JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
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2025
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IF 4.7
Long Li,Quanyou Chai,Chunling Guo,Junyi Wei,Yuqiao Qin,Huimin Liu,Zhaoyang Lu
Aim Vascular calcification (VC) is a major adverse cardiovascular event in chronic kidney disease (CKD) patients. N6-methyladenosine (m6A) modification is vital for many biological processes, but its function and possible molecular mechanisms in VC are poorly understood. This study aimed to clarify the function and molecular mechanisms of N6-adenosine-methyltransferase-like 3 (METTL3) in VC. Methods and results The results of the bioinformatic analysis showed that METTL3 expression was significantly upregulated in calcified VSMCs. This finding was corroborated by phosphate-induced VSMCs calcification models and 5/6 nephrectomy-induced CKD mouse VC models. Afterward, Alizarin Red S staining and m6A dot blot analysis demonstrated METTL3 overexpression elevated m6A levels and encouraged calcification in VSMCs and mouse aortic rings, while METTL3 knockdown decreased m6A levels and inhibited calcium deposition in these experimental models. Furthermore, METTL3 promoted VC via the PTEN/AKT pathway, and MeRIP verified that METTL3 induced PTEN mRNA degradation by modifying it with m6A. In addition, molecular docking simulations and DARTS assays revealed that quercetin is a natural small-molecule inhibitor of METTL3. The current investigation demonstrated that quercetin mitigated VC by reducing METTL3-dependent m6A levels in vivo and in vitro. Conclusion In conclusion, this study unraveled the pathogenic mechanism of METTL3-mediated m6A modification in VC and provided new insights to establish METTL3 as a therapeutic target for VC.
研究领域:
分子生物学
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心血管疾病
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Turkish Journal of Gastroenterology
·
2025
·Vol. 36
·期 7
·431
·
IF 1.6
Ying Jiang,Xinjie Wang,Zhenyang Wang,Shengliang Zhang,Jianhua Wang,Xianglong Wang,Yang Zhang
Background/Aims: Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy that carries a dismal prognosis. Tanshinone IIA (Tan-IIA) is involved in the regulation of N6-methyladenosine (m6A) modification and plays an anti-tumor role in HCC, but whether Tan-IIA regulates HCC by mediating m6A modification is unclear. Methods and Materials: Cell apoptosis, invasion, proliferation, viability, and stemness were estimated with flow cytometry, transwell, 5-ethynyl-2’-deoxyuridine, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, and sphere-forming assays. Methyltransferase-like 14 (METTL14) and 3 (METTL3) mRNA and protein levels were detected with reverse transcription-quantitative polymerase chain reaction and western blotting. Total m6A levels were measured using an m6A RNA methylation quantification kit. A possible regulation of tribbles pseudokinase-3 (TRIB3) expression by METTL3 in an m6A-modified manner was predicted through RM2Target and SRAMP and verified by m6A methylated RNA immunoprecipitation (MeRIP) and RIP. Mouse xenograft models assessed the action of Tan-IIA in HCC tumorigenesis. Results: Tanshinone IIA restrained HCC cell viability, proliferation, invasion, and stemness, and induced HCC cell apoptosis invitro, as well as repressed tumor growth in xenograft models. METTL3 and TRIB3 were upregulated in HCC samples and downregulated in Tan-IIA-treated HCC cells and xenograft tumors. METTL3 facilitated HCC cell viability, proliferation, invasion, and stemness by enhancing TRIB3 mRNA stability through m6A modification. Tan-IIA played its role by downregulating TRIB3, and Tan-IIA mediated TRIB3 expression by METTL3. Conclusion: Tanshinone IIA restrained HCC progression by regulating METTL3-mediated m6A modification of TRIB3 mRNA, offering evidence to support the clinical translation of Tan-IIA.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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药理学
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转化医学
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产品关联
DOI
PubMed
高影响因子
MEDIATORS OF INFLAMMATION
·
2025
·Vol. 2025
·期 1
·4955849
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IF 4.2
Zhengrong Chen,Dingwei Yan,Suyu Guo,Yiyi Song,Xinxing Zhang,Wenjing Gu,Heting Dong,Li Huang
Background: This study aimed to explore the mechanisms underlying T-cell differentiation in asthma. Methods and Results: Flow cytometry was performed to detect Th cells. LC-MS/MS was performed to assess lipid metabolism. HE staining was performed to assess the pathological changes of the lung tissues. ELISA was performed to detect cytokine levels. The results of quantitative real-time polymerase chain reaction (qRT-PCR) and western blot showed that miR-192-5p expression was decreased, while SCD1 expression was increased in CD4 + T cells isolated from the peripheral blood of children with asthma. The dual luciferase reporter assay determined the direct interaction between miR-192-5p and SCD1. MiR-192-5p inhibitor reduced ASCL3 and PPARα, increased FASN and SREBP1c mRNA expression and protein levels in mouse spleen CD4 + T cells, and elevated Th2 and Th17 cells, but these effects were reversed by the SCD1 inhibitor. Oleic acid (OA) reduced Th1 cells and increased Th2 and Th17 cells in mouse spleen CD4 + T cells treated with an SCD1 inhibitor. Additionally, pri-miR-192-5p expression was increased in CD4 + T cells isolated from the peripheral blood of asthmatic children, and the deletion of METTL3 upregulated pri-miR-192-5p expression in an m6A-dependent manner. MiR-192-5p mimic and inhibitor both reversed miR-192-5p and SCD1 expression affected by overexpression or deletion of METTL3, both in vivo and in vitro . Furthermore, METTL3 overexpression attenuated lung inflammation, elevated Th1 cells, and reduced Th2 and Th17 cells in CD4 + T cells isolated from the peripheral blood of asthmatic mice. These effects were reversed by the miR-192-5p inhibitor. Conclusion: These results suggest that METTL3/miR-192-5p/SCD1 axis regulates lipid metabolism and affects T cell differentiation, thus affecting asthma progression. This study may provide novel insights into the pathogenesis of asthma and a new treatment strategy.
