Macrophage DGKζ-mediated phosphatidic acid remodeling aggravates acute liver failure.
10.1016/j.apsb.2025.06.019
- Author:
Yumeng MIAO
1
;
Tzuchun LIN
1
;
Bianlin WANG
2
;
Junyu XU
3
;
Chongxian LI
4
;
Zuopeng LI
2
;
Xinwen ZHANG
3
;
Chendong ZHOU
3
;
Tuerganaili AJI
5
;
Minjia TAN
3
;
Haji Akber AISA
2
;
Jingya LI
3
Author Information
1. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
2. Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China.
3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
5. The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China.
- Publication Type:Journal Article
- Keywords:
Acute liver failure;
Diacylglycerol kinase ζ;
Inflammation;
Interleukin-1β;
Macrophages;
Phosphatidic acid;
Signal transducer and activator of transcription 3;
Xanthohumol derivative
- From:
Acta Pharmaceutica Sinica B
2025;15(8):4078-4095
- CountryChina
- Language:English
-
Abstract:
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-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ 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-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-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 DGKζ as a novel therapeutic target.
