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This study investigates how senkyunolide A (SenA) limits cholangiocyte overproliferation by uncovering mechanisms behind its protective effects. Using RNA sequencing, CHIP, truncation and mutagenesis, plus SenA derivative development, effects were tested in bile duct ligation mice and primary cholangiocytes. SenA epigenetically suppresses c-MYC, disrupts H19/Let-7a/Lin28a downstream signaling, and mechanistically separates the TRAF6-HDAC3 complex to enhance transcriptional 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does SenA affect the TRAF6-HDAC3 pathway mechanistically?",{"text":121,"@type":113},"SenA interferes with the TRAF6-HDAC3 interaction, facilitating HDAC3 binding to the MYC promoter region to enhance histone deacetylation and transcriptional suppression.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},434400,1791059982,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},1099523885074,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","Journal of Advanced Research 79 (2026) 935–951  \nContents lists available at ScienceDirect  \nJournal of Advanced Research  \njournal [homepage: www. elsevier. com/locate/jare](homepage: www. elsevier. com/locate/jare)  \nSenkyunolide A interrupts TRAF6-HDAC3 interaction to epigenetically suppress c-MYC and attenuate cholestatic liver injury  \nYajing Li a, 1, Runping Liu b, 1,⁎, Jianan Li a, Feng Gaob, Zhi Ma a, Kaihong Xie a, Fanghong Li Qi Zheng b, Yajie Caib, Jiaorong Qu a, Xiaoyong Xue a, Kexin Jia a, Xiaojiaoyang Li a,⁎  \na School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China  \nb School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China  \nb, Bing Xu b,  \nh i g h l i g h t s  \n• SenA alleviated cholangiocyte proliferation by inhibiting c-MYCrelated H19-Let-7a axis activation incholestasis.  \n• SenA occupied binding site on TRAF6 that interacted with HDAC3 and rescuing HDAC3 from c-MYC promoters.  \n• SenA promoted H3K9 deacetylation and subsequently inhibited c-MYC transcription.  \n• This study identified SenA as a potential candidate drug for cholangiopathy-associated liver fibrosis.  \n• This study unveiled a novel approach for discovering epigenetic regulators by targeting protein-protein interactions.  \ng r a p h i c a l a b s t r a c t  \na r t i c l e i n f o  \nArticle history:  \nReceived 23 July 2024 Revised 12 March 2025 Accepted 1 April 2025 Available online 3 April 2025  \nKeywords:  \nCholestatic liver diseases c-Myc  \nH19  \nTRAF6  \na b s t r a c t  \nIntroduction Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. Objective: This study aims to unveil the underlying mechanisms of the protective effects of senkyunolide A (SenA) on cholangiocyte overproliferation in cholestatic liver diseases. Methods: Through comprehensive characterization using RNA sequencing, CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we explored the effects and mechanisms of SenA in vivo in bile duct ligation mice and in vitro in primary cholangiocytes. Results: We demonstrated that SenA effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19, Let-7a and Lin28a. Mechanically, we identified a potential interaction between the  \nAbbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BDL, bile duct ligation; CETSA, Cellular thermal shift assay; cMyc, cellular myelocytomatosis oncogene; DARTS, Drug affinity responsive target stability; DEGs, different expression genes; DR, ductular reaction; HAT, histone acetyltransferase; HDAC3, histone deacetylase 3; H3K9ac, acetylation of histone 3 lysine 9; ICR, imprinting control region; Pcna, proliferating cell nuclear antigen; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SenA, senkyunolide A; SPR, Surface plasmon resonance; TCA, taurocholate acid; TBA, total bile acid; TRAF6, TNF receptor associated factor 6.  \n⁎ Corresponding authors.  \nE-mail addresses: [liurunping@bucm.edu.cn](liurunping@bucm.edu.cn) (R. Liu), [xiaojiaoyang.li@bucm.edu.cn](xiaojiaoyang.li@bucm.edu.cn) (X. Li).  \n1 These authors contributed equally: Yajing Li and Runping Liu.  \n[https://doi.org/10.1016/j.jare.2025.04.002](https://doi.org/10.1016/j.jare.2025.04.002)  \n2090-1232/© 2025 The Authors. Published by Elsevier B.V. on behalf of Cairo University.  \nThis is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)).  \nY. Li, R. Liu, J. Li et al. Journal of Advanced Research 79 (2026) 935–951  \nHDAC3  \nSenky","cbCaip8JR9xsfkcM","https://ap.wps.com/l/cbCaip8JR9xsfkcM","pdf",8700016,17,"English","# Introduction\n# Objective\n# Methods\n# Results\n# Conclusion","[{\"question\":\"What problem does the study address in cholestatic liver diseases?\",\"answer\":\"Cholestatic liver diseases gradually destroy bile ducts, impair bile flow, and lead to bile acid retention, promoting inflammation, ductular reaction, fibrosis, and eventual liver failure.\"},{\"question\":\"What is the main protective mechanism of senkyunolide A (SenA) proposed here?\",\"answer\":\"SenA mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting downstream H19, Let-7a, and Lin28a signaling.\"},{\"question\":\"How does SenA affect the TRAF6-HDAC3 pathway mechanistically?\",\"answer\":\"SenA interferes with the TRAF6-HDAC3 interaction, facilitating HDAC3 binding to the MYC promoter region to enhance histone deacetylation and transcriptional suppression.\"}]","Senkyunolide A interrupts TRAF6-HDAC3 interaction to epigenetically suppress c-MYC and attenuate cholestatic liver injury | PDF",1790669083,43]