Macrophage DGKζ-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<i>β</i> (IL-1<i>β</i>) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase <i>ζ</i> (DGK<i>ζ</i>), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGK<i>ζ</i> 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<i>β</i> production and liver failure. DGK<i>ζ</i> knockdown/ablation or inhibition significantly impairs the DGK<i>ζ</i>-STAT3-IL-1<i>β</i> pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGK<i>ζ</i> inhibitor and acts against inflammation in a DGK<i>ζ</i>-reliant manner. Taken together, CAM12203 inhibits IL-1<i>β</i> transcription in macrophages by binding to DGK<i>ζ</i> and blocking the DGK<i>ζ</i>-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<i>ζ</i> as a novel therapeutic target.