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
  4. 国家级研究中心
  5. 原创新药研究全国重点实验室
The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα

文献类型：期刊论文

作者Xie, Zhifu6,7; Cheng, Long6,7; Hu, Yue8; Song, Gaolei6; Wang, Fan1; Zhang, Mei6; Zhang, Yangming2,6; Zhang, Xinwen6; Zhou, Chendong6; Zhu, Xiaoxue8
刊名CELL METABOLISM
出版日期2025-11-04
卷号37期号:11页码:2149-2166
ISSN号1550-4131
DOI10.1016/j.cmet.2025.09.011
英文摘要The rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. This study discovered that the enedioic acid ATP-citrate lyase (ACLY) inhibitor 326E, an investigational new drug in a phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ACLY to reduce de novo lipogenesis (DNL) but also as a peroxisome proliferator-activated receptor alpha (PPAR alpha) allosteric regulator to increase hepatic fatty acid oxidation (FAO). The efficacy of activated PPAR alpha for MASH is enhanced by suppressed recycling of FAO products to lipid accumulation as a result of ACLY inhibition. Subsequent studies in cynomolgus monkeys (Macaca fascicularis) confirmed the effectiveness of 326E for MASH in primate species. In a randomized phase 1b/2a clinical trial in patients with MASH (NCT06491576), 326E was well tolerated and reduced circulating gamma-glutamyl transferase (gamma-GGT). Taken together, our results indicate the therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPAR alpha.
WOS关键词ATP-CITRATE LYASE ; FATTY LIVER-DISEASE ; NASH ; PATHOGENESIS ; FENOFIBRATE ; ACTIVATION ; STEATOSIS ; LIGANDS ; GENE ; MICE
资助项目National Natural Science Founda-tion of China[92457302] ; National Natural Science Founda-tion of China[82425058] ; National Natural Science Founda-tion of China[92057116] ; National Natural Science Founda-tion of China[82170872] ; Noncommunicable Chronic Diseases-National Science and Technology Major Project[2023ZD0507800] ; Noncommunicable Chronic Diseases-National Science and Technology Major Project[2024ZD0523100] ; Nat-ural Science Foundation of Shanghai's Science and Technology Innovation Action Plan[22XD1400600] ; Nat-ural Science Foundation of Shanghai's Science and Technology Innovation Action Plan[21ZR1475300] ; Capital Construction Funds from the provincial budget in 2020 of Jilin[2020C038-1] ; Capital Construction Funds from the provincial budget in 2020 of Jilin[SOS-120PRO]
WOS研究方向Cell Biology ; Endocrinology & Metabolism
语种英语
WOS记录号WOS:001616123900007
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/321998]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Ding, Yanhua; Nan, Fajun; Li, Jingya
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Burgeon Therapeut Co Ltd, Shanghai 201203, Peoples R China
3.Kunming Biomed Int, Kunming 650500, Peoples R China
4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.First Hosp Jilin Univ, PhaseClin Res Ctr 1, Changchun 130021, Peoples R China
推荐引用方式
GB/T 7714		 Xie, Zhifu,Cheng, Long,Hu, Yue,et al. The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα[J]. CELL METABOLISM,2025,37(11):2149-2166.
APA Xie, Zhifu.,Cheng, Long.,Hu, Yue.,Song, Gaolei.,Wang, Fan.,...&Li, Jingya.(2025).The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα.CELL METABOLISM,37(11),2149-2166.
MLA Xie, Zhifu,et al."The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα".CELL METABOLISM 37.11(2025):2149-2166.

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。