EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Liu-Gen Cui,Miao-Miao Zhai,Jian-Jian Yin,Zhi-Mo Wang,Shu-Hui Wang,Yue-Jiao Zhou,Pei-Pei Li,Yang Wang,Li Xia,Pei Wang,Xue-Xiang Cha,Li-Rong Zhang,Sheng-Na Han
Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m 6 A) with cardiovascular diseases; however, how m 6 A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m 6 A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m 6 A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m 6 A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m 6 A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.
研究领域:
心血管疾病
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表观转录组学
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分子生物学
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PubMed
高影响因子
Arabian Journal of Chemistry
·
2024
·
IF 5.3
Yubin Long,Yuan Ma,Houzhi Yang,Xiangbin Wang,Jigeng Fan,Yong Li,Bo Tao,Tianwei Sun
Promoting osteogenic differentiation and inhibiting osteoclast formation remain significant challenges in the treatment of osteoporosis. With the growing understanding of osteoporosis, increasing literature has highlighted the regulatory role of m6A methylation in this condition. However, there is currently no reliable method to stably regulate cellular m6A methylation levels. Here, we report a novel approach utilizing alendronate (aln)-modified mesoporous silica nanoparticles (MSNs) to deliver sodium bicarbonate and piR7472, modulating cellular behavior. Our experimental results demonstrate that Aln modification enables the nanoparticles to stably target hydroxyapatite, thereby accumulating in osteoporotic regions. Sodium bicarbonate suppresses osteoclastogenesis, while piR7472 enhances m6A methylation, promoting osteogenic differentiation of bone marrow stromal cells (BMSCs). Computed tomography (CT) and hematoxylin and eosin (HE) staining showed that after 2 weeks of treatment with MSNs-Na@piR7472, cortical bone thickened, trabecular bone density increased, collagen fiber thickness improved, and both the number and staining area of osteoclasts were significantly reduced. These findings indicate a marked improvement in osteoporosis.
研究领域:
医学
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分子生物学
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纳米医学
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高影响因子
Cell Reports
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2020
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IF 8.109
Bowen Rong,Qian Zhang,Jinkai Wan,Shenghui Xing,Ruofei Dai,Yuan Li,Jiabin Cai,Jiaying Xie,Yang Song,Jiawei Chen,Lei Zhang,Guoquan Yan,Wen Zhang,Hai Gao,Jing-Dong J. Han,Qianhui Qu,Honghui Ma,Ye Tian,Fei Lan
Summary N6 methylation at adenosine 1832 (m 6 A1832) of mammalian 18S rRNA, occupying a critical position within the decoding center, is modified by a conserved methyltransferase, METTL5. Here, we find that METTL5 shows strong substrate preference toward the 18S A1832 motif but not the other reported m 6 A motifs. Comparison with a yeast ribosome structural model unmodified at this site indicates that the modification may facilitate mRNA binding by inducing conformation changes in the mammalian ribosomal decoding center. METTL5 promotes p70-S6K activation and proper translation initiation, and the loss of METTL5 significantly reduces the abundance of polysome. METTL5 expression is elevated in breast cancer patient samples and is required for growth of several breast cancer cell lines. We further find that Caenorhabditis elegans lacking the homolog metl-5 develop phenotypes known to be associated with impaired translation. Altogether, our findings uncover critical and conserved roles of METTL5 in the regulation of translation.
