 10.1186/s12967-019-2058-1
19. Calabrese EJ Dhawan G Kapoor R Agathokleous E Calabrese V Hormesis: wound healing and fibroblasts Pharmacol Res 2022 184 106449 10.1016/j.phrs.2022.106449 36113746
Calabrese EJ, Dhawan G, Kapoor R, Agathokleous E, Calabrese V. Hormesis: wound healing and fibroblasts. Pharmacol Res. 2022;184: 106449.36113746 10.1016/j.phrs.2022.106449
20. Qian H Shan Y Gong R Fibroblasts in scar formation: biology and clinical translation Oxid Med Cell Longev 2022 2022 4586569 10.1155/2022/4586569 35602101
Qian H, Shan Y, Gong R, et al. Fibroblasts in scar formation: biology and clinical translation. Oxid Med Cell Longev. 2022;2022:4586569.35602101 10.1155/2022/4586569
21. Talbott HE Mascharak S Griffin M Wan DC Longaker MT Wound healing, fibroblast heterogeneity, and fibrosis Cell Stem Cell 2022 29 8 1161 1180 10.1016/j.stem.2022.07.006 35931028
Talbott HE, Mascharak S, Griffin M, Wan DC, Longaker MT. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell. 2022;29(8):1161–80.35931028 10.1016/j.stem.2022.07.006
22. Klingberg F Hinz B White ES The myofibroblast matrix: implications for tissue repair and fibrosis J Pathol 2013 229 2 298 309 10.1002/path.4104 22996908
Klingberg F, Hinz B, White ES. The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol. 2013;229(2):298–309.22996908 10.1002/path.4104
23. Roderfeld M Matrix metalloproteinase functions in hepatic injury and fibrosis Matrix Biol 2018 68–69 452 462 10.1016/j.matbio.2017.11.011 29221811
Roderfeld M. Matrix metalloproteinase functions in hepatic injury and fibrosis. Matrix Biol. 2018;68–69:452–62.29221811 10.1016/j.matbio.2017.11.011
24. Duarte S Baber J Fujii T Coito AJ Matrix metalloproteinases in liver injury, repair and fibrosis Matrix Biol 2015 44–46 147 156 10.1016/j.matbio.2015.01.004 25599939
Duarte S, Baber J, Fujii T, Coito AJ. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biol. 2015;44–46:147–56.25599939 10.1016/j.matbio.2015.01.004
25. Guler Z Roovers JP Role of fibroblasts and myofibroblasts on the pathogenesis and treatment of pelvic organ prolapse Biomolecules 2022 12 1 94 10.3390/biom12010094 35053242
Guler Z, Roovers JP. Role of fibroblasts and myofibroblasts on the pathogenesis and treatment of pelvic organ prolapse. Biomolecules. 2022;12(1):94.35053242 10.3390/biom12010094
26. Oerum S Meynier V Catala M Tisné C A comprehensive review of m6A/m6Am RNA methyltransferase structures Nucleic Acids Res 2021 49 13 7239 7255 10.1093/nar/gkab378 34023900
Oerum S, Meynier V, Catala M, Tisné C. A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res. 2021;49(13):7239–55.34023900 10.1093/nar/gkab378
27. Bokar JA Shambaugh ME Polayes D Matera AG Rottman FM Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase RNA 1997 3 11 1233 1247 9409616
Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997;3(11):1233–47.9409616
28. Wang X Feng J Xue Y Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex Nature 2016 534 7608 575 578 10.1038/nature18298 27281194
Wang X, Feng J, Xue Y, et al. Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature. 2016;534(7608):575–8.27281194 10.1038/nature18298
29. Wang P Doxtader KA Nam Y Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases Mol Cell 2016 63 2 306 317 10.1016/j.molcel.2016.05.041 27373337
Wang P, Doxtader KA, Nam Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell. 2016;63(2):306–17.27373337 10.1016/j.molcel.2016.05.041
30. Liu J Yue Y Han D A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation Nat Chem Biol 2014 10 2 93 95 10.1038/nchembio.1432 24316715
Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10(2):93–5.24316715 10.1038/nchembio.1432
31. Schöller E Weichmann F Treiber T Interactions, localization, and phosphorylation of the m(6)A generating METTL3-METTL14-WTAP complex RNA 2018 24 4 499 512 10.1261/rna.064063.117 29348140
Schöller E, Weichmann F, Treiber T, et al. Interactions, localization, and phosphorylation of the m(6)A generating METTL3-METTL14-WTAP complex. RNA. 2018;24(4):499–512.29348140 10.1261/rna.064063.117
32. Ping XL Sun BF Wang L Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase Cell Res 2014 24 2 177 189 10.1038/cr.2014.3 24407421
Ping XL, Sun BF, Wang L, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24(2):177–89.24407421 10.1038/cr.2014.3
