JOURNAL OF GASTROENTEROLOGY
·
2025
·
IF 5.5
Ren Bingyu,Li Han,Liu Shenglu,Huang Zhiwei,Bai Junjie,Jiang Zhonghao,Xu Tongjie,Gu Boyuan,Yu Wenhao,Sun Lei,Tan Peng,Fu Wenguang
Background and Aims Inflammatory cell infiltration in the liver is a hallmark of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the pathological events that trigger the infiltration of inflammatory cells to mediate MAFLD pathogenesis remains poorly understood. This study aims to investigate the function and mechanism of Hic-5 on hepatic inflammation of MAFLD. Methods MAFLD animal models were fed a methionine- and choline-deficient (MCD) diet in Hic-5 knockout mice. Liver tissues were analyzed by immunohistochemical staining, immunofluorescence and flow cytometry, with a particular focus on the impact on the immune microenvironment. Results Hic-5 deficiency alleviates the severity of MAFLD, particularly the inflammation response. Gain- and loss-of-function experiments revealed that Hic-5 deficiency results in decreased neutrophil proliferation and increased apoptosis, as well as impaired migration. Conversely, Hic-5 overexpression had the opposite effects. This study confirmed that METTL3-mediated methylation of m 6 A stabilizes Hic-5 mRNA and promotes its expression, which in turn regulates the infiltration of neutrophils by the CXCL1-CXCR2 axis. Conclusions The study reveals the role of Hic-5 in regulating neutrophils and indicates that it may be a potential therapeutic target for MAFLD.
研究领域:
肝病学
·
免疫学
·
分子生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
GENOMICS PROTEOMICS & BIOINFORMATICS
·
2020
·
IF 7.051
Yuhuan Li,Qingyang Zhang,Guanshen Cui,Fang Zhao,Xin Tian,Bao-Fa Sun,Ying Yang,Wei Li
N 6 -methyladenosine (m 6 A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m 6 A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 ( Mettl3 ). However, the functions of Mettl3 and m 6 A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m 6 A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance . In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m 6 A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m 6 A in HFD-induced metabolic disorders and hepatogenous diabetes.
研究领域:
分子生物学
·
代谢学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2026
·
IF 6.5
Qu Qiao,Li Zhilong,Wang Dalu,Wu Di,Yin Hongzhuan
Colorectal cancer (CRC) remains a major contributor to cancer-related mortality worldwide. Although minichromosome maintenance protein 10 (MCM10) is known for its role in DNA replication, its involvement in CRC progression has not been fully elucidated. To identify key oncogenic drivers, RNA sequencing was performed on seven paired CRC and adjacent normal tissues, revealing significant upregulation of MCM10 (Log2FC = 2.359, P = 0.003). Public GEO datasets (GSE240623, GSE200427) further confirmed MCM10 overexpression in CRC tissues. This finding was validated in 40 paired clinical samples using qPCR and Western blotting. Prognostic relevance was assessed using hazard ratio (HR). Functional assays in vitro and in vivo were conducted to assess the effects of MCM10 on proliferation, migration, invasion, and M2 macrophage polarization. The m6A modification of MCM10 mRNA was evaluated through METTL3 and YTHDF1 interaction analysis in HCT116 cells. MCM10 was significantly upregulated in CRC tissues and associated with poor prognosis (HR = 1.54, P = 0.00077). MCM10 overexpression promoted CRC cell proliferation and invasion and was correlated with elevated M2 macrophage infiltration in tumor xenografts (6.16 ± 0.85% vs. 11.7 ± 1.13%, P < 0.05). Conditioned media from MCM10-overexpressing cells enhanced THP-1 macrophage polarization by increasing secretion of CCL2, CCL5, and IL10. Mechanistically, METTL3-mediated m6A modification stabilized MCM10 mRNA in a YTHDF1-dependent manner. MCM10 is aberrantly overexpressed in CRC and linked to worse clinical outcomes. Its oncogenic effects involve METTL3/YTHDF1-mediated mRNA stabilization and enhanced M2 macrophage polarization, suggesting a potential role in immune microenvironment modulation.