研究领域:
分子生物学
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癌症研究
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细胞生物学
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遗传学
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DOI
PubMed
高影响因子
ZOOLOGICAL RESEARCH
·
2025
·Vol. 46
·期 3
·722
·
IF 4.7
Chun-Xue Zhou,Si-Qi Wang,Ji-Yu Zhang,Xing Du,Qi-Fa Li
NORHA, a long non-coding RNA (lncRNA), serves as a key inducer of follicular atresia in sows by triggering granulosa cells (GCs) apoptosis. However, its regulation by N6-methyladenosine (m6A)—the most abundant RNA modification—remains unresolved. This study identified NORHA as a functional target of the m6A reader HNRNPA2B1 in sow GCs (sGCs). Transcriptome-wide mapping of RNA modification sites revealed extensive m6A enrichment on NORHA, with HNRNPA2B1 binding directly to the transcript and enhancing its stability via modification of multiple m6A sites, including A261, A441, and A919. HNRNPA2B1 suppressed 17β-estradiol (E2) biosynthesis and promoted sGC apoptosis by activating the NORHA-FoxO1 axis. FoxO1 subsequently repressed expression of cytochrome P450 family 19 subfamily A member 1 (CYP19A1), which encodes the enzyme essential for E2 biosynthesis. Additionally, HNRNPA2B1 functioned as a critical mediator of METTL3-dependent m6A modification, modulating NORHA expression and activity in sGCs. This study highlights an important m6A-dependent regulatory mechanism governing NORHA expression in sGCs.
研究领域:
生殖生物学
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RNA表观遗传学
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分子生殖学
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长非编码RNA
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卵巢生理学
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细胞凋亡
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PubMed
高影响因子
Military Medical Research
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2026
·Vol. 13
·期 1
·100054
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IF 29
Xu-Ying Sun,Jing-Yue Su,Xin Chen,Yi-Xin Yang,Sheng-Wu Yang,Chun-Wu Zhang,Yu-Sheng Li,Jian Xu,Zhen-Han Deng
Background Osteoarthritis (OA) is currently the most common age-related degenerative joint disease, but there remains a lack of disease-modifying therapy for OA treatment. This study aimed to elucidate the critical roles and underlying mechanism of the fat mass and obesity associated gene (FTO) in OA pathogenesis induced by high fat diet (HFD) and HFD coupled with destabilized medial meniscus (DMM) surgery, and to ascertain the synergistic action of the two in OA pathogenesis. Methods Mouse models were established using solely HFD feeding and combined HFD feeding and DMM surgery. Primary mouse chondrocytes were treated with palmitic acid (PA) and interleukin-1β (IL-1β) to simulate lipotoxicity and inflammation. FTO expression was modulated via genetic, adenoviral, or pharmacological methods. Downstream pyruvate dehydrogenase phosphatases 2 (PDP2) and YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2) were similarly manipulated by siRNA or overexpression plasmids; adenovirus-mediated knockdown/overexpression of Pdp2 was applied in vivo . Mechanistic studies included RNA sequencing (RNA-Seq) and methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Results The results revealed reduced FTO expression in the cartilage of both obese OA patients and mouse models. Genetically, adenovirus-induced or pharmacologically-induced FTO inhibition exacerbated OA progression in HFD-fed and HFD+DMM mice. Mechanistically, Fto knockdown downregulated the PDP2 level in an m 6 A-dependent manner via YTHDF2. Pdp2 knockdown exacerbated OA progression in HFD-fed and HFD+DMM mice, whereas PDP2 overexpression markedly alleviated cartilage degeneration. Moreover, YTHDF2 overexpression reversed the role of Fto knockdown in lipid deposition and cartilage degeneration. Conclusions Our study identifies that downregulation of FTO exerts a pivotal effect on OA with obesity. FTO drives disease progression by regulating PDP2 activity, and YTHDF2 mediates the m 6 A modification of FTO to PDP2. Targeting the FTO/YTHDF2/PDP2 axis offers promising therapeutic potential for OA treatment.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Huanhuan Wang,Hanshu Zhao,Jiadi Gao,Sihan Liu,Yuanqi Xu,Xinyue Zhao,Shanshan Yang,Baozhi Gang,Zhongling Zhang