研究领域:
免疫学
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分子生物学
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呼吸病学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2025
·
IF 3.5
Yongna Zhu,Xiang Ge,Zhi Chen,Tingting Chen,Yue Wu,Hebao Wen,Zeyu He,Caiyun Ma
Stem cells from the apical papilla (SCAPs) show strong odontogenic ability and can form root dentin. However, the underlying mechanisms that control the odontogenic differentiation of SCAPs in an inflammatory environment need further exploration. In the present study, we explored the regulatory role of METTL3 in the differentiation of SCAPs originating from tooth with apical periodontitis. Stem cells from the apical papilla derived from healthy teeth (SCAPs) and teeth with apical periodontitis (AP-SCAPs) were successfully isolated and cultured. The expressions of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) were higher in AP-SCAPs. A decrease in METTL3 expression accompanied the decreased osteo-/odontogenic differentiation ability of AP-SCAPs. Exploring the role of METTL3 on the osteo-/odontogenic differentiation of AP-SCAPs revealed that overexpression of METTL3 upregulated the odontogenic ability of AP-SCAPs. However, silencing METTL3 exerted the opposite effect. Overexpression of METTL3 suppressed the expression of TNF-α and IL-6 in AP-SCAPs, whereas knockdown of METTL3 in these cells enhanced TNF-α and IL-6 expression. METTL3 regulates the osteo-/odontogenic differentiation of SCAPs and modulates their inflammatory response. Furthermore, overexpression of METTL3 upregulated the methylation level, mRNA, and protein expression of nuclear factor-IC (NFIC) during mineralization induction. NFIC silencing attenuated osteo-/odontogenic differentiation of METTL3-overexpressed AP-SCAPs. In conclusion, METTL3-mediated-m6A upregulated the odontogenic differentiation of AP-SCAPs via NFIC. This paper elucidates a novel mechanism regulating the odontogenic differentiation of AP-SCAPs, and METTL3 may be a new target for regenerative endodontic treatment.
研究领域:
口腔医学
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干细胞研究
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表观遗传学
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DOI
PubMed
高影响因子
NEUROCHEMISTRY INTERNATIONAL
·
2025
·
IF 4
Ling Zhu,Congyan Liu,Yang Wang,Xuanang Zhu,Lei Wu,Lvan Chen,Jing Zhou,Fan Wang
Background Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. Method Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N 6 -methyladenosine (m 6 A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF. Results Stimulation with Aβ 1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m 6 A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα. Conclusion Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.