33. Jia G Fu Y Zhao X N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO Nat Chem Biol 2011 7 12 885 887 10.1038/nchembio.687 22002720
Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7(12):885–7.22002720 10.1038/nchembio.687
34. Zheng G Dahl JA Niu Y ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility Mol Cell 2013 49 1 18 29 10.1016/j.molcel.2012.10.015 23177736
Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18–29.23177736 10.1016/j.molcel.2012.10.015
35. Jiang X Liu B Nie Z The role of m6A modification in the biological functions and diseases Signal Transduct Target Ther 2021 6 1 74 10.1038/s41392-020-00450-x 33611339
Jiang X, Liu B, Nie Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6(1):74.33611339 10.1038/s41392-020-00450-x
36. Shi H Wang X Lu Z YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA Cell Res 2017 27 3 315 328 10.1038/cr.2017.15 28106072
Shi H, Wang X, Lu Z, et al. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017;27(3):315–28.28106072 10.1038/cr.2017.15
37. Hsu PJ Zhu Y Ma H Ythdc2 is an N(6)-methyladenosine binding protein that regulates mammalian spermatogenesis Cell Res 2017 27 9 1115 1127 10.1038/cr.2017.99 28809393
Hsu PJ, Zhu Y, Ma H, et al. Ythdc2 is an N(6)-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017;27(9):1115–27.28809393 10.1038/cr.2017.99
38. Huang H Weng H Sun W Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation Nat Cell Biol 2018 20 3 285 295 10.1038/s41556-018-0045-z 29476152
Huang H, Weng H, Sun W, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20(3):285–95.29476152 10.1038/s41556-018-0045-z
39. Roundtree IA Luo GZ Zhang Z YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs eLife 2017 6 e31311 10.7554/eLife.31311 28984244
Roundtree IA, Luo GZ, Zhang Z, et al. YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. eLife. 2017;6:e31311.28984244 10.7554/eLife.31311
40. Zhang Y Gu P Xie Y Insights into the mechanism underlying crystalline silica-induced pulmonary fibrosis via transcriptome-wide m(6)A methylation profile Ecotoxicol Environ Saf 2022 247 114215 10.1016/j.ecoenv.2022.114215 36306621
Zhang Y, Gu P, Xie Y, et al. Insights into the mechanism underlying crystalline silica-induced pulmonary fibrosis via transcriptome-wide m(6)A methylation profile. Ecotoxicol Environ Saf. 2022;247: 114215.36306621 10.1016/j.ecoenv.2022.114215
41. Zhang JX Huang PJ Wang DP m(6)A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation Mol Ther 2021 29 12 3436 3448 10.1016/j.ymthe.2021.06.008 34111558
Zhang JX, Huang PJ, Wang DP, et al. m(6)A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation. Mol Ther. 2021;29(12):3436–48.34111558 10.1016/j.ymthe.2021.06.008
42. Ning J Du H Zhang Y N6-methyladenosine modification of CDH1 mRNA promotes PM2.5-induced pulmonary fibrosis via mediating epithelial mesenchymal transition Toxicol Sci 2022 185 2 143 157 10.1093/toxsci/kfab133 34735003
Ning J, Du H, Zhang Y, et al. N6-methyladenosine modification of CDH1 mRNA promotes PM2.5-induced pulmonary fibrosis via mediating epithelial mesenchymal transition. Toxicol Sci. 2022;185(2):143–57.34735003 10.1093/toxsci/kfab133
43. Wang S Luo W Huang J The combined effects of circular RNA methylation promote pulmonary fibrosis Am J Respir Cell Mol Biol 2022 66 5 510 523 10.1165/rcmb.2021-0379OC 35213290
Wang S, Luo W, Huang J, et al. The combined effects of circular RNA methylation promote pulmonary fibrosis. Am J Respir Cell Mol Biol. 2022;66(5):510–23.35213290 10.1165/rcmb.2021-0379OC
44. Ji D Hu C Ning J N(6)-methyladenosine mediates Nrf2 protein expression involved in PM2.5-induced pulmonary fibrosis Ecotoxicol Environ Saf 2023 254 114755 10.1016/j.ecoenv.2023.114755 36917877
Ji D, Hu C, Ning J, et al. N(6)-methyladenosine mediates Nrf2 protein expression involved in PM2.5-induced pulmonary fibrosis. Ecotoxicol Environ Saf. 2023;254:114755.36917877 10.1016/j.ecoenv.2023.114755
45. Deng MS Chen KJ Zhang DD Li GH Weng CM Wang JM m6A RNA methylation regulators contribute to predict and as a therapy target of pulmonary fibrosis Evid Based Complement Altern Med 2022 2022 2425065 10.1155/2022/2425065
Deng MS, Chen KJ, Zhang DD, Li GH, Weng CM, Wang JM. m6A RNA methylation regulators contribute to predict and as a therapy target of pulmonary fibrosis. Evid Based Complement Altern Med. 2022;2022:2425065.10.1155/2022/2425065