Vascular dementia (VaD) is a major cause of cognitive decline in the elderly, with chronic cerebral hypoperfusion (CCH) as its core pathogeny linked to neuroinflammation. Microglial M1 polarization drives CCH-related neuroinflammation, but its epigenetic regulation remains unclear. N6-methyladenosine (m6A) modification, centered on methyltransferase-like 14 (METTL14), is abundant in the brain, while CCAAT enhancer binding protein delta (CEBPD) is associated with central nervous system inflammation. This study explored METTL14’s role in microglial polarization and CCH pathology. In vitro , HMC3 cells induced by LPS/TNF-α (10 μg/mL, 50 ng/mL) showed upregulated METTL14 and CEBPD. METTL14 knockdown via short hairpin RNA inhibited the expression of M1 phenotypic markers (iNOS, CD86), reduced the release of pro-inflammatory factors (IL-1β, IL-6), and blocked NF-κB nuclear translocation, indicating that METTL14 silencing suppresses LPS/TNF-α-induced microglial M1 polarization and inflammatory response. In bilateral common carotid artery occlusion (BCCAo)-induced CCH rats, hippocampal METTL14/CEBPD was elevated. Adeno-associated virus-mediated METTL14 knockdown not only attenuated neuroinflammation and neuronal apoptosis in hippocampal CA1, but also significantly improved spatial learning memory and object recognition ability. Mechanistically, RIP-PCR and MeRIP-qPCR confirmed METTL14 enhances CEBPD mRNA stability via m6A modification. CEBPD overexpression reversed METTL14 knockdown’s effect, identifying it as a key downstream mediator. In conclusion, METTL14 knockdown impairs CEBPD mRNA stability via m6A, inhibits TLR4/MyD88/NF-κB pathway and microglial M1 polarization, alleviating CCH-related neuroinflammation and cognitive impairment, providing a potential epigenetic target for VaD.
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高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2026
·Vol. 45
·期 1
·118
·
IF 14.3
He Yuhui,Gong Yanqing,Wu Yucai,He Shiming,Wang Yang,Gao Wenzhi,Tian Tai,Xu Xinyu,Zhou Liqun,Shi Zhenduo,Han Conghui,Feng Ninghan,Wang Jianfeng,Li Xuesong
Background Bladder cancer (BC) presents a major clinical challenge due to high recurrence and progression rates, highlighting the need for novel therapeutic targets. While the N6-methyladenosine (m6A) writer complex is broadly implicated, the specific function and regulatory mechanism of its adaptor protein RNA binding motif protein 15 (RBM15) remain poorly defined in BC. This study reveals the oncogenic role of RBM15 in BC and its m6A-dependent regulatory axis, providing a new rationale for targeted intervention. Methods The clinical relevance of RBM15 was established by assessing its expression and prognostic significance in public datasets and a large clinical cohort. The biological function of RBM15 and its effect on global m6A methylation were subsequently investigated using a comprehensive suite of in vitro assays and in vivo models. We performed integrated multiomics analyses (RNA-seq, m6A-seq, and RIP-seq) and validated the underlying molecular mechanisms by performing additional targeted assays to elucidate the downstream regulatory network. Finally, the therapeutic potential of targeting this axis was validated in preclinical models using the METTL3 catalytic inhibitor STM2457. Results RBM15 was significantly upregulated in BC, and its elevated expression served as an independent predictor of a poor prognosis. Functionally, RBM15 increased global m6A levels and promoted the malignant progression of BC cells both in vitro and in vivo; these oncogenic effects were reversed upon RBM15 knockdown. Mechanistically, RBM15 bound Zona Occludens 2 (ZO2) mRNA and recruited the methyltransferase 3–methyltransferase 14–Wilms’ tumor 1-associating protein (METTL3-METTL14-WTAP) methyltransferase complex to increase the level of the m6A modification on the ZO2 mRNA. This modification was recognized by YTH N(6)-methyladenosine RNA binding protein 2 (YTHDF2) to accelerate ZO2 mRNA decay. Although ZO2 expression was globally reduced, its preferential nuclear accumulation was increased, which promoted Snail expression and accelerated malignant progression. The METTL3 catalytic inhibitor STM2457 suppressed BC growth and lung metastasis by targeting the METTL3/RBM15/ZO2 axis, with no observable toxicity. Conclusions RBM15 acts as an oncogenic driver in BC by facilitating the m6A-dependent degradation of ZO2 mRNA via the recruitment of the METTL3 complex and recognition by YTHDF2. Targeting this METTL3/RBM15/ZO2 axis with STM2457 represents a promising therapeutic strategy for BC.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Zeming Lei,Yansheng Wang,Liangzi Yin,Ziyuan Wang,Lunhao Bai