✓ 已验证
DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Enjia Zhou,Zeyu Xing,Mingchao Wang,Dongxu Lu,Mengyao Hao,Guodong Tang,Shuying Li,Yiran Chen,Wenjing Zhang,Xinyu Li,Bolin Zhang,Fang Wang,Wenhao Ju,Jing Jin
Epigenetic modifications, particularly N6-methyladenosine (m6A) modifications, alter the phenotype of macrophages. Among the m6A-related proteins, methyltransferase 3 (METTL3), as the catalytic core methyltransferase subunit, plays an essential role in regulating the function of macrophages. This study aimed to explore novel m6A inhibitors from natural products that target METTL3 to modulate the phagocytic function of macrophages in the treatment of colon cancer. In this work, first, a high-throughput screening of biological m6A by colorimetric assay was conducted to rapidly identify candidate inhibitors from a natural product library. Second, bioinformatics analysis and molecular biological methods revealed the underlying mechanisms through which METTL3 regulates macrophage-mediated phagocytosis. Subsequently, Mettl3 f/f Lyz2 -Cre mice were generated to further elucidate the mechanism through which METTL3 inhibition promotes the phagocytic function of macrophages by modulating the mRNA stability of SIRPA, a key phagocytic-related protein, in vivo . We determined that chlorogenic acid (CHA) is a potential therapeutic METTL3 inhibitor because of its influence on METTL3 enzymatic activity and expression. METTL3 inhibition promoted the phagocytic function of macrophages. METTL3 increases the mRNA stability of the intrinsic immune checkpoint SIRPA by activating IGF2BP2 in an m6A-dependent manner, which subsequently increases its protein expression and suppresses the phagocytosis of macrophages both in vivo and in vitro . In conclusion, CHA is a candidate inhibitor compound that targets the METTL3–SIRPA axis through enhancing the phagocytic function of macrophages and is thus a promising therapy for treating colon cancer.
✓ 已验证
DOI
PubMed
高影响因子
Cancer Immunology Research
·
2024
·
IF 8.1
Meng Meng,Zhong Zhaoyang,Song Liang,Zhang Zhaohui,Yin Xiaofeng,Xie Xiqiang,Tian Lei,Wu Wei,Yang Yao,Deng Yafei,Peng Hongyan,Wu Shuting,Ran Guanghe,Lin Yuqing,Lai Qiangqiang,Bi Qinghua,Yan Fulin,Ji Yan,Wang Yang,Li Xiaohui,Yi Ping,Yu Jianhua,Deng Youcai
Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1–SAM signal axis in regulating NK-cell activation and effector functions.
研究领域:
免疫学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-23
·
IF 6.4
Wang Qiuhong,Wei Dong,Li Chunman,Yang Xiawei,Su Kun,Wang Tao,Zou Renchao,Wang Lianmin,Cun Dongyun,Tang Bo,Wu Tao
Section
Background
Pancreatic cancer is highly lethal, and METTL3 plays a crucial role in the regulation of m6A. However, the therapeutic potential of METTL3 in pancreatic cancer is unclear.
Section
Methods
By means of functional gain and loss experiments, the relationship between METTL3 and gemcitabine resistance as well as ferroptosis was explored. The target genes of METTL3 were screened, and the influence of O-GlcNAcylation on the stability and ubiquitination modification of METTL3 was dissected.
Section
Results
We found that METTL3 is highly expressed in pancreatic cancer and regulates ferroptosis and gemcitabine resistance by promoting the degradation of HMGB1 in an m6A-YTHDF2-dependent manner. O-GlcNAcylation modulates the METTL3’s stability. The interaction between the deubiquitinase EIF3H and METTL3 is influenced by O-GlcNAcylation.
