{"title":"METTL3/m6A/miR-34a-5p轴的抑制通过Wnt/β-catenin途径抑制硝酸甘油诱导偏头痛的三叉神经血管激活。","authors":"Hui Zhang, Minming Shao, Feng Zhang, Caiyan He, Jiabi Li, Shengdong He","doi":"10.1186/s10194-025-02144-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation is a key driver of migraine pathogenesis, particularly by promoting neuronal sensitization. METTL3-mediated m<sup>6</sup>A methylation has emerged as a critical epigenetic regulator in neuroinflammatory responses. This study aims to investigate the role of METTL3 in migraine, focusing on its m<sup>6</sup>A-dependent regulatory mechanisms.</p><p><strong>Methods: </strong>A rat migraine model was induced via chronic intermittent nitroglycerin administration. Behavioral tests assessed migraine-like symptoms. Protein and RNA levels of METTL3, miR-34a-5p, and downstream targets were analyzed using Western blot, qPCR, ELISA, and immunofluorescence. The interaction among METTL3, miR-34a-5p, and Wnt1 was validated through Co-IP, RIP, and luciferase reporter assays.</p><p><strong>Results: </strong>METTL3 expression was significantly upregulated in the trigeminal ganglia of migraine rats. Knockdown of METTL3 reduced trigeminovascular system (TGVS) activation and alleviated migraine symptoms. Mechanistically, METTL3 enhanced miR-34a-5p expression via m<sup>6</sup>A modification, leading to suppression of the Wnt1/β-catenin pathway. Overexpression of miR-34a-5p further aggravated migraine-related responses by inhibiting Wnt1 signaling.</p><p><strong>Conclusion: </strong>METTL3 contributes to migraine pathogenesis through m<sup>6</sup>A-dependent upregulation of miR-34a-5p, which suppresses the Wnt1/β-catenin axis and promotes TGVS activation. Targeting this pathway may offer new therapeutic avenues for migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"197"},"PeriodicalIF":7.9000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490098/pdf/","citationCount":"0","resultStr":"{\"title\":\"Inhibition of the METTL3/m<sup>6</sup>A/miR-34a-5p axis suppresses trigeminovascular activation in nitroglycerin-induced migraine via the Wnt/β-catenin pathway.\",\"authors\":\"Hui Zhang, Minming Shao, Feng Zhang, Caiyan He, Jiabi Li, Shengdong He\",\"doi\":\"10.1186/s10194-025-02144-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Neuroinflammation is a key driver of migraine pathogenesis, particularly by promoting neuronal sensitization. METTL3-mediated m<sup>6</sup>A methylation has emerged as a critical epigenetic regulator in neuroinflammatory responses. This study aims to investigate the role of METTL3 in migraine, focusing on its m<sup>6</sup>A-dependent regulatory mechanisms.</p><p><strong>Methods: </strong>A rat migraine model was induced via chronic intermittent nitroglycerin administration. Behavioral tests assessed migraine-like symptoms. Protein and RNA levels of METTL3, miR-34a-5p, and downstream targets were analyzed using Western blot, qPCR, ELISA, and immunofluorescence. The interaction among METTL3, miR-34a-5p, and Wnt1 was validated through Co-IP, RIP, and luciferase reporter assays.</p><p><strong>Results: </strong>METTL3 expression was significantly upregulated in the trigeminal ganglia of migraine rats. Knockdown of METTL3 reduced trigeminovascular system (TGVS) activation and alleviated migraine symptoms. Mechanistically, METTL3 enhanced miR-34a-5p expression via m<sup>6</sup>A modification, leading to suppression of the Wnt1/β-catenin pathway. Overexpression of miR-34a-5p further aggravated migraine-related responses by inhibiting Wnt1 signaling.</p><p><strong>Conclusion: </strong>METTL3 contributes to migraine pathogenesis through m<sup>6</sup>A-dependent upregulation of miR-34a-5p, which suppresses the Wnt1/β-catenin axis and promotes TGVS activation. Targeting this pathway may offer new therapeutic avenues for migraine.</p>\",\"PeriodicalId\":16013,\"journal\":{\"name\":\"Journal of Headache and Pain\",\"volume\":\"26 1\",\"pages\":\"197\"},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2025-10-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490098/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Headache and Pain\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s10194-025-02144-7\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Headache and Pain","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s10194-025-02144-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Inhibition of the METTL3/m6A/miR-34a-5p axis suppresses trigeminovascular activation in nitroglycerin-induced migraine via the Wnt/β-catenin pathway.
Background: Neuroinflammation is a key driver of migraine pathogenesis, particularly by promoting neuronal sensitization. METTL3-mediated m6A methylation has emerged as a critical epigenetic regulator in neuroinflammatory responses. This study aims to investigate the role of METTL3 in migraine, focusing on its m6A-dependent regulatory mechanisms.
Methods: A rat migraine model was induced via chronic intermittent nitroglycerin administration. Behavioral tests assessed migraine-like symptoms. Protein and RNA levels of METTL3, miR-34a-5p, and downstream targets were analyzed using Western blot, qPCR, ELISA, and immunofluorescence. The interaction among METTL3, miR-34a-5p, and Wnt1 was validated through Co-IP, RIP, and luciferase reporter assays.
Results: METTL3 expression was significantly upregulated in the trigeminal ganglia of migraine rats. Knockdown of METTL3 reduced trigeminovascular system (TGVS) activation and alleviated migraine symptoms. Mechanistically, METTL3 enhanced miR-34a-5p expression via m6A modification, leading to suppression of the Wnt1/β-catenin pathway. Overexpression of miR-34a-5p further aggravated migraine-related responses by inhibiting Wnt1 signaling.
Conclusion: METTL3 contributes to migraine pathogenesis through m6A-dependent upregulation of miR-34a-5p, which suppresses the Wnt1/β-catenin axis and promotes TGVS activation. Targeting this pathway may offer new therapeutic avenues for migraine.
期刊介绍：
The Journal of Headache and Pain, a peer-reviewed open-access journal published under the BMC brand, a part of Springer Nature, is dedicated to researchers engaged in all facets of headache and related pain syndromes. It encompasses epidemiology, public health, basic science, translational medicine, clinical trials, and real-world data.
With a multidisciplinary approach, The Journal of Headache and Pain addresses headache medicine and related pain syndromes across all medical disciplines. It particularly encourages submissions in clinical, translational, and basic science fields, focusing on pain management, genetics, neurology, and internal medicine. The journal publishes research articles, reviews, letters to the Editor, as well as consensus articles and guidelines, aimed at promoting best practices in managing patients with headaches and related pain.
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