46. Ning J Pei Z Wang M Site-specific Atg13 methylation-mediated autophagy regulates epithelial inflammation in PM2.5-induced pulmonary fibrosis J Hazard Mater 2023 457 131791 10.1016/j.jhazmat.2023.131791 37295326
Ning J, Pei Z, Wang M, et al. Site-specific Atg13 methylation-mediated autophagy regulates epithelial inflammation in PM2.5-induced pulmonary fibrosis. J Hazard Mater. 2023;457:131791.37295326 10.1016/j.jhazmat.2023.131791
47. Sun W Li Y Ma D ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1 Cell Mol Biol Lett 2022 27 1 26 10.1186/s11658-022-00329-5 35279083
Sun W, Li Y, Ma D, et al. ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1. Cell Mol Biol Lett. 2022;27(1):26.35279083 10.1186/s11658-022-00329-5
48. Han B Chu C Su X N(6)-methyladenosine-dependent primary microRNA-126 processing activated PI3K-AKT-mTOR pathway drove the development of pulmonary fibrosis induced by nanoscale carbon black particles in rats Nanotoxicology 2020 14 1 1 20 10.1080/17435390.2019.1661041 31502903
Han B, Chu C, Su X, et al. N(6)-methyladenosine-dependent primary microRNA-126 processing activated PI3K-AKT-mTOR pathway drove the development of pulmonary fibrosis induced by nanoscale carbon black particles in rats. Nanotoxicology. 2020;14(1):1–20.31502903 10.1080/17435390.2019.1661041
49. Li T Zhuang Y Yang W Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts FASEB J 2021 35 2 e21162 10.1096/fj.201903169R 33150686
Li T, Zhuang Y, Yang W, et al. Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts. FASEB J. 2021;35(2): e21162.33150686 10.1096/fj.201903169R
50. Zhou Y Song K Tu B METTL3 boosts glycolysis and cardiac fibroblast proliferation by increasing AR methylation Int J Biol Macromol 2022 223 Pt A 899 915 10.1016/j.ijbiomac.2022.11.042 36370857
Zhou Y, Song K, Tu B, et al. METTL3 boosts glycolysis and cardiac fibroblast proliferation by increasing AR methylation. Int J Biol Macromol. 2022;223(Pt A):899–915.36370857 10.1016/j.ijbiomac.2022.11.042
51. Ding JF Sun H Song K IGFBP3 epigenetic promotion induced by METTL3 boosts cardiac fibroblast activation and fibrosis Eur J Pharmacol 2023 942 175494 10.1016/j.ejphar.2023.175494 36657656
Ding JF, Sun H, Song K, et al. IGFBP3 epigenetic promotion induced by METTL3 boosts cardiac fibroblast activation and fibrosis. Eur J Pharmacol. 2023;942: 175494.36657656 10.1016/j.ejphar.2023.175494
52. Tu B Song K Zhou Y METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation Pharmacol Res 2023 194 106840 10.1016/j.phrs.2023.106840 37379961
Tu B, Song K, Zhou Y, et al. METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation. Pharmacol Res. 2023;194: 106840.37379961 10.1016/j.phrs.2023.106840
53. Cheng H Li L Xue J Ma J Ge J TNC accelerates hypoxia-induced cardiac injury in a METTL3-dependent manner Genes (Basel) 2023 14 3 591 10.3390/genes14030591 36980863
Cheng H, Li L, Xue J, Ma J, Ge J. TNC accelerates hypoxia-induced cardiac injury in a METTL3-dependent manner. Genes (Basel). 2023;14(3):591.36980863 10.3390/genes14030591
54. Zhuang Y Li T Hu X MetBil as a novel molecular regulator in ischemia-induced cardiac fibrosis via METTL3-mediated m6A modification FASEB J 2023 37 3 e22797 10.1096/fj.202201734R 36753405
Zhuang Y, Li T, Hu X, et al. MetBil as a novel molecular regulator in ischemia-induced cardiac fibrosis via METTL3-mediated m6A modification. FASEB J. 2023;37(3): e22797.36753405 10.1096/fj.202201734R
55. Mathiyalagan P Adamiak M Mayourian J FTO-Dependent N(6)-methyladenosine regulates cardiac function during remodeling and repair Circulation 2019 139 4 518 532 10.1161/CIRCULATIONAHA.118.033794 29997116
Mathiyalagan P, Adamiak M, Mayourian J, et al. FTO-Dependent N(6)-methyladenosine regulates cardiac function during remodeling and repair. Circulation. 2019;139(4):518–32.29997116 10.1161/CIRCULATIONAHA.118.033794
56. Ju W Liu K Ouyang S Liu Z He F Wu J Changes in N6-methyladenosine modification modulate diabetic cardiomyopathy by reducing myocardial fibrosis and myocyte hypertrophy Front Cell Dev Biol 2021 9 702579 10.3389/fcell.2021.702579 34368154
Ju W, Liu K, Ouyang S, Liu Z, He F, Wu J. Changes in N6-methyladenosine modification modulate diabetic cardiomyopathy by reducing myocardial fibrosis and myocyte hypertrophy. Front Cell Dev Biol. 2021;9: 702579.34368154 10.3389/fcell.2021.702579