研究领域:
神经生物学
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医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2025
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IF 2.8
Chenxi Yan,Guilan Li,Lian Huang,Zhaohui Zhang
Beryllium (Be) is a recognised environmental toxicant associated with pulmonary fibrosis. Epithelial–mesenchymal transition (EMT), a critical process in cell phenotype conversion, plays a key role in its pathophysiology. Methyltransferase-like 3 (METTL3), a major N6-methyladenosine methyltransferase, regulates gene expression and cellular functions. However, its role in Be-induced EMT remains unclear. In this study, human bronchial epithelial cell line (16HBE cells) were exposed to varying concentrations of beryllium sulphate (BeSO 4 ) to assess changes in METTL3 expression. METTL3 overexpression vectors were constructed, and quantitative reverse transcription-polymerase chain reaction, western blotting and immunofluorescence were used to detect METTL3, EMT markers and Wingless/Integrated (Wnt)/β-catenin pathway proteins. The Wnt/β-catenin pathway inhibitor ICG-001 was also employed to explore the role of the Wnt/β-catenin pathway in BeSO 4 -induced EMT. The study demonstrated that BeSO 4 suppressed METTL3 expression, induced EMT and activated the Wnt/β-catenin pathway in 16HBE cells. Both METTL3 overexpression and ICG-001 pretreatment mitigated BeSO 4 -induced EMT and Wnt/β-catenin pathway activation. These findings suggest that METTL3 inhibits BeSO 4 -induced EMT by suppressing the Wnt/β-catenin pathway, offering novel mechanistic insights into beryllium toxicity and a potential therapeutic target for Be-related pulmonary fibrosis.
研究领域:
细胞生物学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
DIABETES
·
2023
·Vol. 72
·期 8
·1083-1094
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IF 7.7
Xie Renxiang,Yan Sujun,Zhou Xiaoling,Gao Yunyi,Qian Yu,Hou Jingyu,Chen Zhanghui,Lai Kairan,Gao Xiangwei,Wei Saisai
The induction of beige adipocytes in white adipose tissue (WAT), also known as WAT beiging, improves glucose and lipid metabolism. However, the regulation of WAT beiging at the posttranscriptional level remains to be studied. Here, we report that METTL3, the methyltransferase of N6-methyladenosine (m 6 A) mRNA modification, is induced during WAT beiging in mice. Adipose-specific depletion of the Mettl3 gene undermines WAT beiging and impairs the metabolic capability of mice fed with a high-fat diet. Mechanistically, METTL3-catalyzed m 6 A installation on thermogenic mRNAs, including Krüppel-like factor 9 ( Klf9 ), prevents their degradation. Activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate promotes WAT beiging, reduces body weight, and corrects metabolic disorders in diet-induced obese mice. These findings uncover a novel epitranscriptional mechanism in WAT beiging and identify METTL3 as a potential therapeutic target for obesity-associated diseases. Article Highlights METTL3, the methyltransferase of N6-methyladenosine (m 6 A) mRNA modification, is induced during WAT beiging. Depletion of Mettl3 undermines WAT beiging and impairs thermogenesis. METTL3-mediated m 6 A installation promotes the stability of Krüppel-like factor 9 ( Klf9 ). KLF9 rescues impaired beiging elicited by Mettl3 depletion. Pharmaceutical activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate induces WAT beiging. Methyl piperidine-3-carboxylate corrects obesity-associated disorders. The METTL3-KLF9 pathway may serve as a potential therapeutic target for obesity-associated diseases.
研究领域:
分子生物学
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代谢
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肥胖研究
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
·
2023
·
IF 9.7
Jiaoshun Chen,Haoxiang Zhang,Chaoyang Xiu,Chenggang Gao,Shihong Wu,Jianwei Bai,Qiang Shen,Tao Yin
In eukaryotes, N 6 -methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
TISSUE & CELL
·
2025
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IF 2.5
Xiaoxue Zhao,Bingyu Zhang,Sining Duan,Tengfei Wu,Xiaojiao Yang,Yuxiang Liu
Growing evidence demonstrated the involvement of ferroptosis in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). The nature compound Wedelolactone (Wed) exhibits anti-ferroptosis effects. The current study aims to explore the impact of Wed on MIRI and reveal whether Wed could protect cardiomyocytes from ferroptosis. Rats underwent cardiac IR operation, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Rats or cell in Wed-treated group were subdivided into 2 different dose regimens: low and high. Wed intervention alleviated myocardial infarction and left ventricle dysfunction, and diminished the levels of biochemical markers for cardiac injury caused by cardiac IR. The content of Fe 2+ and MDA, 4-HNE expression, and ROS production were increased in infarct zone, as well as GSH content, GSH-Px activity, and the levels of ferroptosis-related proteins were reduced. Treatment with Wed reversed the aforementioned changes. Similar results were observed in vitro experiments. Molecular docking analysis showed good binding affinity between Wed and the target protein METTL3. In OGD/R-induced H9c2 cells, Wed downregulated METTL3 protein expression and further blocked METTL3-mediated m 6 A modification of BRD4 mRNA. Overexpression of METTL3 reversed the antagonistic effect of Wed on cardiomyocyte ferroptosis. Collectively, our findings uncovered that Wed showed anti-ferroptosis effects in cardiomyocytes through downregulating the METTL3/BRD4 axis, thereby ameliorating MIRI.
