中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Unveiling p65 as the target of diphyllin in ameliorating metabolic dysfunction-associated steatotic liver disease via targeted protein degradation technology

文献类型：期刊论文

作者Zhu, Xuejing5,6,7; Zhang, Lei4; Cui, Wenqian4; Wang, Liangjie4; Xu, Fengjing4; Liu, Mengyuan4; Chen, Shuangcheng3; Jiang, Haowen2; He, Zhiying5,6,7; Peng, Chang1,2
刊名FRONTIERS IN PHARMACOLOGY
出版日期2025-04-28
卷号16页码:12
关键词metabolic dysfunction-associated steatotic liver disease diphyllin p65 targeted protein degradation technology NRF2
DOI10.3389/fphar.2025.1567639
通讯作者He, Zhiying(zhiyinghe2002@163.com) ; Peng, Chang(paulpengchang@163.com) ; Li, Jinlong(jinlongli@ntu.edu.cn)
英文摘要Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic steatosis, inflammation and fibrosis, is becoming a global epidemic. However, the currently available effective clinical strategies remain limited.Methods We conducted the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced MASH mouse model to explore the effects of diphyllin on MASLD mice. We employ the targeted protein degradation technology applied for the discovery of compound/protein-protein interaction to identify p65 as a potential target protein.Results We determine that diphyllin, a natural arylnaphthalene lignan lactone, is effective on MASLD, evidenced by the inhibition of hepatic lipid accumulation through promoting fatty acid oxidation in vivo and in vitro. To uncover the underlying mechanisms, we design and synthesis diphyllin-based protac and identify p65 as a potential target protein. Under p65 deficiency, the effects of diphyllin on lipid metabolism are blocked in vitro. As p65 as an antagonist of NRF2, diphyllin interacts with p65, leading to the induction of the NRF2 transcriptional activity and the enhancement of antioxidant capacity. When NFR2 is inhibited, the lowering effects of diphyllin on lipid is abolished.Discussion Our study presents diphyllin as a potential lead compound for MASLD therapy but also offers a novel approach for elucidating the mechanisms of action of natural products.
WOS关键词NF-KAPPA-B ; IMPROVES INSULIN SENSITIVITY ; V-ATPASE INHIBITOR ; NLRP3 INFLAMMASOME ; NRF2 ; FIBROSIS ; ACTIVATION ; MECHANISMS ; NAFLD ; NASH
资助项目National Key RandD Program of China[2022YFA1303800] ; Natural Science Foundation of China[82273983] ; Natural Science Foundation of Nantong[JC2023089] ; Nantong Health Commission Project[QN2023048] ; Science and Technology Commission of Shanghai Municipality[23ZR1474700] ; Shanghai Institute of Materia Medica ; Chinese Academy of Science ; China Postdoctoral Science Foundation[2024M760704]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001485183900001
出版者FRONTIERS MEDIA SA
源URL[http://119.78.100.183/handle/2S10ELR8/317902]  
专题中国科学院上海药物研究所
通讯作者He, Zhiying; Peng, Chang; Li, Jinlong
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai, Peoples R China
3.Nantong Hlth Coll Jiangsu Prov, Dept Pharm, Nantong, Jiangsu, Peoples R China
4.Nantong Univ, Sch Pharm, Nantong, Jiangsu, Peoples R China
5.Shanghai East Hosp, Shanghai Engn Res Ctr Stem Cells Translat Med, Shanghai, Peoples R China
6.Tongji Univ, Shanghai East Hosp, Med Innovat Ctr, Sch Life Sci & Technol, Shanghai, Peoples R China
7.Tongji Univ, Inst Regenerat Med, State Key Lab Cardiol, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Xuejing,Zhang, Lei,Cui, Wenqian,et al. Unveiling p65 as the target of diphyllin in ameliorating metabolic dysfunction-associated steatotic liver disease via targeted protein degradation technology[J]. FRONTIERS IN PHARMACOLOGY,2025,16:12.
APA Zhu, Xuejing.,Zhang, Lei.,Cui, Wenqian.,Wang, Liangjie.,Xu, Fengjing.,...&Li, Jinlong.(2025).Unveiling p65 as the target of diphyllin in ameliorating metabolic dysfunction-associated steatotic liver disease via targeted protein degradation technology.FRONTIERS IN PHARMACOLOGY,16,12.
MLA Zhu, Xuejing,et al."Unveiling p65 as the target of diphyllin in ameliorating metabolic dysfunction-associated steatotic liver disease via targeted protein degradation technology".FRONTIERS IN PHARMACOLOGY 16(2025):12.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。