57. Li XX Mu B Li X Bie ZD circCELF1 inhibits myocardial fibrosis by regulating the expression of DKK2 through FTO/m(6)A and miR-636 J Cardiovasc Transl Res 2022 15 5 998 1009 10.1007/s12265-022-10209-0 35132536
Li XX, Mu B, Li X, Bie ZD. circCELF1 inhibits myocardial fibrosis by regulating the expression of DKK2 through FTO/m(6)A and miR-636. J Cardiovasc Transl Res. 2022;15(5):998–1009.35132536 10.1007/s12265-022-10209-0
58. Liu K Ju W Ouyang S Exercise training ameliorates myocardial phenotypes in heart failure with preserved ejection fraction by changing N6-methyladenosine modification in mice model Front Cell Dev Biol 2022 10 954769 10.3389/fcell.2022.954769 36120562
Liu K, Ju W, Ouyang S, et al. Exercise training ameliorates myocardial phenotypes in heart failure with preserved ejection fraction by changing N6-methyladenosine modification in mice model. Front Cell Dev Biol. 2022;10: 954769.36120562 10.3389/fcell.2022.954769
59. Kmietczyk V Oelschläger J Gupta P Ythdf2 regulates cardiac remodeling through its mRNA target transcripts J Mol Cell Cardiol 2023 181 57 66 10.1016/j.yjmcc.2023.06.001 37315764
Kmietczyk V, Oelschläger J, Gupta P, et al. Ythdf2 regulates cardiac remodeling through its mRNA target transcripts. J Mol Cell Cardiol. 2023;181:57–66.37315764 10.1016/j.yjmcc.2023.06.001
60. Peng T Liu M Hu L LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis Biol Direct 2022 17 1 32 10.1186/s13062-022-00346-6 36384975
Peng T, Liu M, Hu L, et al. LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis. Biol Direct. 2022;17(1):32.36384975 10.1186/s13062-022-00346-6
61. Kang T Liu L Tan F Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner Exp Cell Res 2023 424 2 113505 10.1016/j.yexcr.2023.113505 36736607
Kang T, Liu L, Tan F, et al. Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner. Exp Cell Res. 2023;424(2): 113505.36736607 10.1016/j.yexcr.2023.113505
62. Cui Z Huang N Liu L Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis Epigenomics 2020 12 19 1707 1723 10.2217/epi-2019-0365 33174480
Cui Z, Huang N, Liu L, et al. Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis. Epigenomics. 2020;12(19):1707–23.33174480 10.2217/epi-2019-0365
63. Shu B Zhang RZ Zhou YX He C Yang X METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-β1/Smad signaling pathway Cell Death Discov 2022 8 1 266 10.1038/s41420-022-01036-y 35585044
Shu B, Zhang RZ, Zhou YX, He C, Yang X. METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-β1/Smad signaling pathway. Cell Death Discov. 2022;8(1):266.35585044 10.1038/s41420-022-01036-y
64. Shu B Zhou YX Li H Zhang RZ He C Yang X The METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization of macrophages and contributes to liver fibrosis Cell Death Discov 2021 7 1 368 10.1038/s41420-021-00756-x 34839365
Shu B, Zhou YX, Li H, Zhang RZ, He C, Yang X. The METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization of macrophages and contributes to liver fibrosis. Cell Death Discov. 2021;7(1):368.34839365 10.1038/s41420-021-00756-x
65. Li Y Kang X Zhou Z The m(6)A methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis Mol Ther 2022 30 12 3714 3728 10.1016/j.ymthe.2022.07.020 35923112
Li Y, Kang X, Zhou Z, et al. The m(6)A methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis. Mol Ther. 2022;30(12):3714–28.35923112 10.1016/j.ymthe.2022.07.020
66. Li W Tan M Wang H METTL3-mediated m6A mRNA modification was involved in cadmium-induced liver injury Environ Pollut 2023 331 Pt 2 121887 10.1016/j.envpol.2023.121887 37236586
Li W, Tan M, Wang H, et al. METTL3-mediated m6A mRNA modification was involved in cadmium-induced liver injury. Environ Pollut. 2023;331(Pt 2): 121887.37236586 10.1016/j.envpol.2023.121887
67. Feng Y Hu Y Hou Z Sun Q Jia Y Zhao R Chronic corticosterone exposure induces liver inflammation and fibrosis in association with m(6)A-linked post-transcriptional suppression of heat shock proteins in chicken Cell Stress Chaperones 2020 25 1 47 56 10.1007/s12192-019-01034-7 31745845
Feng Y, Hu Y, Hou Z, Sun Q, Jia Y, Zhao R. Chronic corticosterone exposure induces liver inflammation and fibrosis in association with m(6)A-linked post-transcriptional suppression of heat shock proteins in chicken. Cell Stress Chaperones. 2020;25(1):47–56.31745845 10.1007/s12192-019-01034-7
68. Feng Y Dong H Sun B METTL3/METTL14 transactivation and m6A-dependent TGF-β1 translation in activated Kupffer cells Cell Mol Gastroenterol Hepatol 2021 12 3 839 856 10.1016/j.jcmgh.2021.05.007 33992834
