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Aberrant activation of these pathways drives migraine onset and chronicity. The ubiquitin-proteasome system (UPS) is involved in neurological and inflammatory disorders. ubiquitination in the UPS is achieved through a cascade of enzymes, including Ub-activating enzyme (E1), Ub-coupling enzyme (E2), and Ub-ligase (E3). The aim of this review is to systematically explore the role of ubiquitination in the regulation of MAPK and NF-\u03baB signaling pathways, with a focus on the mechanisms of ubiquitinating enzymes in neuroinflammation and pain signal amplification, and to explore their potential as diagnostics, biomarkers, predictors of response to therapy, and monitoring of chronicity in migraine disease.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1534389","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T06:44:10Z","timestamp":1738305850000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Exploring the role of ubiquitination modifications in migraine 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