Notch1 Inhibition Exacerbates APAP-Induced Liver Injury via β-Catenin and Macrophage Polarization
- Front Biosci (Landmark Ed). 2025 Sep 25;30(9):43853. doi: 10.31083/FBL43853.
- 1. Department of Respiratory and Critical Care Medicine, Affiliated People's Hospital of Jiangsu University, 212001 Zhenjiang, Jiangsu, China.
- 2. Zhenjiang School of Clinical Medicine With Nanjing Medical University, 212001 Zhenjiang, Jiangsu, China.
- 3. Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China.
Background: Notch1 signaling regulates innate immune-mediated inflammation in acute liver injury (ALI). However, the precise mechanism by which Notch1 governs macrophage polarization during ALI remains poorly understood.
Methods: Wild-type (WT) mice received DAPT (10 mg/kg) prior to acetaminophen (APAP)-induced ALI. In parallel, bone marrow-derived macrophages (BMMs) were pretreated with either the β-catenin Inhibitor XAV939 or the activator SKL2001, exposed to DAPT, and then challenged with lipopolysaccharide (LPS). Liver injury and inflammation were evaluated by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, immunofluorescence, quantitative Real-Time PCR (RT-PCR), and western blotting.
Results: Unexpectedly, DAPT treatment exacerbated APAP-induced liver injury (AILI), resulting in more severe hepatocellular damage and inflammation than in controls. DAPT-treated macrophages exhibited enhanced pro-inflammatory cytokines expression and a shift toward an M1-like phenotype. Mechanistically, the β-catenin/glycogen synthase kinase 3 beta (GSK3β) signaling pathway emerged as a pivotal regulator of macrophage polarization.
Conclusions: Notch1 inhibition unexpectedly worsens AILI by amplifying macrophage-driven pro-inflammatory responses via β-catenin signaling. These findings highlight the Notch1-β-catenin axis as a key regulator of hepatic macrophage function and a potential therapeutic target for sterile liver inflammation.