Macrophage DGK-mediated phosphatidic acid remodeling aggravates acute liver failure.

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 (IL-1) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase (DGK), 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 (IP)-Ca signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1 production and liver failure. DGK knockdown/ablation or inhibition significantly impairs the DGK-STAT3-IL-1 pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGK inhibitor and acts against inflammation in a DGK-reliant manner. Taken together, CAM12203 inhibits IL-1 transcription in macrophages by binding to DGK and blocking the DGK-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 as a novel therapeutic target.