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 (CCl 4 )‐induced liver fibrosis. ATF3 induction was confirmed in bone marrow‐derived macrophages following lipopolysaccharide stimulation in vitro. Myeloid‐specific Atf3 knockout mice ( Atf3 fl/fl LysM ‐Cre+) and littermate controls were subjected to CCl 4 treatment to determine the impact of ATF3 loss in vivo. Myeloid ATF3 deficiency significantly exacerbated CCl 4 ‐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.