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Eupalinolide B (EB) is a sesquiterpenoid natural product extracted from Eupatorium lindleyanum and has been reported as a potential drug for cancers and immune disorders. Here, we explored the ameliorative effects and underlying molecular mechanism of EB on periodontitis for the first time. We demonstrated that EB ameliorates periodontal inflammation and alveolar bone resorption with a ligated periodontitis mouse model. In addition, the impact of EB on macrophages inflammation was examined in the Raw264.7 cell line. We identified ubiquitin\u2010conjugating enzyme, UBE2D3, as the direct covalent binding protein targets of EB by using a chemoproteomic method based on activity\u2010based protein profiling, biolayer interferometry method, and cellular thermal shift assay. Furthermore, the direct binding site of EB to UBE2D3 was identified using high\u2010resolution mass spectrometry and confirmed by experiments. Taken together, EB ameliorates periodontitis by targeting UBE2D3 to suppress the ubiquitination degradation of I\u03baB\u03b1, leading to inactivation of nuclear transcription factor\u2010\u03baB signaling pathway. And this was confirmed by siRNA\u2010mediated gene knockdown in inflammatory macrophages. Our results suggested that EB may be a new kind of UBE2D3 inhibitor and may become a promising therapeutic agent for anti\u2010periodontitis.<\/jats:p>","DOI":"10.1002\/mco2.70034","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T12:50:01Z","timestamp":1736859001000},"source":"Crossref","is-referenced-by-count":12,"title":["Eupalinolide B inhibits periodontitis development by targeting ubiquitin conjugating enzyme UBE2D3"],"prefix":"10.1002","volume":"6","author":[{"given":"Wenhua","family":"Kuang","sequence":"first","affiliation":[{"name":"Department of Urology, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruishen","family":"Zhuge","sequence":"additional","affiliation":[{"name":"Department of 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Xiyuan Hospital, China Academy of Chinese Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letai","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology  Shenzhen China"},{"name":"Inner Mongolia Medical University  Hohhot China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao\u2010di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences  Beijing 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