Feng Y, Dong H, Sun B, et al. METTL3/METTL14 transactivation and m6A-dependent TGF-β1 translation in activated Kupffer cells. Cell Mol Gastroenterol Hepatol. 2021;12(3):839–56.33992834 10.1016/j.jcmgh.2021.05.007
69. Zhu Y Pan X Du N ASIC1a regulates miR-350/SPRY2 by N(6) -methyladenosine to promote liver fibrosis FASEB J 2020 34 11 14371 14388 10.1096/fj.202001337R 32949431
Zhu Y, Pan X, Du N, et al. ASIC1a regulates miR-350/SPRY2 by N(6) -methyladenosine to promote liver fibrosis. FASEB J. 2020;34(11):14371–88.32949431 10.1096/fj.202001337R
70. Wang J Du M Meng L Integrative analysis implicates the significance of m6A in the liver fibrosis of biliary atresia by regulating THY1 Hepatol Commun 2023 7 1 e0004 10.1097/HC9.0000000000000004 36633486
Wang J, Du M, Meng L, et al. Integrative analysis implicates the significance of m6A in the liver fibrosis of biliary atresia by regulating THY1. Hepatol Commun. 2023;7(1): e0004.36633486 10.1097/HC9.0000000000000004
71. Gao H Wang X Ma H METTL16 regulates m(6)A methylation on chronic hepatitis B associated gene HLA-DPB1 involved in liver fibrosis Front Genet 2022 13 996245 10.3389/fgene.2022.996245 36406135
Gao H, Wang X, Ma H, et al. METTL16 regulates m(6)A methylation on chronic hepatitis B associated gene HLA-DPB1 involved in liver fibrosis. Front Genet. 2022;13: 996245.36406135 10.3389/fgene.2022.996245
72. Shen M Li Y Wang Y N(6)-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells Redox Biol 2021 47 102151 10.1016/j.redox.2021.102151 34607160
Shen M, Li Y, Wang Y, et al. N(6)-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells. Redox Biol. 2021;47: 102151.34607160 10.1016/j.redox.2021.102151
73. Fan C Ma Y Chen S Comprehensive analysis of the transcriptome-wide m6A methylation modification difference in liver fibrosis mice by high-throughput m6A sequencing Front Cell Dev Biol 2021 9 767051 10.3389/fcell.2021.767051 34869362
Fan C, Ma Y, Chen S, et al. Comprehensive analysis of the transcriptome-wide m6A methylation modification difference in liver fibrosis mice by high-throughput m6A sequencing. Front Cell Dev Biol. 2021;9: 767051.34869362 10.3389/fcell.2021.767051
74. Wei A Zhao F Hao A Liu B Liu Z N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) mitigates the liver fibrosis via WTAP/m(6)A/Ptch1 axis through Hedgehog pathway Gene 2022 813 146125 10.1016/j.gene.2021.146125 34921949
Wei A, Zhao F, Hao A, Liu B, Liu Z. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) mitigates the liver fibrosis via WTAP/m(6)A/Ptch1 axis through Hedgehog pathway. Gene. 2022;813: 146125.34921949 10.1016/j.gene.2021.146125
75. Shen M Guo M Li Y m(6)A methylation is required for dihydroartemisinin to alleviate liver fibrosis by inducing ferroptosis in hepatic stellate cells Free Radic Biol Med 2022 182 246 259 10.1016/j.freeradbiomed.2022.02.028 35248719
Shen M, Guo M, Li Y, et al. m(6)A methylation is required for dihydroartemisinin to alleviate liver fibrosis by inducing ferroptosis in hepatic stellate cells. Free Radic Biol Med. 2022;182:246–59.35248719 10.1016/j.freeradbiomed.2022.02.028
76. Wang J Yang Y Sun F ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation Pharmacol Res 2023 187 106608 10.1016/j.phrs.2022.106608 36566000
Wang J, Yang Y, Sun F, et al. ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation. Pharmacol Res. 2023;187: 106608.36566000 10.1016/j.phrs.2022.106608
77. Yang JJ Wang J Yang Y ALKBH5 ameliorated liver fibrosis and suppressed HSCs activation via triggering PTCH1 activation in an m(6)A dependent manner Eur J Pharmacol 2022 922 174900 10.1016/j.ejphar.2022.174900 35318034
Yang JJ, Wang J, Yang Y, et al. ALKBH5 ameliorated liver fibrosis and suppressed HSCs activation via triggering PTCH1 activation in an m(6)A dependent manner. Eur J Pharmacol. 2022;922: 174900.35318034 10.1016/j.ejphar.2022.174900
78. Chen Y Zhou P Deng Y ALKBH5-mediated m(6) A demethylation of TIRAP mRNA promotes radiation-induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma Clin Transl Med 2023 13 2 e1198 10.1002/ctm2.1198 36792369
Chen Y, Zhou P, Deng Y, et al. ALKBH5-mediated m(6) A demethylation of TIRAP mRNA promotes radiation-induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma. Clin Transl Med. 2023;13(2): e1198.36792369 10.1002/ctm2.1198
