Macrophage β-catenin-Ihh axis induces hepatic stellate cell activation and fibrosis in metabolic dysfunction-associated steatohepatitis
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Updated: Mar 29, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
Rongsheng Zhang1, Yelin Yang2, Feng Xiao3
1Department of Hepatobiliary Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University; Wuxi People's Hospital; Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
Background & Aims:
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.
Methods:
Myeloid-specific β-catenin deficiency (β-cateninM-KO) mice and the floxed β-catenin (β-cateninFL/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.
Results:
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-cateninM-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.
Conclusion:
Our findings identify the macrophage β-catenin-Ihh axis as a key regulator for controlling hepatic steatosis and fibrosis during MASH.
Insights
Targeting macrophage beta-catenin and Indian hedgehog (Ihh) signaling offers a new approach to combat liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study reveals a key pathway regulating MASH progression.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) lacks targeted therapies for macrophage-hepatic stellate cell (HSC) crosstalk.
- The role of macrophage beta-catenin in MASH-associated hepatic fibrosis is not fully understood.
Purpose of the Study:
- To investigate the role of macrophage beta-catenin signaling in MASH-induced hepatic fibrosis.
- To identify downstream mechanisms linking macrophage activation to HSCs in MASH.
Main Methods:
- Mice with myeloid-specific beta-catenin deficiency (beta-catenin(M-KO)) were fed a high-fat diet (HFD).
- Indian hedgehog (Ihh) was delivered in vivo to macrophages using jetPEI-Man nanoparticles.
- In vitro co-culture experiments assessed macrophage-HSC interactions.
Main Results:
- Myeloid-specific beta-catenin deficiency protected against HFD-induced steatosis and fibrosis in mice.
- Beta-catenin deficiency in macrophages suppressed Ihh expression, a key mediator.
- Restoring Ihh negated the protective effects of beta-catenin deficiency, highlighting its role.
Conclusions:
- The macrophage beta-catenin-Ihh axis is a critical regulator of hepatic steatosis and fibrosis in MASH.
- This pathway represents a potential therapeutic target for MASH treatment.