Section
Conclusion
METTL3 affects pancreatic cancer progression by promoting degradation of HMGB1. The O-GlcNAcylation of METTL3 not only stabilizes METTL3 but also augments EIF3H-mediated deubiquitination. These findings uncover potential mechanisms underlying gemcitabine resistance in pancreatic cancer and offer potential therapeutic strategies for the treatment of this disease.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 40
·
IF 11.7
Lian Cui,You Wu,Zeyu Chen,Bingjie Li,Jiangluyi Cai,Zhanhe Chang,Weide Xiao,Yuanyuan Wang,Nan Yang,Yu Wang,Zengyang Yu,Lingling Yao,Rui Ma,Xin Wang,Youdong Chen,Qianyu Chen,Hao Mei,Zhiyi Lan,Yingyuan Yu,Rongfen Chen,Xingbiao Wu,Qian Yu,Jiajing Lu,Ning Yu,Xilin Zhang,Jun Liu,Lingjuan Zhang,Yuping Lai,Shaorong Gao,Yawei Gao,Chunyuan Guo,Yuling Shi
Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification–lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases.
研究领域:
免疫学
·
分子生物学
·
皮肤病学
✓ 已验证
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-19
·
IF 9.6
Chen Shengjun,Wang Yujie,Zhang Jinjin,Liu Bo,Liu Weili,Cao Guohong,Li Rongrong,Li Hongbo,Zhai Nailiang,Song Xiaodong,Zhang Songzi,Lv Changjun
Fibroblast-to-myofibroblast differentiation is the main cytopathologic characteristic of pulmonary fibrosis. However, its underlying molecular mechanism remains poorly understood. This study elucidated that the nuclear export of lncNONMMUT062668.2 (lnc668) exacerbated pulmonary fibrosis by activating fibroblast-to-myofibroblast differentiation. Mechanistic research revealed that histone H3K9 lactylation in the promoter region of the N6-methyladenosine (m 6 A) writer METTL3 was enriched to enhance METTL3 transcription, leading to the lnc668 m 6 A modification. Meanwhile, the m 6 A reader YTHDC1 recognized m 6 A-modified lnc668 and elevated the METTL3-mediated lnc668 modification. Subsequently, phase-separating YTHDC1 promoted the nuclear export of m 6 A-modified lnc668. In this process, the phase-separating YTHDC1 formed a nuclear pore complex with serine/arginine-rich splicing factor 3, Aly/REF export factor, and exportin-5 to assist the translocation of m 6 A-modified lnc668 from nucleus to cytoplasm. After nuclear export, lnc668 facilitated the translation and stability of its host gene phosphatidylinositol-binding clathrin assembly protein to activate fibroblast-to-myofibroblast differentiation, leading to the aggravation of pulmonary fibrosis, which also depended on YTHDC1 phase separation. This study first clarified that YTHDC1 phase separation is crucial for the m 6 A modification, nuclear export, and profibrotic role of lnc668 in exacerbating pulmonary fibrosis. These findings provide new insights into the nuclear export of cytoplasmic lncRNAs and identified potential targets for pulmonary fibrosis therapy.
研究领域:
分子生物学
·
表观遗传学
·
肺病学
·
RNA生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Guisong Shan,Wanrong Wang,Xueqian Li,Zhaoxing Zhai,Mengyu Liu,Rui Peng,Qiuting Sun,Huiru Zhang,Tao Guo,Xiaoyan He
Epithelial–mesenchymal transition (EMT) is a key driver of chemoresistance and poor clinical outcomes in cancer. Strategies to reverse EMT-mediated drug resistance and to dynamically monitor treatment response are critical for improving therapeutic efficacy. Previous studies have implicated METTL3-regulated N 6 -methyladenosine (m 6 A) methylation in promoting EMT and tumor progression,highlighting its potential as a therapeutic target. Here, we develop a glutathione-responsive biomimetic nanomedicine (termed ACVS) that encapsulates METTL3 inhibitors within tumor-targeting cell membrane vesicles for controlled drug release. ACVS effectively reverse EMT phenotypes in vitro in transforming growth factor-β (TGF-β)-induced EMT cell models and restory chemosensitivity to standard therapeutics. In vivo validation in tumor-bearing mice and patient-derived circulating tumor cells (CTCs) further demonstrate that METTL3 inhibition enhance tumor suppression when combine with chemotherapy. To dynamically assess the relationship between EMT and chemoresistance, we implement single-cell resolution in situ mRNA profiling, which revealed spatial heterogeneity in EMT marker expression correlated with drug response. These findings propose a combinatorial strategy to overcome chemoresistance through METTL3-targeted modulation of EMT, while providing a methodological framework for real-time treatment monitoring in personalized oncology.