79. Feng Y Guo S Zhao Y DNA 5mC and RNA m(6)A modification successively facilitates the initiation and perpetuation stages of HSC activation in liver fibrosis progression Cell Death Differ 2023 30 5 1211 1220 10.1038/s41418-023-01130-3 36841889
Feng Y, Guo S, Zhao Y, et al. DNA 5mC and RNA m(6)A modification successively facilitates the initiation and perpetuation stages of HSC activation in liver fibrosis progression. Cell Death Differ. 2023;30(5):1211–20.36841889 10.1038/s41418-023-01130-3
80. Sun R Tian X Li Y The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis Redox Biol 2022 54 102378 10.1016/j.redox.2022.102378 35779442
Sun R, Tian X, Li Y, et al. The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis. Redox Biol. 2022;54: 102378.35779442 10.1016/j.redox.2022.102378
81. Chen L Xia S Wang F m(6)A methylation-induced NR1D1 ablation disrupts the HSC circadian clock and promotes hepatic fibrosis Pharmacol Res 2023 189 106704 10.1016/j.phrs.2023.106704 36813093
Chen L, Xia S, Wang F, et al. m(6)A methylation-induced NR1D1 ablation disrupts the HSC circadian clock and promotes hepatic fibrosis. Pharmacol Res. 2023;189: 106704.36813093 10.1016/j.phrs.2023.106704
82. Li X Fan X Yin X Liu H Yang Y Alteration of N(6)-methyladenosine epitranscriptome profile in unilateral ureteral obstructive nephropathy Epigenomics 2020 12 14 1157 1173 10.2217/epi-2020-0126 32543222
Li X, Fan X, Yin X, Liu H, Yang Y. Alteration of N(6)-methyladenosine epitranscriptome profile in unilateral ureteral obstructive nephropathy. Epigenomics. 2020;12(14):1157–73.32543222 10.2217/epi-2020-0126
83. Liu E Lv L Zhan Y METTL3/N6-methyladenosine/miR-21-5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF-κB pathway activation J Cell Mol Med 2021 25 16 7660 7674 10.1111/jcmm.16603 34164910
Liu E, Lv L, Zhan Y, et al. METTL3/N6-methyladenosine/miR-21-5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF-κB pathway activation. J Cell Mol Med. 2021;25(16):7660–74.34164910 10.1111/jcmm.16603
84. Sun Y Ge J Shao F Long noncoding RNA AI662270 promotes kidney fibrosis through enhancing METTL3-mediated m(6) A modification of CTGF mRNA FASEB J 2023 37 8 e23071 10.1096/fj.202202012RRR 37389924
Sun Y, Ge J, Shao F, et al. Long noncoding RNA AI662270 promotes kidney fibrosis through enhancing METTL3-mediated m(6) A modification of CTGF mRNA. FASEB J. 2023;37(8): e23071.37389924 10.1096/fj.202202012RRR
85. Liu P Zhang B Chen Z m(6)A-induced lncRNA MALAT1 aggravates renal fibrogenesis in obstructive nephropathy through the miR-145/FAK pathway Aging (Albany NY) 2020 12 6 5280 5299 10.18632/aging.102950 32203053
Liu P, Zhang B, Chen Z, et al. m(6)A-induced lncRNA MALAT1 aggravates renal fibrogenesis in obstructive nephropathy through the miR-145/FAK pathway. Aging (Albany NY). 2020;12(6):5280–99.32203053 10.18632/aging.102950
86. Tang W Zhao Y Zhang H Peng Y Rui Z METTL3 enhances NSD2 mRNA stability to reduce renal impairment and interstitial fibrosis in mice with diabetic nephropathy BMC Nephrol 2022 23 1 124 10.1186/s12882-022-02753-3 35354439
Tang W, Zhao Y, Zhang H, Peng Y, Rui Z. METTL3 enhances NSD2 mRNA stability to reduce renal impairment and interstitial fibrosis in mice with diabetic nephropathy. BMC Nephrol. 2022;23(1):124.35354439 10.1186/s12882-022-02753-3
87. Zheng Y Zhang Z Zheng D Yi P Wang S METTL14 promotes the development of diabetic kidney disease by regulating m(6)A modification of TUG1 Acta Diabetol 2023 60 1567 10.1007/s00592-023-02145-5 37428236
Zheng Y, Zhang Z, Zheng D, Yi P, Wang S. METTL14 promotes the development of diabetic kidney disease by regulating m(6)A modification of TUG1. Acta Diabetol. 2023;60:1567.37428236 10.1007/s00592-023-02145-5
88. Yang Y Li Q Ling Y m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis Front Immunol 2022 13 1094556 10.3389/fimmu.2022.1094556 36685533
Yang Y, Li Q, Ling Y, et al. m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis. Front Immunol. 2022;13:1094556.36685533 10.3389/fimmu.2022.1094556
89. Zhang J Chen J Lu Y TWIK-related acid-sensitive K(+) channel 2 promotes renal fibrosis by inducing cell-cycle arrest iScience 2022 25 12 105620 10.1016/j.isci.2022.105620 36465115
Zhang J, Chen J, Lu Y, et al. TWIK-related acid-sensitive K(+) channel 2 promotes renal fibrosis by inducing cell-cycle arrest. iScience. 2022;25(12):105620.36465115 10.1016/j.isci.2022.105620
