Macrophage DGKζ-mediated phosphatidic acid remodeling aggravates acute liver failure
文献类型：期刊论文
| 作者 | Miao, Yumeng4,5; Lin, Tzuchun5; Wang, Bianlin3; Xu, Junyu4; Li, Chongxian2; Li, Zuopeng3; Zhang, Xinwen4; Zhou, Chendong4; Aji, Tuerganaili1; Tan, Minjia4 |
| 刊名 | ACTA PHARMACEUTICA SINICA B
 |
| 出版日期 | 2025-08-01 |
| 卷号 | 15期号:8页码:4078-4095 |
| 关键词 | Xanthohumol derivative Macrophages Acute liver failure Diacylglycerol kinase zeta Phosphatidic acid Signal transducer and activator of transcription 3 Interleukin-1/3 Inflammation |
| ISSN号 | 2211-3835 |
| DOI | 10.1016/j.apsb.2025.06.019 |
| 通讯作者 | Tan, Minjia(mjtan@simm.ac.cn) ; Aisa, Haji Akber(haji@ms.xjb.ac.cn) ; Li, Jingya(jyli@simm.ac.cn) |
| 英文摘要 | Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + D-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1/3 (IL-1/3) transcription. Through biotin labeling-mediated pull-down and LC -MS/MS analysis, diacylglycerol kinase zeta (DGK zeta), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGK is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP3)-Ca2+ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1 /3 production and liver failure. DGK knockdown/ablation or inhibition significantly impairs the DGK zeta-STAT3-IL-1/3 pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGK inhibitor and acts against inflammation in a DGK zeta-reliant manner. Taken together, CAM12203 inhibits IL-1/3 transcription in macrophages by binding to DGK and blocking the DGK zeta-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGK zeta as a novel therapeutic target. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| WOS关键词 | LIPID-METABOLISM ; PHOSPHOLIPASE-C ; KINASE ; ACTIVATION ; CELLS ; LIPOPOLYSACCHARIDE ; XANTHOHUMOL ; INHIBITOR ; ALPHA ; INTERLEUKIN-1-BETA |
| 资助项目 | National Science and Technology Major Project (China)[2024ZD0523103] ; National Natural Science Foundation of China[92457302] ; National Natural Science Foundation of China[82425058] ; National Natural Science Foundation of China[82304500] ; National Natural Science Foundation of China[22494693] ; National Key R&D Program of China[2020YFE0205600] ; Yangfan Project of Shanghai Science and Technology Commission (China)[23YF1456500] ; Shanghai Super Postdoctoral Incentive Plan (China)[2022692] ; Youth Innovation Promotion Association of Chinese Academy of Sciences (China)[E32R4001] ; China Postdoctoral Science Foundation[2023M733630] ; Tian-Shan Talent Program (China)[2022TSYCLJ0064] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001562025100009 |
| 出版者 | INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321393]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Tan, Minjia; Aisa, Haji Akber; Li, Jingya |
| 作者单位 | 1.Xinjiang Med Univ, Affiliated Hosp 1, Urumqi 830054, Peoples R China 2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 3.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Urumqi 830011, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 5.Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Dept Cardiol, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Miao, Yumeng,Lin, Tzuchun,Wang, Bianlin,et al. Macrophage DGKζ-mediated phosphatidic acid remodeling aggravates acute liver failure[J]. ACTA PHARMACEUTICA SINICA B,2025,15(8):4078-4095. |
| APA | Miao, Yumeng.,Lin, Tzuchun.,Wang, Bianlin.,Xu, Junyu.,Li, Chongxian.,...&Li, Jingya.(2025).Macrophage DGKζ-mediated phosphatidic acid remodeling aggravates acute liver failure.ACTA PHARMACEUTICA SINICA B,15(8),4078-4095. |
| MLA | Miao, Yumeng,et al."Macrophage DGKζ-mediated phosphatidic acid remodeling aggravates acute liver failure".ACTA PHARMACEUTICA SINICA B 15.8(2025):4078-4095. |
入库方式： OAI收割
来源：上海药物研究所
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