研究领域:
癌症生物学
·
纳米医学
·
表观遗传学
·
药理学
·
分子生物学
·
精准医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
IF 10.753
Haowei Fu,Xiaofang Zhu,Qiannan Di,Jiahui Sun,Qianqian Jiang,Qian Xu
Di(2-ethyl-hexyl) phthalate (DEHP), an environmental endocrine disruptor, can destroy the sperm genomic integrity and impairs spermatogenesis. N6-methyladenosine (m6A) is involved in the cellular effects of DEHP. However, the genotoxic effect of DEHP on spermatocytes and the possible role of m6A in this process remain unclear. This study demonstrated that m6A alleviates DEHP genotoxicity in GC-2 cells. In DEHP-treated mice, DNA double-strand breaks (DSBs) were induced in the testis and spermatocytes. To further explore the molecular mechanism of DEHP genotoxicity on spermatocytes, GC-2 cells were exposed to DEHP. DEHP produced distinct genotoxicity and caused DSBs, which led to the inhibition of DNA synthesis and cell cycle arrest. The DNA damage response (DDR) was initiated to repair the DSBs induced by environmentally relevant levels of DEHP (100 μM and 200 μM). During this process, METTL3 upregulated m6A, which facilitated the DDR via stabilizing the DNA damage repair factors ( Rad51 and Xrcc5 ) mRNA to maintain the pro-survival state. Moreover, Mettl3 knockdown partially inhibited DDR. Interestingly, high-dose DEHP (400 μM and 600 μM) directly induced apoptosis rather than the pro-survival state. Altogether: METTL3-mediated m6A participates in maintaining the pro-survival state by upregulating DDR, providing guidance for mitigating the genotoxicity of environment-related level DEHP exposure.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2022
·
IF 6.78
Xiaofang Zhu,Haowei Fu,Jiahui Sun,Qiannan Di,Qian Xu
Aims Di (2-ethylhexyl) phthalate (DEHP), as an environmental endocrine-disrupting chemical (EDC), can induce male reproductive injury. N6-methyladenosine (m6A) plays a vital role in environmental exposure-induced diseases by regulating gene expression. Therefore, we aim to investigate the role of m6A in DEHP-induced reproductive injury. Main methods We established an in vivo model of mice exposed to DEHP to explore the effect of DEHP on reproductive injury and m6A. To further explore the molecular mechanism of DEHP toxicity, we built a model of GC-2 cells exposed to mono-(2-ethylhexyl) phthalate (MEHP) in vitro and further silenced Mettl3 in GC-2cells. Besides, we also conducted MeRIP-qPCR and RIP assays to identify the target genes for m6A modification. Key findings DEHP induced testicular injury and senescence. And telomeres shortening, reduced levels of telomere repeat–binding factor 1 (TRF1), TRF2, protection of telomeres 1 (POT1), and telomerase reverse transcriptase (TERT) can be observed in DEHP-treated testes. MEHP also induced GC-2 cellular senescence and telomere dysfunction. Besides, increased m6A mediated by METTL3 stabilized homeobox containing 1 ( Hmbox1 ) in an m6A-dependent manner in MEHP-exposed GC-2 cells. Mettl3 knockdown led to lower m6A modification and reduced Hmbox1 stability, resulting in further shortening of telomere length. Significance our work uncovered that DEHP led to male reproductive injury by telomere dysfunction and m6A modified Hmbox1 contributed to maintaining telomere homeostasis in this process, suggesting that accurate regulation of m6A modification level by drugs has potential value in the treatment of DEHP-induced male reproductive injury.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
·
表观遗传学
✓ 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）