研究领域:
药理学
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心脏病学
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分子生物学
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生物化学
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生物医学研究
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2024
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IF 18
Zilin Tan,Liangjie Tian,Yang Luo,Kexin Ai,Xuehua Zhang,Haitao Yuan,Jinfan Zhou,Guangyao Ye,Shuofei Yang,Ming Zhong,Gaohua Li,Yanan Wang
Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.
研究领域:
肿瘤学
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分子生物学
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免疫疗法
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Biology Direct
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2024
·Vol. 19
·期 1
·1-17
·
IF 5.7
Yu Zhengtao,Xia Ying,Li Jiameng,Jiang Junwen,Li You,Li Youjun,Wang Liu
Background Ischemia/reperfusion (I/R) injury is a severe brain disorder with currently limited effective treatments. This study aims to explore the role of N6-methyladenosine (m6A) modification and associated regulatory factors in I/R to identify potential therapeutic targets. Methods We utilized a middle cerebral artery occlusion (MCAO) rat model and SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to assess m6A levels and investigate the impact of METTL3 overexpression on long non-coding RNA (lncRNA) CRNDE expression. The effects of silencing lncRNA CRNDE on the interaction between YTHDC1 and ATG10 mRNA, as well as the stability of ATG10 mRNA, were evaluated. Additionally, apoptosis rates, pro-inflammatory and anti-inflammatory factor levels, ATG10 expression, and autophagic activity were analyzed to determine the effects of METTL3 . The reverse effects of YTHDC1 overexpression were also examined. Results MCAO rats and OGD/R-treated SH-SY5Y cells exhibited reduced m6A levels. METTL3 overexpression significantly inhibited lncRNA CRNDE expression. Silencing lncRNA CRNDE mitigated OGD/R-induced apoptosis and inflammation in SH-SY5Y cells, while enhancing autophagy and stabilizing ATG10 mRNA. METTL3 overexpression decreased cell apoptosis, reduced the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and increased IL-10 secretion. Furthermore, METTL3 overexpression upregulated ATG10 expression and promoted autophagy. Conversely, lncRNA CRNDE overexpression negated these effects. Conclusion The inhibition of lncRNA CRNDE affects the interaction between YTHDC1 and ATG10 mRNA and stabilizes ATG10 mRNA, mediated by METTL3 overexpression. These findings suggest that targeting lncRNA CRNDE to reduce apoptosis, inhibit inflammation, increase ATG10 expression, and enhance autophagy could offer new therapeutic strategies for I/R injury.
研究领域:
神经科学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Biomolecules
·
2025
·Vol. 15
·期 10
·1353
·
IF 4.8
Hao Zhang,Yajin Guan,Meng Li,Yilin Wu,Xiaoou Sun
Cerebral ischemia/reperfusion (I/R) injury is a devastating neurological disorder with limited treatment options. Emerging evidence suggests that the N6-methyladenosine (m6A) modification and its regulatory factors play pivotal roles in the pathophysiology of I/R. This study aimed to elucidate the function of METTL3-mediated m6A modification of the long non-coding RNA (lncRNA) AU020206 in ferroptosis during cerebral I/R injury and to identify potential molecular targets for neuroprotection. A murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) and N2a cells subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) were established to assess m6A levels and ferroptosis-related changes. Effects of METTL3 overexpression and lncRNA-AU020206 silencing on neuronal apoptosis, inflammation, and ferroptosis were investigated in vitro and in vivo. The interaction between lncRNA-AU020206 and YTHDC2 and the resulting regulation of SLC7A11 mRNA stability and GPX4 expression were evaluated using molecular and biochemical assays. Both MCAO/R mice and OGD/R-treated N2a cells exhibited decreased m6A levels and upregulation of lncRNA-AU020206 accompanied by enhanced ferroptosis. METTL3 overexpression increased the m6A modification of AU020206, promoting its degradation and attenuating neuronal injury, whereas silencing AU020206 or overexpressing YTHDC2 decreased SLC7A11 mRNA stability and enhanced ferroptosis. Restoring the expression of SLC7A11/GPX4 can enhance cell viability, alleviate neuronal apoptosis, and reduce Fe2+overload. Disruption of the METTL3–AU020206–YTHDC2 axis abolished these neuroprotective effects. METTL3-mediated m6A modification of lncRNA-AU020206 restrained ferroptosis and neuronal injury in cerebral I/R by maintaining the stability of the SLC7A11/GPX4 axis via interactions with YTHDC2. Targeting this epitranscriptomic signalling pathway may represent a promising therapeutic strategy for the treatment of ischemic stroke and related neurological disorders.
研究领域:
神经生物学
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表观遗传学
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分子生物学
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脑血管病学
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细胞死亡机制
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RNA代谢
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）