Wear particle-induced periprosthetic osteolysis (PPO) represents the primary reason for implant failure following joint replacement, driven by macrophage polarization and excessive osteoclastogenesis. While cell migration inducing hyaluronidase 1 (CEMIP) has been implicated in inflammation and bone metabolism, its role in wear particle-induced PPO remains unexplored. Here, we discover that CEMIP expression was upregulated in Ti particle-induced calvarial osteolysis model. Functional studies revealed that CEMIP knockdown could attenuate Ti particle-triggered bone resorption via suppressing macrophage M1 polarization, promoting M2 polarization, and inhibiting osteoclast differentiation, as evidenced by reduced M1 markers, increased M2 markers, decreased inflammatory cytokines, and osteoclast-specific gene expression. In vitro, CEMIP silencing suppressed IFNγ-induced M1 polarization, enhanced IL-4-induced M2 polarization, and RANKL/M-CSF-triggered osteoclastogenesis in bone marrow-derived macrophages (BMDMs). Mechanistically, wear particle exposure decreases N6-methyladenosine (m6A) modification of CEMIP mRNA, impairing m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2)-mediated recognition and subsequent mRNA decay, thereby stabilizing CEMIP transcripts and enhancing their expression. Furthermore, CEMIP knockdown counteracted the enhancement of M1 macrophage polarization and osteoclast differentiation resulting from YTHDF2 silencing. Collectively, these findings highlight the critical role of the YTHDF2/CEMIP axis in regulating macrophage polarization and osteoclast differentiation, thus offering a promising therapeutic target for wear particle-induced PPO.
研究领域:
分子生物学
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骨科
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免疫学
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骨代谢
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表观遗传学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 24
·15761
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IF 6.208
Zixuan Zhou,Aijia Zhang,Xinyi Liu,Yang Yang,Ruqian Zhao,Yimin Jia
Excess fat deposition in broilers leads to great economic losses and is harmful to consumers’ health. Chronic stress in the life cycle of chickens could be an important trigger. However, the underlying mechanisms are still unclear. In this study, 30-day-old chickens were subcutaneously injected with 2 mg/kg corticosterone (CORT) twice a day for 14 days to simulate long-term stress. It was shown that chronic CORT exposure significantly increased plasma triglyceride concentrations and enlarged the adipocyte sizes in chickens. Meanwhile, chronic CORT administration significantly enlarged the adipocyte sizes, increased the protein contents of FASN and decreased HSL, ATGL, Beclin1 and PPARA protein levels. Moreover, global m6A methylations were significantly reduced and accompanied by downregulated METTL3 and YTHDF2 protein expression by CORT treatment. Interestingly, the significant differences of site-specific m6A demethylation were observed in exon7 ofPPARAmRNA. Additionally, a mutation of the m6A site in the PPARA gene fused GFP and revealed that demethylated RRACH in PPARA CDS impaired protein translation in vitro. In conclusion, these results indicated that m6A-mediated PPARA translational suppression contributes to CORT-induced visceral fat deposition in chickens, which may provide a new target for the treatment of Cushing’s syndrome.Keywords:adipose tissues;chicken;corticosterone;m6A;PPARA
研究领域:
动物科学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
JOURNAL OF CLINICAL INVESTIGATION
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2026
·
IF 14.3
Sun Liu,Qihuan Ren,Guiling Mo,Zengguang Li,Huili Huang,Yuhao Zhou,Ziteng Miao,Xin Cao,Bilian Wu,Zhuoyu Xiao,Shihui Yu,Guangjin Wu,Linjian Xia,Jinru Cui,Junyuan Mo,Yuan Li,Laixin Xia,Juan Shen,Shan Xiao
Despite substantial progress in understanding the molecular pathology of Parkinson’s disease (PD), the underlying drivers of PD in many cases remain unknown. Here we investigate the role of RNA modification in PD, following observations of selective m6A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic (DA) neurons from PD patients. We find preferential m6A deposition on transcripts of PD risk genes and a previously unreported heterozygous METTL3 p.K480R mutation in PD patients. Mettl3K480R/+ mice exhibit progressive METTL3 reduction and m6A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and non-motor deficits, mimicking PD progression. Dopamine transporter-specific METTL3 knockout mice recapitulate m6A hypomethylation, neurodegeneration and levodopa-responsive parkinsonism. Mechanistically, m6A deficiency disrupts mitochondrial biogenesis and function through regulating Tfam expression, while mitochondrial dysfunction reciprocally impairs m6A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhances m6A modification, disrupts the pathogenic loop and alleviates parkinsonism in mouse models. Our findings reveal m6A dysregulation as an important contributor to PD pathogenesis, provide a valuable preclinical mouse model for PD progression, and highlight RNA methylation-targeted therapies as a promising strategy for PD intervention.
