Background &amp; aims <p>Currently, there are no approaches to specifically target macrophage-hepatic stellate cell (HSC) crosstalk in metabolic dysfunction-associated steatohepatitis (MASH). Although the β-catenin signaling pathway has been implicated in fibrotic diseases, the role and downstream mechanism of macrophage β-catenin in MASH-associated hepatic fibrosis remains incompletely understood.</p> Methods <p>Myeloid-specific β-catenin deficiency (β-catenin^M−KO) mice and the floxed β-catenin (β-catenin^FL/FL) mice were subjected to high-fat diet (HFD) feeding for 28 weeks. We delivered indian hedgehog (Ihh) plasmid in vivo using polyethylenimine nanoparticles, in vivo jetPEI-Man, that specifically deliver to macrophages.</p> Results <p>Although increased β-catenin activation was observed in the fibrotic liver macrophages of mice after HFD feeding, myeloid-specific β-catenin deficiency protected the liver against HFD-induced steatosis and fibrosis. Furthermore, we found that myeloid-specific β-catenin deficiency suppressed Ihh expression in liver macrophages. In vivo jetPEI-Man-mediated Ihh restoration prevented the improvement in MASH-induced fibrosis that we observed in β-catenin^M−KO mice. In vitro co-culture experiments indicated that β-catenin activation in macrophages induced Ihh expression and secretion, which then promoted the activation of HSCs.</p> Conclusion <p>Our findings identify the macrophage β-catenin-Ihh axis as a key regulator for controlling hepatic steatosis and fibrosis during MASH.</p>