Work

Macrophage DGKζ-mediated phosphatidic acid remodeling aggravates acute liver failure

Year: 2025

Type: article

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

Source: Acta Pharmaceutica Sinica B

DOI: 10.1016/j.apsb.2025.06.019