90. Li X Li Y Wang Y He X The m(6)A demethylase FTO promotes renal epithelial-mesenchymal transition by reducing the m(6)A modification of lncRNA GAS5 Cytokine 2022 159 156000 10.1016/j.cyto.2022.156000 36058192
Li X, Li Y, Wang Y, He X. The m(6)A demethylase FTO promotes renal epithelial-mesenchymal transition by reducing the m(6)A modification of lncRNA GAS5. Cytokine. 2022;159: 156000.36058192 10.1016/j.cyto.2022.156000
91. Ning Y Chen J Shi Y Genistein ameliorates renal fibrosis through regulation snail via m6A RNA demethylase ALKBH5 Front Pharmacol 2020 11 579265 10.3389/fphar.2020.579265 33364952
Ning Y, Chen J, Shi Y, et al. Genistein ameliorates renal fibrosis through regulation snail via m6A RNA demethylase ALKBH5. Front Pharmacol. 2020;11: 579265.33364952 10.3389/fphar.2020.579265
92. Chen J Xu C Yang K Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment Nat Commun 2023 14 1 1161 10.1038/s41467-023-36747-y 36859428
Chen J, Xu C, Yang K, et al. Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment. Nat Commun. 2023;14(1):1161.36859428 10.1038/s41467-023-36747-y
93. Xing J He YC Wang KY Wan PZ Zhai XY Involvement of YTHDF1 in renal fibrosis progression via up-regulating YAP FASEB J 2022 36 2 e22144 10.1096/fj.202100172RR 34990050
Xing J, He YC, Wang KY, Wan PZ, Zhai XY. Involvement of YTHDF1 in renal fibrosis progression via up-regulating YAP. FASEB J. 2022;36(2): e22144.34990050 10.1096/fj.202100172RR
94. Wang Y Chen Y Liang J METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition J Mol Cell Biol. 2023 15 mjad005 10.1093/jmcb/mjad005 36945110
Wang Y, Chen Y, Liang J, et al. METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition. J Mol Cell Biol. 2023;15:mjad005.36945110 10.1093/jmcb/mjad005
95. Ma X Long C Wang F METTL3 attenuates proliferative vitreoretinopathy and epithelial-mesenchymal transition of retinal pigment epithelial cells via wnt/β-catenin pathway J Cell Mol Med 2021 25 9 4220 4234 10.1111/jcmm.16476 33759344
Ma X, Long C, Wang F, et al. METTL3 attenuates proliferative vitreoretinopathy and epithelial-mesenchymal transition of retinal pigment epithelial cells via wnt/β-catenin pathway. J Cell Mol Med. 2021;25(9):4220–34.33759344 10.1111/jcmm.16476
96. Sun J Liu G Chen R PARP1 is upregulated by hyperglycemia via N6-methyladenosine modification and promotes diabetic retinopathy Discov Med 2022 34 172 115 129 36333113
Sun J, Liu G, Chen R, et al. PARP1 is upregulated by hyperglycemia via N6-methyladenosine modification and promotes diabetic retinopathy. Discov Med. 2022;34(172):115–29.36333113
97. Li X Gao Y Chen W N6-methyladenosine modification contributes to arecoline-mediated oral submucosal fibrosis J Oral Pathol Med 2022 51 5 474 482 10.1111/jop.13292 35377493
Li X, Gao Y, Chen W, et al. N6-methyladenosine modification contributes to arecoline-mediated oral submucosal fibrosis. J Oral Pathol Med. 2022;51(5):474–82.35377493 10.1111/jop.13292
98. Xiao L Hu B Ding B N(6)-methyladenosine RNA methyltransferase like 3 inhibits extracellular matrix synthesis of endplate chondrocytes by downregulating sex-determining region Y-Box transcription factor 9 expression under tension Osteoarthr Cartil 2022 30 4 613 625 10.1016/j.joca.2022.01.002
Xiao L, Hu B, Ding B, et al. N(6)-methyladenosine RNA methyltransferase like 3 inhibits extracellular matrix synthesis of endplate chondrocytes by downregulating sex-determining region Y-Box transcription factor 9 expression under tension. Osteoarthr Cartil. 2022;30(4):613–25.10.1016/j.joca.2022.01.002
99. Liu Q Li M Jiang L Jiang R Fu B METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte Biochem Biophys Res Commun 2019 516 1 22 27 10.1016/j.bbrc.2019.05.168 31186141
Liu Q, Li M, Jiang L, Jiang R, Fu B. METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte. Biochem Biophys Res Commun. 2019;516(1):22–7.31186141 10.1016/j.bbrc.2019.05.168
100. Gao J Li Y Liu Z Wang D Zhang H Acetaminophen changes the RNA m6A levels and m6A-related proteins expression in IL-1β-treated chondrocyte cells BMC Mol Cell Biol 2022 23 1 45 10.1186/s12860-022-00444-3 36303109
Gao J, Li Y, Liu Z, Wang D, Zhang H. Acetaminophen changes the RNA m6A levels and m6A-related proteins expression in IL-1β-treated chondrocyte cells. BMC Mol Cell Biol. 2022;23(1):45.36303109 10.1186/s12860-022-00444-3
