Abstract

Acute-on-chronic liver failure (ACLF) is a critical syndrome marked by severe illness, rapid progression, and poor prognosis. We aimed to investigate immunoregulatory mechanisms governing macrophage function during ACLF progression and identify potential molecular therapeutic targets. Differentially expressed genes (DEGs) in macrophages from patients with ACLF were identified using Gene Expression Omnibus datasets and single-cell RNA sequencing. Their expression patterns and prognostic value were assessed in 222 individuals, including healthy controls, patients with chronic hepatitis B, with hepatitis B cirrhosis, and those with hepatitis B virus-related ACLF. In vitro experiments using inhibitors, plasmid transfection, and transcriptome sequencing were performed to clarify how key DEGs regulate macrophage polarization. An ACLF mouse model induced by CCl₄/D-GalN/LPS was used for in vivo validation. Matrix metalloproteinase 8 (MMP8) emerged as a significantly upregulated gene in macrophages during ACLF. MMP8 levels were elevated in liver tissue, serum, peripheral blood mononuclear cells, and CD86⁺ macrophages and showed strong diagnostic efficacy for the early identification and progression prediction of ACLF. Functional studies revealed that MMP8 promotes macrophage M1 polarization, pro-inflammatory cytokine release, and pyroptosis through the peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway. In vivo, the MMP8/PPAR-γ axis amplified hepatic inflammation and liver necrosis. These findings highlight a central role for the MMP8/PPAR-γ pathway in ACLF pathogenesis and highlight its potential as a molecular target for future therapy. The alternative text for this image may have been generated using AI.