Myeloid ATF3 Protects Against Liver Fibrosis by Modulating the Extracellular Microenvironment and Macrophage Inflammatory Signaling.

Activating transcription factor 3 (ATF3) is a stress-inducible transcription factor that regulates inflammatory responses; however, its cell-type-specific role in liver fibrosis remains incompletely defined. We investigated the function of myeloid cell-specific ATF3 in carbon tetrachloride (CCl4)-induced liver fibrosis. ATF3 induction was confirmed in bone marrow-derived macrophages following lipopolysaccharide stimulation in vitro. Myeloid-specific Atf3 knockout mice (Atf3fl/fl LysM-Cre+) and littermate controls were subjected to CCl4 treatment to determine the impact of ATF3 loss in vivo. Myeloid ATF3 deficiency significantly exacerbated CCl4-induced liver injury, reflected by elevated serum ALT and AST levels, increased collagen deposition, and higher fibrosis scores. ATF3 loss enhanced hepatic stellate cell activation, as evidenced by increased α-SMA protein and elevated Acta2 and Col1a1 expression. Although total macrophage abundance was unchanged, ATF3 deficiency shifted macrophage composition toward increased Ly6C+ infiltrating monocyte-derived macrophages and reduced Kupffer cell markers. Mechanistically, Atf3-deficient livers displayed increased inflammatory chemokine expression (Ccl3, Ccl4, Ccl5, Ccl8), reduced matrix metalloproteinases (Mmp2, Mmp8, and Mmp9), increased tissue inhibitor of metalloproteinases 1 (Timp1), and enhanced activation of transforming growth factor-beta1 (TGF-β1)/SMAD signaling. These findings identify myeloid ATF3 as a protective regulator that restrains inflammatory amplification and extracellular matrix accumulation during liver fibrosis. Modulation of ATF3-dependent pathways may represent a potential therapeutic strategy for fibrotic liver disease.