101. Hu B Zou X Yu Y Jiang Y Xu H METTL3 promotes SMSCs chondrogenic differentiation by targeting the MMP3, MMP13, and GATA3 Regen Ther 2023 22 148 159 10.1016/j.reth.2023.01.005 36793308
Hu B, Zou X, Yu Y, Jiang Y, Xu H. METTL3 promotes SMSCs chondrogenic differentiation by targeting the MMP3, MMP13, and GATA3. Regen Ther. 2023;22:148–59.36793308 10.1016/j.reth.2023.01.005
102. Li L Wang B Zhou X METTL3-mediated long non-coding RNA MIR99AHG methylation targets miR-4660 to promote bone marrow mesenchymal stem cell osteogenic differentiation Cell Cycle 2023 22 4 476 493 10.1080/15384101.2022.2125751 36369887
Li L, Wang B, Zhou X, et al. METTL3-mediated long non-coding RNA MIR99AHG methylation targets miR-4660 to promote bone marrow mesenchymal stem cell osteogenic differentiation. Cell Cycle. 2023;22(4):476–93.36369887 10.1080/15384101.2022.2125751
103. Shen L Yu Y Jiang M Zhao J Alteration of the m(6)A methylation landscape in a mouse model of scleroderma Epigenomics 2021 13 23 1867 1883 10.2217/epi-2021-0369 34791892
Shen L, Yu Y, Jiang M, Zhao J. Alteration of the m(6)A methylation landscape in a mouse model of scleroderma. Epigenomics. 2021;13(23):1867–83.34791892 10.2217/epi-2021-0369
104. Ren S Ji Y Wang M Ye M Huang L Cai X The m6A demethylase FTO promotes keloid formation by up-regulating COL1A1 Ann Transl Med 2023 11 1 15 10.21037/atm-22-6021 36760238
Ren S, Ji Y, Wang M, Ye M, Huang L, Cai X. The m6A demethylase FTO promotes keloid formation by up-regulating COL1A1. Ann Transl Med. 2023;11(1):15.36760238 10.21037/atm-22-6021
105. Liu SY Wu JJ Chen ZH The m(6)A RNA modification modulates gene expression and fibrosis-related pathways in hypertrophic scar Front Cell Dev Biol 2021 9 748703 10.3389/fcell.2021.748703 34869335
Liu SY, Wu JJ, Chen ZH, et al. The m(6)A RNA modification modulates gene expression and fibrosis-related pathways in hypertrophic scar. Front Cell Dev Biol. 2021;9: 748703.34869335 10.3389/fcell.2021.748703
106. Han J Du S Wu C METTL3 participates in glioma development by regulating the methylation level of COL4A1 J BUON 2021 26 4 1556 1562 34565019
Han J, Du S, Wu C, et al. METTL3 participates in glioma development by regulating the methylation level of COL4A1. J BUON. 2021;26(4):1556–62.34565019
107. Li Y Li X Deng M Ye C Peng Y Lu Y Cancer-associated fibroblasts hinder lung squamous cell carcinoma oxidative stress-induced apoptosis via METTL3 mediated m(6)A methylation of COL10A1 Oxid Med Cell Longev 2022 2022 4320809 10.1155/2022/4320809 36246404
Li Y, Li X, Deng M, Ye C, Peng Y, Lu Y. Cancer-associated fibroblasts hinder lung squamous cell carcinoma oxidative stress-induced apoptosis via METTL3 mediated m(6)A methylation of COL10A1. Oxid Med Cell Longev. 2022;2022:4320809.36246404 10.1155/2022/4320809
108. Shi Y Zheng C Jin Y Reduced expression of METTL3 promotes metastasis of triple-negative breast cancer by m6A methylation-mediated COL3A1 up-regulation Front Oncol 2020 10 1126 10.3389/fonc.2020.01126 32766145
Shi Y, Zheng C, Jin Y, et al. Reduced expression of METTL3 promotes metastasis of triple-negative breast cancer by m6A methylation-mediated COL3A1 up-regulation. Front Oncol. 2020;10:1126.32766145 10.3389/fonc.2020.01126
109. Chen YT Xiang D Zhao XY Chu XY Upregulation of lncRNA NIFK-AS1 in hepatocellular carcinoma by m(6)A methylation promotes disease progression and sorafenib resistance Hum Cell 2021 34 6 1800 1811 10.1007/s13577-021-00587-z 34374933
Chen YT, Xiang D, Zhao XY, Chu XY. Upregulation of lncRNA NIFK-AS1 in hepatocellular carcinoma by m(6)A methylation promotes disease progression and sorafenib resistance. Hum Cell. 2021;34(6):1800–11.34374933 10.1007/s13577-021-00587-z
110. Li E Wei B Wang X Kang R METTL3 enhances cell adhesion through stabilizing integrin β1 mRNA via an m6A-HuR-dependent mechanism in prostatic carcinoma Am J Cancer Res 2020 10 3 1012 1025 32266107
Li E, Wei B, Wang X, Kang R. METTL3 enhances cell adhesion through stabilizing integrin β1 mRNA via an m6A-HuR-dependent mechanism in prostatic carcinoma. Am J Cancer Res. 2020;10(3):1012–25.32266107
111. Li S Hu W Gong S The Role of PRRC2B in Cerebral Vascular Remodeling Under Acute Hypoxia in Mice Adv Sci (Weinh). 2023 10 892
Li S, Hu W, Gong S, et al. The Role of PRRC2B in Cerebral Vascular Remodeling Under Acute Hypoxia in Mice. Adv Sci (Weinh). 2023;10:892.