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PubMed
高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 6
·e71640
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IF 4.3
Weijian Lun,Yongjia Liu,Canhua Luo,Huihuan Wu
Colorectal cancer (CRC) continues to be a significant global health concern. Emerging studies emphasize the tumor microenvironment (TME) as a key regulator of therapeutic response, particularly in its ability to suppress CD8 + T cell-mediated tumor clearance under chronic stimulation. However, the precise mechanisms responsible for this immunosuppressive effect remain unclear and require further exploration. Functional experiments evaluated CRC cell proliferation, migration, and invasion. CD8 + T cell infiltration and cytotoxicity were assessed using flow cytometry and LDH cytotoxicity assays. Mechanistic studies involved RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays to investigate the METTL5/YTHDF1-mediated regulation of COPS6 and the transcriptional activation of METTL5 by ZNF460. An in vivo CRC mouse model was established. The results indicated COPS6 was significantly upregulated in CRC and associated with poor prognosis. Knockdown of COPS6 suppressed CRC proliferation, migration, and invasion while enhancing CD8 + T cell infiltration and cytotoxicity. METTL5 was identified as an upstream regulator of COPS6, stabilizing its mRNA via m6A modification in a YTHDF1-dependent manner. ZNF460 bound to the METTL5 promoter, enhancing its transcription. In vivo, depletion of ZNF460 or METTL5 inhibited tumor growth and increased CD8 + T cell activity, whereas METTL5 overexpression reversed these effects. The ZNF460/METTL5/COPS6 axis promotes CRC progression and immune evasion by regulating COPS6 stability and CD8 + T cell infiltration. Targeting this pathway may offer new therapeutic strategies for CRC treatment. Graphical This study uncovers the ZNF460/METTL5/COPS6 regulatory axis in CRC, promoting tumor progression and immune escape. ZNF460 activates METTL5 transcription, enhancing COPS6 mRNA stability via m6A methylation in a YTHDF1-dependent manner. Elevated COPS6 impairs CD8⁺ T cell-mediated cytotoxicity. Disruption of this pathway reduces tumor growth and boosts immune infiltration. Targeting this mechanism may offer novel therapeutic strategies to restore antitumor immunity in CRC.
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高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-20
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IF 16.6
Han Xiao,Liu Lijuan,Huang Saihua,Xiao Wenfeng,Gao Yajing,Zhou Weitao,Zhang Caiyan,Zheng Hongmei,Yang Lan,Xie Xueru,Liang Qiuyan,Tu Zikun,Yu Hongmiao,Fu Jinrong,Wang Libo,Zhang Xiaobo,Qian Liling,Zhou Yufeng
N 6 -methyladenosine (m 6 A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m 6 A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m 6 A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m 6 A-sequencing shows that loss of METTL3 impairs the m 6 A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m 6 A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m 6 A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.
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高影响因子
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