Macrophage-Derived CXCR4 Accelerates the Progression of Acute-on-chronic Liver Failure by Promoting Liver Fibrosis and Inflammation via the TGF-β/SMAD and MAPK Pathways

This study aimed to elucidate the functional role and underlying mechanism of C-X-C chemokine receptor type 4 (CXCR4) in ACLF pathogenesis. Using an integrated multiomics approach encompassing transcriptomic reanalysis, clinical validation, and single-cell RNA sequencing (scRNA-seq) of livers from a murine ACLF model, we identified a Cxcr4+ macrophage subpopulation that served as a central communication hub.

In vivo gain- and loss-of-function studies demonstrated that AAV-mediated macrophage-specific CXCR4 overexpression exacerbated liver injury, inflammation, fibrosis, and mortality, whereas pharmacological inhibition with AMD3100 conferred significant protection. Mechanistically, transcriptomic and biochemical analyses revealed that CXCR4 coordinately hyperactivated the TGF-β/SMAD and MAPK signaling networks. In vitro coculture assays further confirmed that genetic knockdown of Cxcr4 in macrophages abolished their capacity to activate hepatic stellate cells.